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Title: software architecture metrics: a literature review.

Abstract: In Software Engineering, early detection of architectural issues is key. It helps mitigate the risk of poor performance, and lowers the cost of repairing these issues. Metrics give a quick overview of the project which helps designers with the detection of flaws or degradation in their architecture. Even though studies unveiled architectural metrics more than 25 years ago, they have not yet been embraced by the industry nor the open source community. In this study, we aim at conducting a review of existing metrics focused on the software architecture for evaluating quality, early in the design flow and throughout the project's lifetime. We also give guidelines of their usage and study their relevance in different contexts.

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Systematic literature review on software quality for AI-based software

• Published: 17 March 2022
• Volume 27 , article number  66 , ( 2022 )

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• Bahar Gezici   ORCID: orcid.org/0000-0001-6704-3134 1 &
• Ayça Kolukısa Tarhan 1  

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There is a widespread demand for Artificial Intelligence (AI) software, specifically Machine Learning (ML). It is getting increasingly popular and being adopted in various applications we use daily. AI-based software quality is different from traditional software quality because it generally addresses distinct and more complex kinds of problems. With the fast advance of AI technologies and related techniques, how to build high-quality AI-based software becomes a very prominent subject. This paper aims at investigating the state of the art on software quality (SQ) for AI-based systems and identifying quality attributes, applied models, challenges, and practices that are reported in the literature. We carried out a systematic literature review (SLR) from 1988 to 2020 to (i) analyze and understand related primary studies and (ii) synthesize limitations and open challenges to drive future research. Our study provides a road map for researchers to understand quality challenges, attributes, and practices in the context of software quality for AI-based software better. From the empirical evidence that we have gathered by this SLR, we suggest future work on this topic be structured under three categories which are Definition/Specification, Design/Evaluation, and Process/Socio-technical.

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Bahar Gezici & Ayça Kolukısa Tarhan

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Gezici, B., Tarhan, A.K. Systematic literature review on software quality for AI-based software. Empir Software Eng 27 , 66 (2022). https://doi.org/10.1007/s10664-021-10105-2

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Systematic literature review of real-world evidence for treatments in HR+/HER2- second-line LABC/mBC after first-line treatment with CDK4/6i

• Veronique Lambert   ORCID: orcid.org/0000-0002-6984-0038 1 ,
• Sarah Kane   ORCID: orcid.org/0009-0006-9341-4836 2   na1 ,
• Belal Howidi   ORCID: orcid.org/0000-0002-1166-7631 2   na1 ,
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• David Chandiwana   ORCID: orcid.org/0009-0002-3499-2565 3 ,
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BMC Cancer volume  24 , Article number:  631 ( 2024 ) Cite this article

Metrics details

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are currently recommended by the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Medical Oncology (ESMO) guidelines as the first-line (1 L) treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced/metastatic breast cancer (HR+/HER2- LABC/mBC). Although there are many treatment options, there is no clear standard of care for patients following 1 L CDK4/6i. Understanding the real-world effectiveness of subsequent therapies may help to identify an unmet need in this patient population. This systematic literature review qualitatively synthesized effectiveness and safety outcomes for treatments received in the real-world setting after 1 L CDK4/6i therapy in patients with HR+/ HER2- LABC/mBC.

MEDLINE®, Embase, and Cochrane were searched using the Ovid® platform for real-world evidence studies published between 2015 and 2022. Grey literature was searched to identify relevant conference abstracts published from 2019 to 2022. The review was conducted in accordance with PRISMA guidelines (PROSPERO registration: CRD42023383914). Data were qualitatively synthesized and weighted average median real-world progression-free survival (rwPFS) was calculated for NCCN/ESMO-recommended post-1 L CDK4/6i treatment regimens.

Twenty records (9 full-text articles and 11 conference abstracts) encompassing 18 unique studies met the eligibility criteria and reported outcomes for second-line (2 L) treatments after 1 L CDK4/6i; no studies reported disaggregated outcomes in the third-line setting or beyond. Sixteen studies included NCCN/ESMO guideline-recommended treatments with the majority evaluating endocrine-based therapy; five studies on single-agent ET, six studies on mammalian target of rapamycin inhibitors (mTORi) ± ET, and three studies with a mix of ET and/or mTORi. Chemotherapy outcomes were reported in 11 studies. The most assessed outcome was median rwPFS; the weighted average median rwPFS was calculated as 3.9 months (3.3-6.0 months) for single-agent ET, 3.6 months (2.5–4.9 months) for mTORi ± ET, 3.7 months for a mix of ET and/or mTORi (3.0–4.0 months), and 6.1 months (3.7–9.7 months) for chemotherapy. Very few studies reported other effectiveness outcomes and only two studies reported safety outcomes. Most studies had heterogeneity in patient- and disease-related characteristics.

Conclusions

The real-world effectiveness of current 2 L treatments post-1 L CDK4/6i are suboptimal, highlighting an unmet need for this patient population.

Peer Review reports

Introduction

Breast cancer (BC) is the most diagnosed form of cancer in women with an estimated 2.3 million new cases diagnosed worldwide each year [ 1 ]. BC is the second leading cause of cancer death, accounting for 685,000 deaths worldwide per year [ 2 ]. By 2040, the global burden associated with BC is expected to surpass three million new cases and one million deaths annually (due to population growth and aging) [ 3 ]. Numerous factors contribute to global disparities in BC-related mortality rates, including delayed diagnosis, resulting in a high number of BC cases that have progressed to locally advanced BC (LABC) or metastatic BC (mBC) [ 4 , 5 , 6 ]. In the United States (US), the five-year survival rate for patients who progress to mBC is three times lower (31%) than the overall five-year survival rate for all stages (91%) [ 6 , 7 ].

Hormone receptor (HR) positive (i.e., estrogen receptor and/or progesterone receptor positive) coupled with negative human epidermal growth factor 2 (HER2) expression is the most common subtype of BC, accounting for ∼ 60–70% of all BC cases [ 8 , 9 ]. Historically, endocrine therapy (ET) through estrogen receptor modulation and/or estrogen deprivation has been the standard of care for first-line (1 L) treatment of HR-positive/HER2-negative (HR+/HER2-) mBC [ 10 ]. However, with the approval of the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib in combination with the aromatase inhibitor (AI) letrozole in 2015 by the US Food and Drug Administration (FDA), 1 L treatment practice patterns have evolved such that CDK4/6i (either in combination with AIs or with fulvestrant) are currently considered the standard of care [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Other CDK4/6i (ribociclib and abemaciclib) in combination with ET are approved for the treatment of HR+/HER2- LABC/mBC; 1 L use of ribociclib in combination with an AI was granted FDA approval in March 2017 for postmenopausal women (with expanded approval in July 2018 for pre/perimenopausal women and for use in 1 L with fulvestrant for patients with disease progression on ET as well as for postmenopausal women), and abemaciclib in combination with fulvestrant was granted FDA approval in September 2017 for patients with disease progression following ET and as monotherapy in cases where disease progression occurs following ET and prior chemotherapy in mBC (with expanded approval in February 2018 for use in 1 L in combination with an AI for postmenopausal women) [ 18 , 19 , 20 , 21 ].

Clinical trials investigating the addition of CDK4/6i to ET have demonstrated significant improvement in progression-free survival (PFS) and significant (ribociclib) or numerical (palbociclib and abemaciclib) improvement in overall survival (OS) compared to ET alone in patients with HR+/HER2- advanced or mBC, making this combination treatment the recommended option in the 1 L setting [ 22 , 23 , 24 , 25 , 26 , 27 ]. However, disease progression occurs in a significant portion of patients after 1 L CDK4/6i treatment [ 28 ] and the optimal treatment sequence after progression on CDK4/6i remains unclear [ 29 ]. At the time of this review (literature search conducted December 14, 2022), guidelines by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) recommend various options for the treatment of HR+/HER2- advanced BC in the second-line (2 L) setting, including fulvestrant monotherapy, mammalian target of rapamycin inhibitors (mTORi; e.g., everolimus) ± ET, alpelisib + fulvestrant (if phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation positive [PIK3CA-m+]), poly-ADP ribose polymerase inhibitors (PARPi) including olaparib or talazoparib (if breast cancer gene/partner and localizer of BRCA2 positive [BRCA/PALB2m+]), and chemotherapy (in cases when a visceral crisis is present) [ 15 , 16 ]. CDK4/6i can also be used in 2 L [ 16 , 30 ]; however, limited data are available to support CDK4/6i rechallenge after its use in the 1 L setting [ 15 ]. Depending on treatments used in the 1 L and 2 L settings, treatment in the third-line setting is individualized based on the patient’s response to prior treatments, tumor load, duration of response, and patient preference [ 9 , 15 ]. Understanding subsequent treatments after 1 L CDK4/6i, and their associated effectiveness, is an important focus in BC research.

Treatment options for HR+/HER2- LABC/mBC continue to evolve, with ongoing research in both clinical trials and in the real-world setting. Real-world evidence (RWE) offers important insights into novel therapeutic regimens and the effectiveness of treatments for HR+/HER2- LABC/mBC. The effectiveness of the current treatment options following 1 L CDK4/6i therapy in the real-world setting highlights the unmet need in this patient population and may help to drive further research and drug development. In this study, we conducted a systematic literature review (SLR) to qualitatively summarize the effectiveness and safety of treatment regimens in the real-world setting after 1 L treatment with CDK4/6i in patients with HR+/HER2- LABC/mBC.

Literature search

An SLR was performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [ 31 ] and reported in alignment with the Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses (PRISMA) statement [ 32 ] to identify all RWE studies assessing the effectiveness and safety of treatments used for patients with HR+/HER2- LABC/mBC following 1 L CDK4/6i therapy and received subsequent treatment in 2 L and beyond (2 L+). The Ovid® platform was used to search MEDLINE® (including Epub Ahead of Print and In-Process, In-Data-Review & Other Non-Indexed Citations), Ovid MEDLINE® Daily, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews by an experienced medical information specialist. The MEDLINE® search strategy was peer-reviewed independently by a senior medical information specialist before execution using the Peer Review of Electronic Search Strategies (PRESS) checklist [ 33 ]. Searches were conducted on December 14, 2022. The review protocol was developed a priori and registered with the International Prospective Register of Systematic Review (PROSPERO; CRD42023383914) which outlined the population, intervention, comparator, outcome, and study design (PICOS) criteria and methodology used to conduct the review (Table  1 ).

Search strategies utilized a combination of controlled vocabulary (e.g., “HER2 Breast Cancer” or “HR Breast Cancer”) and keywords (e.g., “Retrospective studies”). Vocabulary and syntax were adjusted across databases. Published and validated filters were used to select for study design and were supplemented using additional medical subject headings (MeSH) terms and keywords to select for RWE and nonrandomized studies [ 34 ]. No language restrictions were included in the search strategy. Animal-only and opinion pieces were removed from the results. The search was limited to studies published between January 2015 and December 2022 to reflect the time at which FDA approval was granted for the first CDK4/6i agent (palbociclib) in combination with AI for the treatment of LABC/mBC [ 35 ]. Further search details are presented in Supplementary Material 1 .

Grey literature sources were also searched to identify relevant abstracts and posters published from January 2019 to December 2022 for prespecified relevant conferences including ESMO, San Antonio Breast Cancer Symposium (SABCS), American Society of Clinical Oncology (ASCO), the International Society for Pharmacoeconomics and Outcomes Research (ISPOR US), and the American Association for Cancer Research (AACR). A search of ClinicalTrials.gov was conducted to validate the findings from the database and grey literature searches.

Study selection, data extraction & weighted average calculation

Studies were screened for inclusion using DistillerSR Version 2.35 and 2.41 (DistillerSR Inc. 2021, Ottawa, Canada) by two independent reviewers based on the prespecified PICOS criteria (Table  1 ). A third reviewer was consulted to resolve any discrepancies during the screening process. Studies were included if they reported RWE on patients aged ≥ 18 years with HR+/HER2- LABC/mBC who received 1 L CDK4/6i treatment and received subsequent treatment in 2 L+. Studies were excluded if they reported the results of clinical trials (i.e., non-RWE), were published in any language other than English, and/or were published prior to 2015 (or prior to 2019 for conference abstracts and posters). For studies that met the eligibility criteria, data relating to study design and methodology, details of interventions, patient eligibility criteria and baseline characteristics, and outcome measures such as efficacy, safety, tolerability, and patient-reported outcomes (PROs), were extracted (as available) using a Microsoft Excel®-based data extraction form (Microsoft Corporation, WA, USA). Data extraction was performed by a single reviewer and was confirmed by a second reviewer. Multiple publications identified for the same RWE study, patient population, and setting that reported data for the same intervention were linked and extracted as a single publication. Weighted average median real-world progression-free survival (rwPFS) values were calculated by considering the contribution to the median rwPFS of each study proportional to its respective sample size. These weighted values were then used to compute the overall median rwPFS estimate.

Quality assessment

The Newcastle-Ottawa scale (NOS) for nonrandomized (cohort) studies was used to assess the risk of bias for published, full-text studies [ 36 ]. The NOS allocates a maximum of nine points for the least risk of bias across three domains: (1) Formation of study groups (four points), (2) Comparability between study groups (two points), (3) Outcome ascertainment (three points). NOS scores can be categorized in three groups: very high risk of bias (0 to 3 points), high risk of bias (4 to 6), and low risk of bias (7 to 9) [ 37 ]. Risk of bias assessment was performed by one reviewer and validated by a second independent reviewer to verify accuracy. Due to limited methodological data by which to assess study quality, risk of bias assessment was not performed on conference abstracts or posters. An amendment to the PROSPERO record (CRD42023383914) for this study was submitted in relation to the quality assessment method (specifying usage of the NOS).

The database search identified 3,377 records; after removal of duplicates, 2,759 were screened at the title and abstract stage of which 2,553 were excluded. Out of the 206 reports retrieved and assessed for eligibility, an additional 187 records were excluded after full-text review; most of these studies were excluded for having patients with mixed lines of CDK4/6i treatment (i.e., did not receive CDK4/6i exclusively in 1 L) (Fig.  1 and Table S1 ). The grey literature search identified 753 records which were assessed for eligibility; of which 752 were excluded mainly due to the population not meeting the eligibility criteria (Fig.  1 ). In total, the literature searches identified 20 records (9 published full-text articles and 11 conference abstracts/posters) representing 18 unique RWE studies that met the inclusion criteria. The NOS quality scores for the included full-text articles are provided in Table S2 . The scores ranged from four to six points (out of a total score of nine) and the median score was five, indicating that all the studies suffered from a high risk of bias [ 37 ].

Most studies were retrospective analyses of chart reviews or medical registries, and all studies were published between 2017 and 2022 (Table S3 ). Nearly half of the RWE studies (8 out of 18 studies) were conducted in the US [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ], while the remaining studies included sites in Canada, China, Germany, Italy, Japan, and the United Kingdom [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Sample sizes ranged from as few as 4 to as many as 839 patients across included studies, with patient age ranging from 26 to 86 years old.

Although treatment characteristics in the 1 L setting were not the focus of the present review, these details are captured in Table S3 . Briefly, several RWE studies reported 1 L CDK4/6i use in combination with ET (8 out of 18 studies) or as monotherapy (2 out of 18 studies) (Table S3 ). Treatments used in combination with 1 L CDK4/6i included letrozole, fulvestrant, exemestane, and anastrozole. Where reported (4 out of 18 studies), palbociclib was the most common 1 L CDK4/6i treatment. Many studies (8 out of 18 studies) did not report which specific CDK4/6i treatment(s) were used in 1 L or if its administration was in combination or monotherapy.

Characteristics of treatments after 1 L CDK4/6i therapy

Across all studies included in this review, effectiveness and safety data were only available for treatments administered in the 2 L setting after 1 L CDK4/6i treatment. No studies were identified that reported outcomes for patients treated in the third-line setting or beyond after 1 L CDK4/6i treatment. All 18 studies reported effectiveness outcomes in 2 L, with only two of these studies also describing 2 L safety outcomes. The distribution of outcomes reported in these studies is provided in Table S4 . Studies varied in their reporting of outcomes for 2 L treatments; some studies reported outcomes for a group of 2 L treatments while others described independent outcomes for specific 2 L treatments (i.e., everolimus, fulvestrant, or chemotherapy agents such as eribulin mesylate) [ 42 , 45 , 50 , 54 , 55 ]. Due to the heterogeneity in treatment classes reported in these studies, this data was categorized (as described below) to align with the guidelines provided by NCCN and ESMO [ 15 , 16 ]. The treatment class categorizations for the purpose of this review are: single-agent ET (patients who exclusively received a single-agent ET after 1 L CDK4/6i treatment), mTORi ± ET (patients who exclusively received an mTORi with or without ET after 1 L CDK4/6i treatment), mix of ET and/or mTORi (patients who may have received only ET, only mTORi, and/or both treatments but the studies in this group lacked sufficient information to categorize these patients in the “single-agent ET” or “mTOR ± ET” categories), and chemotherapy (patients who exclusively received chemotherapy after 1 L CDK4/6i treatment). Despite ESMO and NCCN guidelines indicating that limited evidence exists to support rechallenge with CDK4/6i after 1 L CDK4/6i treatment [ 15 , 16 ], two studies reported outcomes for this treatment approach. Data for such patients were categorized as “ CDK4/6i ± ET ” as it was unclear how many patients receiving CDK4/6i rechallenge received concurrent ET. All other patient groups that lacked sufficient information or did not report outcome/safety data independently (i.e., grouped patients with mixed treatments) to categorize as one of the treatment classes described above were grouped as “ other ”.

The majority of studies reported effectiveness outcomes for endocrine-based therapy after 1 L CDK4/6i treatment; five studies for single-agent ET, six studies for mTORi ± ET, and three studies for a mix of ET and/or mTORi (Fig.  2 ). Eleven studies reported effectiveness outcomes for chemotherapy after 1 L CDK4/6i treatment, and only two studies reported effectiveness outcomes for CDK4/6i rechallenge ± ET. Eight studies that described effectiveness outcomes were grouped into the “other” category. Safety data was only reported in two studies: one study evaluating the chemotherapy agent eribulin mesylate and one evaluating the mTORi everolimus.

Effectiveness outcomes

Real-world progression-free survival

Median rwPFS was described in 13 studies (Tables  2 and Table S5 ). Across the 13 studies, the median rwPFS ranged from 2.5 months [ 49 ] to 17.3 months [ 39 ]. Out of the 13 studies reporting median rwPFS, 10 studies reported median rwPFS for a 2 L treatment recommended by ESMO and NCCN guidelines, which ranged from 2.5 months [ 49 ] to 9.7 months [ 45 ].

Weighted average median rwPFS was calculated for 2 L treatments recommended by both ESMO and NCCN guidelines (Fig.  3 ). The weighted average median rwPFS for single-agent ET was 3.9 months ( n  = 92 total patients) and was derived using data from two studies reporting median rwPFS values of 3.3 months ( n  = 70) [ 38 ] and 6.0 months ( n  = 22) [ 40 ]. For one study ( n  = 7) that reported outcomes for single agent ET, median rwPFS was not reached during the follow-up period; as such, this study was excluded from the weighted average median rwPFS calculation [ 49 ].

The weighted average median rwPFS for mTORi ± ET was 3.6 months ( n  = 128 total patients) and was derived based on data from 3 studies with median rwPFS ranging from 2.5 months ( n  = 4) [ 49 ] to 4.9 months ( n  = 25) [ 54 ] (Fig.  3 ). For patients who received a mix of ET and/or mTORi but could not be classified into the single-agent ET or mTORi ± ET treatment classes, the weighted average median rwPFS was calculated to be 3.7 months ( n  = 17 total patients). This was calculated based on data from two studies reporting median rwPFS values of 3.0 months ( n  = 5) [ 46 ] and 4.0 months ( n  = 12) [ 49 ]. Notably, one study of patients receiving ET and/or everolimus reported a median rwPFS duration of 3.0 months; however, this study was excluded from the weighted average median rwPFS calculation for the ET and/or mTORi class as the sample size was not reported [ 53 ].

The weighted average median rwPFS for chemotherapy was 6.1 months ( n  = 499 total patients), calculated using data from 7 studies reporting median rwPFS values ranging from 3.7 months ( n  = 249) [ 38 ] to 9.7 months ( n  = 121) [ 45 ] (Fig.  3 ). One study with a median rwPFS duration of 5.6 months was not included in the weighted average median rwPFS calculation as the study did not report the sample size [ 53 ]. A second study was excluded from the calculation since the reported median rwPFS was not reached during the study period ( n  = 7) [ 41 ].

Although 2 L CDK4/6i ± ET rechallenge lacks sufficient information to support recommendation by ESMO and NCCN guidelines, the limited data currently available for this treatment have shown promising results. Briefly, two studies reported median rwPFS for CDK4/6i ± ET with values of 8.3 months ( n  = 302) [ 38 ] and 17.3 months ( n  = 165) (Table  2 ) [ 39 ]. The remaining median rwPFS studies reported data for patients classified as “Other” (Table S5 ). The “Other” category included median rwPFS outcomes from seven studies, and included a myriad of treatments (e.g., ET, mTOR + ET, chemotherapy, CDK4/6i + ET, alpelisib + fulvestrant, chidamide + ET) for which disaggregated median rwPFS values were not reported.

Overall survival

Median OS for 2 L treatment was reported in only three studies (Table  2 ) [ 38 , 42 , 43 ]. Across the three studies, the 2 L median OS ranged from 5.2 months ( n  = 3) [ 43 ] to 35.7 months ( n  = 302) [ 38 ]. Due to the lack of OS data in most of the studies, weighted averages could not be calculated. No median OS data was reported for the single-agent ET treatment class whereas two studies reported median OS for the mTORi ± ET treatment class, ranging from 5.2 months ( n  = 3) [ 43 ] to 21.8 months ( n  = 54) [ 42 ]. One study reported 2 L median OS of 24.8 months for a single patient treated with chemotherapy [ 43 ]. The median OS data in the CDK4/6i ± ET rechallenge group was 35.7 months ( n  = 302) [ 38 ].

Patient mortality was reported in three studies [ 43 , 44 , 45 ]. No studies reported mortality for the single-agent ET treatment class and only one study reported this outcome for the mTORi ± ET treatment class, where 100% of patients died ( n  = 3) as a result of rapid disease progression [ 43 ]. For the chemotherapy class, one study reported mortality for one patient receiving 2 L capecitabine [ 43 ]. An additional study reported eight deaths (21.7%) following 1 L CDK4/6i treatment; however, this study did not disclose the 2 L treatments administered to these patients [ 44 ].

Other clinical endpoints

The studies included limited information on additional clinical endpoints; two studies reported on time-to-discontinuation (TTD), two reported on duration of response (DOR), and one each on time-to-next-treatment (TTNT), time-to-progression (TTP), objective response rate (ORR), clinical benefit rate (CBR), and stable disease (Tables  2 and Table S5 ).

Safety, tolerability, and patient-reported outcomes

Safety and tolerability data were reported in two studies [ 40 , 45 ]. One study investigating 2 L administration of the chemotherapy agent eribulin mesylate reported 27 patients (22.3%) with neutropenia, 3 patients (2.5%) with febrile neutropenia, 10 patients (8.3%) with peripheral neuropathy, and 14 patients (11.6%) with diarrhea [ 45 ]. Of these, neutropenia of grade 3–4 severity occurred in 9 patients (33.3%) [ 45 ]. A total of 55 patients (45.5%) discontinued eribulin mesylate treatment; 1 patient (0.83%) discontinued treatment due to adverse events [ 45 ]. Another study reported that 5 out of the 22 patients receiving the mTORi everolimus combined with ET in 2 L (22.7%) discontinued treatment due to toxicity [ 40 ]. PROs were not reported in any of the studies included in the SLR.

The objective of this study was to summarize the existing RWE on the effectiveness and safety of therapies for patients with HR+/HER2- LABC/mBC after 1 L CDK4/6i treatment. We identified 18 unique studies reporting specifically on 2 L treatment regimens after 1 L CDK4/6i treatment. The weighted average median rwPFS for NCCN- and ESMO- guideline recommended 2 L treatments ranged from 3.6 to 3.9 months for ET-based treatments and was 6.1 months when including chemotherapy-based regimens. Treatment selection following 1 L CDK4/6i therapy remains challenging primarily due to the suboptimal effectiveness or significant toxicities (e.g., chemotherapy) associated with currently available options [ 56 ]. These results highlight that currently available 2 L treatments for patients with HR+/HER2- LABC/mBC who have received 1 L CDK4/6i are suboptimal, as evidenced by the brief median rwPFS duration associated with ET-based treatments, or notable side effects and toxicity linked to chemotherapy. This conclusion is aligned with a recent review highlighting the limited effectiveness of treatment options for HR+/HER2- LABC/mBC patients post-CDK4/6i treatment [ 56 , 57 ]. Registrational trials which have also shed light on the short median PFS of 2–3 months achieved by ET (i.e., fulvestrant) after 1 L CDK4/6i therapy emphasize the need to develop improved treatment strategies aimed at prolonging the duration of effective ET-based treatment [ 56 ].

The results of this review reveal a paucity of additional real-world effectiveness and safety evidence after 1 L CDK4/6i treatment in HR+/HER2- LABC/mBC. OS and DOR were only reported in two studies while other clinical endpoints (i.e., TTD, TTNT, TTP, ORR, CBR, and stable disease) were only reported in one study each. Similarly, safety and tolerability data were only reported in two studies each, and PROs were not reported in any study. This hindered our ability to provide a comprehensive assessment of real-world treatment effectiveness and safety following 1 L CDK4/6i treatment. The limited evidence may be due to the relatively short period of time that has elapsed since CDK4/6i first received US FDA approval for 1 L treatment of HR+/HER2- LABC/mBC (2015) [ 35 ]. As such, almost half of our evidence was informed by conference abstracts. Similarly, no real-world studies were identified in our review that reported outcomes for treatments in the third- or later-lines of therapy after 1 L CDK4/6i treatment. The lack of data in this patient population highlights a significant gap which limits our understanding of the effectiveness and safety for patients receiving later lines of therapy. As more patients receive CDK4/6i therapy in the 1 L setting, the number of patients requiring subsequent lines of therapy will continue to grow. Addressing this data gap over time will be critical to improve outcomes for patients with HR+/HER2- LABC/mBC following 1 L CDK4/6i therapy.

There are several strengths of this study, including adherence to the guidelines outlined in the Cochrane Handbook to ensure a standardized and reliable approach to the SLR [ 58 ] and reporting of the SLR following PRISMA guidelines to ensure transparency and reproducibility [ 59 ]. Furthermore, the inclusion of only RWE studies allowed us to assess the effectiveness of current standard of care treatments outside of a controlled environment and enabled us to identify an unmet need in this patient population.

This study had some notable limitations, including the lack of safety and additional effectiveness outcomes reported. In addition, the dearth of studies reporting PROs is a limitation, as PROs provide valuable insight into the patient experience and are an important aspect of assessing the impact of 2 L treatments on patients’ quality of life. The studies included in this review also lacked consistent reporting of clinical characteristics (e.g., menopausal status, sites of metastasis, prior surgery) making it challenging to draw comprehensive conclusions or comparisons based on these factors across the studies. Taken together, there exists an important gap in our understanding of the long-term management of patients with HR+/HER2- LABC/mBC. Additionally, the effectiveness results reported in our evidence base were informed by small sample sizes; many of the included studies reported median rwPFS based on less than 30 patients [ 39 , 40 , 41 , 46 , 49 , 51 , 60 ], with two studies not reporting the sample size at all [ 47 , 53 ]. This may impact the generalizability and robustness of the results. Relatedly, the SLR database search was conducted in December 2022; as such, novel agents (e.g., elacestrant and capivasertib + fulvestrant) that have since received FDA approval for the treatment of HR+/HER2- LABC/mBC may impact current 2 L rwPFS outcomes [ 61 , 62 ]. Finally, relative to the number of peer-reviewed full-text articles, this SLR identified eight abstracts and one poster presentation, comprising half (50%) of the included unique studies. As conference abstracts are inherently limited by how much content that can be described due to word limit constraints, this likely had implications on the present synthesis whereby we identified a dearth of real-world effectiveness outcomes in patients with HR+/HER2- LABC/mBC treated with 1 L CDK4/6i therapy.

Future research in this area should aim to address the limitations of the current literature and provide a more comprehensive understanding of optimal sequencing of effective and safe treatment for patients following 1 L CDK4/6i therapy. Specifically, future studies should strive to report robust data related to effectiveness, safety, and PROs for patients receiving 2 L treatment after 1 L CDK4/6i therapy. Future studies should also aim to understand the mechanism underlying CDK4/6i resistance. Addressing these gaps in knowledge may improve the long-term real-world management of patients with HR+/HER2- LABC/mBC. A future update of this synthesis may serve to capture a wider breadth of full-text, peer-reviewed articles to gain a more robust understanding of the safety, effectiveness, and real-world treatment patterns for patients with HR+/HER2- LABC/mBC. This SLR underscores the necessity for ongoing investigation and the development of innovative therapeutic approaches to address these gaps and improve patient outcomes.

This SLR qualitatively summarized the existing real-world effectiveness data for patients with HR+/HER2- LABC/mBC after 1 L CDK4/6i treatment. Results of this study highlight the limited available data and the suboptimal effectiveness of treatments employed in the 2 L setting and underscore the unmet need in this patient population. Additional studies reporting effectiveness and safety outcomes, in addition to PROs, for this patient population are necessary and should be the focus of future research.

PRISMA flow diagram. *Two included conference abstracts reported the same information as already included full-text reports, hence both conference abstracts were not identified as unique. Abbreviations: 1 L = first-line; AACR = American Association of Cancer Research; ASCO = American Society of Clinical Oncology; CDK4/6i = cyclin-dependent kinase 4/6 inhibitor; ESMO = European Society for Medical Oncology; ISPOR = Professional Society for Health Economics and Outcomes Research; n = number of studies; NMA = network meta-analysis; pts = participants; SABCS = San Antonio Breast Cancer Symposium; SLR = systematic literature review.

Number of studies reporting effectiveness outcomes exclusively for each treatment class. *Studies that lack sufficient information on effectiveness outcomes to classify based on the treatment classes outlined in the legend above. Abbreviations: CDK4/6i = cyclin-dependent kinase 4/6 inhibitor; ET = endocrine therapy; mTORi = mammalian target of rapamycin inhibitor.

Weighted average median rwPFS for 2 L treatments (recommended in ESMO/NCCN guidelines) after 1 L CDK4/6i treatment. Circular dot represents weighted average median across studies. Horizontal bars represent the range of values reported in these studies. Abbreviations: CDK4/6i = cyclin-dependent kinase 4/6 inhibitor; ESMO = European Society for Medical Oncology; ET = endocrine therapy, mTORi = mammalian target of rapamycin inhibitor; n = number of patients; NCCN = National Comprehensive Cancer Network; rwPFS = real-world progression-free survival.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files]. This study is registered with PROSPERO (CRD42023383914).

Abbreviations

Second-line

Second-line treatment setting and beyond

American Association of Cancer Research

Aromatase inhibitor

American Society of Clinical Oncology

• Breast cancer

breast cancer gene/partner and localizer of BRCA2 positive

Clinical benefit rate

Cyclin-dependent kinase 4/6 inhibitor

Complete response

Duration of response

European Society for Medical Oncology

Food and Drug Administration

Human epidermal growth factor receptor 2

Human epidermal growth factor receptor 2 negative

Hormone receptor

Hormone receptor positive

Professional Society for Health Economics and Outcomes Research

Locally advanced breast cancer

Metastatic breast cancer

Medical Literature Analysis and Retrieval System Online

Medical subject headings

Mammalian target of rapamycin inhibitor

National Comprehensive Cancer Network

Newcastle Ottawa Scale

Objective response rate

Poly-ADP ribose polymerase inhibitor

Progression-free survival

Population, Intervention, Comparator, Outcome, Study Design

Partial response

Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses

Patient-reported outcomes

• Real-world evidence

San Antonio Breast Cancer Symposium

• Systematic literature review

Time-to-discontinuation

Time-to-next-treatment

Time-to-progression

United States

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Acknowledgements

The authors would like to acknowledge Joanna Bielecki who developed, conducted, and documented the database searches.

This study was funded by Pfizer Inc. (New York, NY, USA) and Arvinas (New Haven, CT, USA).

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Sarah Kane, Belal Howidi, Bao-Ngoc Nguyen and Imtiaz A. Samjoo contributed equally to this work.

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VL, IAS, SK, BH, BN, DC, YW, and ME participated in the conception and design of the study. IAS, SK, BH and BN contributed to the literature review, data collection, analysis, and interpretation of the data. VL, IAS, SK, BH, BN, DC, YW, and ME contributed to the interpretation of the data and critically reviewed for the importance of intellectual content for the work. VL, IAS, SK, BH, BN, DC, YW, and ME were responsible for drafting or reviewing the manuscript and for providing final approval. VL, IAS, SK, BH, BN, DC, YW, and ME meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given their approval for this version to be published.

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The authors of this manuscript declare that the research presented was funded by Pfizer Inc. and Arvinas. While the support from Pfizer Inc. and Arvinas was instrumental in facilitating this research, the authors affirm that their interpretation of the data and the content of this manuscript were conducted independently and without bias to maintain the transparency and integrity of the research. IAS, SK, BH, and BN are employees of EVERSANA, Canada, which was a paid consultant to Pfizer in connection with the development of this manuscript.

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Lambert, V., Kane, S., Howidi, B. et al. Systematic literature review of real-world evidence for treatments in HR+/HER2- second-line LABC/mBC after first-line treatment with CDK4/6i. BMC Cancer 24 , 631 (2024). https://doi.org/10.1186/s12885-024-12269-8

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Severe fever with thrombocytopenia syndrome with central nervous system symptom onset: a case report and literature review

• Dawei Shan 1 ,
• Weibi Chen 1 ,
• Gang Liu 1 ,
• Huimin Zhang 1 ,
• Shuting Chai 1 &
• Yan Zhang 1  

BMC Neurology volume  24 , Article number:  158 ( 2024 ) Cite this article

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Severe fever with thrombocytopenia syndrome (SFTS) is a natural focal disease transmitted mainly by tick bites, and the causative agent is SFTS virus (SFTSV). SFTS can rapidly progress to severe disease, with multiple-organ failure (MOF) manifestations such as shock, respiratory failure, disseminated intravascular coagulation (DIC) and death, but cases of SFTS patients with central nervous system (CNS) symptoms onset and marked persistent involuntary shaking of the perioral area and limbs have rarely been reported.

Case presentation

A 69-year-old woman with fever and persistent involuntary shaking of the perioral area and limbs was diagnosed with SFTS with CNS symptom onset after metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) and peripheral blood identified SFTSV. The patient developed a cytokine storm and MOF during the course of the disease, and after aggressive antiviral, glucocorticoid, and gamma globulin treatments, her clinical symptoms improved, her laboratory indices returned to normal, and she had a good prognosis.

This case gives us great insight that when patients with CNS symptoms similar to those of viral encephalitis combined with thrombocytopenia and leukopenia are encountered in the clinic, it is necessary to consider the possibility of SFTS involving the CNS. Testing for SFTSV nucleic acid in CSF and blood (mNGS or polymerase chain reaction (PCR)) should be carried out, especially in critically ill patients, and treatment should be given accordingly.

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Severe fever with thrombocytopenia syndrome (SFTS) is a natural focal disease transmitted mainly by tick bites, and the causative agent is a novel Bunyavirus, also known as SFTS virus (SFTSV), belonging to the Phenuiviridae family and the Bandavirus genus, which was first isolated from patient serum by the Chinese Centre for Disease Control and Prevention in 2010 [ 1 ]. The main features of SFTS include fever, thrombocytopenia, leukopenia and gastrointestinal symptoms, and in severe cases, patients may present with multiple‑organ failure (MOF) symptoms such as shock, respiratory failure, disseminated intravascular coagulation (DIC) and death, with a mortality rate of 5–30% in East Asia [ 2 , 3 ]. SFTS may also present with central nervous system (CNS) involvement, which can severely affect the patient’s disease progression and prognosis and is manifested by seizures, psychiatric symptoms, cognitive impairment, and disorders of consciousness [ 4 , 5 ]. However, reports of patients who present with CNS symptoms as the first symptom and with marked persistent involuntary shaking of the perioral area and limbs are rare.

A 69-year-old female patient was admitted to the hospital with fever for 4 days, involuntary shaking around the mouth and limbs for 3 days, and mental abnormalities for 1 day. The patient was admitted to the emergency department of another hospital 4 days before admission because of fever, where her body temperature reached 38.7 °C and she showed poor mental status, less talking, a loss of appetite, but no headache, vomiting, and limb twitching. A routine blood examination showed a white blood cell (WBC) count of 2.28 × 10 9 /L and a platelet count of 165 × 10 9 /L. When given a cooling infusion for symptomatic treatment, her body temperature would temporarily return to normal. Three days before admission, she experienced persistent involuntary trembling around the mouth and lips, as well as trembling of the tongue and extremities. The trembling of the lips, mouth, and both distal upper limbs was especially bothersome and was aggravated by emotional excitement and accompanied by slurred speech. Two days before admission, she had persistent fever, with a body temperature up to 39.6 °C, and the effect of antipyretic drugs was not good. A routine blood examination performed in another hospital showed a WBC count of 1.78 × 10 9 /L and a platelet count of 81 × 10 9 /L, which was significantly decreased compared with the count from the previous examination. One day prior to admission, the patient experienced babbling, restlessness, irritability, and a decline in time and place orientation and calculation power.

The patient had a many-year history of hypertension, diabetes mellitus and hyperlipidaemia; denied a history of working and living in hilly, forested and mountainous areas and travelling; denied a recent history of mosquito bites; and reported a history of close contact with a pet dog in the last month.

Neurological examination after admission showed that the patient had normal arousal but had unclear speech, hyperactivity, irritability. Her time and place orientation and calculation power decreased. The patient was uncooperative in the pharyngeal reflex examination, and involuntary tongue twitching could be seen when the tongue was stretched out. The remaining cranial nerve examination did not show any abnormalities. Perioral and limb involuntary shaking was obvious and persistent, especially in the perioral area and distal part of both upper limbs. Bilateral tendon reflexes were symmetrical, bilateral pathological signs were negative, and meningeal irritation signs were negative.

On admission, viral encephalitis was considered, and intravenous acyclovir antiviral therapy (0.5 g, q8h) was empirically administered. A comprehensive examination revealed that the patient had MOF: (1) Her platelet count further decreased to 63 × 10 9 /L (normal: 100–300 × 10 9 /L), toxic granules were seen in some granulocytes of the peripheral blood smear, and heterogeneous lymphocytes accounted for 21% of the total. (2) She had impaired liver function with elevated liver enzymes (alanine aminotransferase (ALT), 76 IU/L (normal: 5–40 IU/L); aspartate aminotransferase (AST), 188 IU/L (normal: 8–40 IU/L); and gamma-glutamyl transpeptidase (γ-GT), 177 IU/L (normal: 7–50 IU/L)), which was treated with magnesium isoglycyrrhizinate injection and vitamin C for liver protection. (3) She had acute myocardial injury, with an increased heart rate of > 120 beats/minute and markedly elevated myocardial enzyme and B-type natriuretic peptide levels (myoglobin, 299 ng/mL (normal: 25–58 ng/mL); troponin T, 209 ng/L (normal: 0–14 ng/L); and B-type natriuretic peptide, 9,355 pg/mL (normal: 0-125 pg/mL)). Electrocardiograms (ECGs) showed various atypical manifestations, such as short PR intervals; atrial premature, mild ST-segment depression in leads V2V3; and T-wave changes in multiple leads. Cardiac ultrasound showed a normal left ventricular ejection fraction but abnormal segmental motion of the left ventricular wall, biventricular diastolic insufficiency and a small amount of pericardial effusion. Coenzyme Q10 and trimetazidine were given to improve myocardial energy metabolism, and fluid intake and output were closely monitored. (4) The patient had a bacterial infection of the lungs, combined with type I respiratory failure, which were treated with tracheal intubation and mechanical ventilation immediately to assist respiration and antibiotic antimicrobial therapy. The patient did not have prolonged hypoxic injury. (5) She had impaired renal function, with elevated blood urea nitrogen (BUN) (17.33 mmol/L) (normal: 1.7–8.3 mmol/L) and urinary protein. We administered measures to ensure fluid intake and without the use of nephrotoxic drugs. (6) She had impaired pancreatic function, with elevated lipase (56.5 U/L) (normal: 5.6–51.3 U/L); we administered acid-suppressing drugs to inhibit pancreatic secretion and reduce the load and damage to pancreatic tissue. (7) She had abnormal coagulation, with a prolonged prothrombin time (PT) and thrombin time (TT) (15.7 s (normal: 11–15 s) for PT and 22.6 s (normal: 14–21 s) for TT), decreased fibrinogen (1.8 g/L) (normal: 2–4 g/L), and markedly elevated plasma D-dimer (9.01 µg/mL) (normal: 0.01–0.5 µg/mL) and fibrinogen degradation products (FDPs) (28.36 µg/mL) (normal: 0–5 µg/mL). (8) A thrombus had formed in her right peroneal vein and the intermuscular veins of the right and left calves, for which low molecular heparin anticoagulation was given. (9) Her muscle enzyme profiles were variably elevated (creatine kinase (CK), 335 IU/L (normal: 24–195 IU/L); lactate dehydrogenase (LDH), 1347 IU/L (normal: 109–245 IU/L); and alpha-hydroxybutyrate dehydrogenase (α-HBDH), 645 IU/L (normal: 72–182 IU/L)), correlating with inflammatory response-mediated organ damage. (10) The patient experienced a cytokine storm, with significantly increased inflammatory factors (ferritin > 1500 ng/mL (normal: 11-306.8 ng/mL), interleukin (IL)-6 = 49.88 pg/mL (normal: 0–20 pg/mL), IL-8 = 45.99 pg/mL (normal: 0-21.4 pg/mL), and IL-10 = 25.67 pg/mL (normal: 0-5.9 pg/mL), interferon (IFN)-α = 9.76 pg/mL (normal: 0-7.9 pg/mL), and IFN-γ = 18.7 pg/mL (normal: 0-17.3 pg/mL)) in serum (Table  1 ). (11) Finally, the patient showed an electrolyte balance disorder, as evidenced by hypernatremia (154 mmol/L) (normal: 135–145 mmol/L), hyperchloremia (119 mmol/L) (normal: 96–108 mmol/L), hypocalcaemia (1.92 mmol/L) (normal: 2.03–2.67 mmol/L), and hypophosphatemia (0.54 mmol/L) (normal: 0.84–1.65 mmol/L), and treatments included calcium supplementation, phosphorus supplementation, nasal administration of plain water, and a reduction of sodium and chlorine intake.

Lumbar puncture was performed on the second day after admission (Table  2 ). Cerebrospinal fluid (CSF) was colourless and clear, with a pressure of 190 mmH 2 O (normal: 80–180 mmH 2 O) and a WBC count of 3 × 10 6 /L. CSF cytology showed scattered lymphocytes and a few mononuclear cells. The glucose level and protein counts were normal, chloride was slightly elevated (134 mmol/L) (normal: 118–128 mmol/L), immunoglobulins (Ig) were slightly elevated (IgA, 1.03 mg/dL (normal: 0-0.2 mg/dL); IgM, 0.22 mg/dL (normal: 0-0.2 mg/dL); and IgG, 6.68 mg/dL (normal: 0.48–5.86 mg/dL)), and CSF cytokine levels of IL-6 (27.46 pg/mL) (normal: 0–20 pg/mL) and IL-8 (546.93 pg/mL) (normal: 0-21.4 pg/mL) were elevated. CSF was negative for an autoimmune encephalitis antibody profile (NMDAR, CASPR2, AMPAR1, AMPAR2, LGI1, GABABR, DPPX, and IgLON5), neuroparaneoplastic syndrome antibody profile (Hu, Ri, Yo, CV2, Amphiphysin, GAD65, PNMA2, Recoverin, SOX1, Titin, Tr, and Zic4), and CNS demyelination antibody profile (AQP4, GFAP, MBP, and MOG). Metagenomic next-generation sequencing (mNGS) showed that the number of sequences of a novel Bunyavirus of the Bandavirus genus was 59 in the blood and 12 in the CSF. We also excluded acute febrile illnesses by serum and CSF mNGS, such as dengue fever, chikungunya fever, EB virus infection, renal syndrome hemorrhagic fever, and rickettsial disease.

A diagnosis of SFTS that started with symptoms of CNS and encephalitis due to a novel Bunyavirus was considered based on the patient’s clinical presentation and laboratory test results. With immediate effect, acyclovir was adjusted to the broad-spectrum antiviral drug Foscarnet sodium (3 g, q8h); intravenous infusion of dexamethasone (10 mg qd for five days) and intravenous immunoglobulin (IVIG) (0.4 g/kg for five days) were administered to regulate immune function and inhibit the cytokine storm; nifedipine and benidipine hydrochloride were given to reduce the viral-induced calcium inflow to inhibit viral replication, reduce the viral load and increase the platelet count; clonazepam (1 mg, q8h) was given to relieve the patient’s obvious symptoms of involuntary shaking; and adequate symptomatic supportive therapy was given to ensure adequate calorie and protein intake and to maintain water, electrolyte, blood glucose and acid‒base balance.

After 3 days of hospitalization, the patient’s platelet and WBC counts began to rise gradually and returned to normal levels. After 5 days of hospitalization, the patient’s involuntary shaking and psychiatric symptoms were less severe than before, but compliance with activities was still poor, and her cognitive level still had not returned to normal. After 11 days of hospitalization, the lung infection was better than before, and ventilator withdrawal training was started. After 12 days of hospitalization, cranial magnetic resonance imaging (MRI) was performed, which showed slightly high signals in the bilateral anterior temporal lobe, temporal lobe hook gyrus, insular cortex, and bilateral thalamus on fluid attenuated inversion recovery (FLAIR) and diffusion weighted imaging (DWI) (Fig.  1 a-f). After 13 days of hospitalization, a blood sample was negative for novel Bunyavirus nucleic acid. After 16 days of hospitalization, her condition was significantly better than before, she could perform activities as instructed and answer questions correctly, her time and place orientation returned to normal, and her cognitive level was better than before. A electroencephalogram (EEG) was performed, and a full-lead low-wave amplitude state was observed (Fig.  2 ). After 17 days of hospitalization, the ventilator was completely withdrawn, and the tracheal tube was removed. A repeat lumbar puncture 3 weeks after hospitalization showed a pressure of 110 mmH 2 O, a WBC count of 4 × 10 6 /L, a normal protein count, a slightly elevated glucose level (5.19 mmol/L, compared with a glucose of 7.9 mmol/L over the same period), a slightly elevated chlorine level (130 mmol/L), and a return of Ig to normal. The levels of cytokines IL-6 (4.35 pg/mL) and IL-8 (96.17 pg/mL) decreased significantly compared with the previous levels, and the levels of whole-blood cytokines returned to the normal range (IL-6, 12.22 pg/mL; IL-8, 4.62 pg/mL; IL-10, 1.27 pg/mL; IFN-α, 0 pg/mL; and IFN-γ, 1.14 pg/mL) in serum (Table  1 ). No further novel Bunyaviruses were detected by mNGS of the CSF. Meanwhile, MOF gradually recovered, and liver, heart, lung, kidney, pancreas and coagulation function; the muscle enzyme profile; inflammatory factors; and electrolyte levels gradually returned to normal levels.

After antiviral therapy, immunotherapy, life support and symptomatic treatment, the patient’s vital signs were stable 3 weeks after admission, with clear speech and normal higher cortical function to perform tasks correctly on command. The muscle strength of all four limbs was grade 5, muscle tone was normal, bilateral tendon reflexes existed symmetrically, an ataxia test was normal, bilateral pathological signs were negative, and meningeal irritation signs were negative. She was discharged from the hospital in 23 days after admission. The patient was followed up 1 month after she was discharged from the hospital and is now back to her normal living conditions, with normal functioning of the higher cortex, the ability to take care of herself, and the ability to perform all of the activities she regularly engages in.

Cranial MRI of the patient 12 days after admission. Bilateral anterior temporal lobe (a and d) , temporal lobe leptomeningeal gyrus (a and d) , insular cortex (b and e) , and bilateral thalamus (c and f) FLAIR and DWI sequences with slightly high signals

Sixteen-lead resting-state EEG of the patient 16 days after admission. Simultaneous display an EEG record in monopolar and bipolar montages. A low-amplitude state can be seen in all leads. (a) monopolar montage EEG, (b) bipolar montage EEG

Discussion and conclusions

SFTS is an infectious disease caused by SFTSV infection. The epidemic period is mainly in May-August, and SFTSV is mainly transmitted by tick bites to humans. In recent years, interpersonal and human-animal transmission has also been found. An epidemiological survey of SFTS found that 48% of the patients had had close contact with their pets within two weeks of the onset of the disease [ 6 ]. The general population is susceptible, with a higher risk of infection in residents living in areas such as hills, mountains and forests and in people who spend time outdoors. In this case, SFTSV was isolated from blood and CSF. There was no history of tick bites or travel in the wild, but there was a history of close contact with a pet dog within the past month, and we hypothesized that the infected dog might have been the source of SFTSV in this patient.

The pathogenesis of CNS involvement in SFTS patients is unclear. Previous studies have demonstrated that Bunyaviruses have neurological properties of attack, and Park et al. found viral transcripts of novel Bunyaviruses in the brain and spinal cord of an aged model ferret. It is hypothesized that novel Bunyaviruses also involve the CNS, with consequent symptoms [ 7 ]. Possible mechanisms by which SFTSV attacks the CNS include direct invasion, cytokine storms, and impaired immune function. Kaneko et al. [ 8 ] performed an autopsy on a patient with SFTS with rapid CNS involvement, and the pathological findings revealed a massive infiltration of macrophages with high haematoxylin content and inflammatory cells around the microvessels of the cerebral pontine, fibrin deposition in the vessels, and focal degenerative lesions in some neuronal cells. In a variety of brain tissues, positive SFTSV nucleocapsid protein antigens were observed in the immunoblasts infiltrating the vascular lumen, suggesting that SFTSV can invade the CNS directly for disease development. The availability of agents that recognize these antigens also suggest immunoassays are possible and available for serodiagnosis. For example, serum enzyme linked immunosorbent assay or immunofluorescence to determine SFTSV antigens and antibodies have been used for clinical diagnosis [ 9 ]. Several studies [ 10 , 11 , 12 , 13 , 14 , 15 ] have found that the blood levels of several cytokines, including IFN-α, IFN-γ, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and monocyte chemotactic protein (MCP)-1, are elevated in patients with SFTS, and IL-8 and MCP-1 levels in the CSF are significantly higher than the blood of those who present with CNS symptoms [ 10 ], suggesting that a cytokine storm may increase vascular permeability and prompt SFTSV to cross the blood‒brain barrier (BBB) and invade the CNS. SFTSV was found in the CSF of this patient, suggesting that the virus had invaded the patient’s CNS. The patient’s blood levels of IL-6, IL-8, IL-10, IFN-α, and IFN-γ were markedly elevated compared with normal ranges; IL-6 and IL-8 were elevated in the CSF; and CSF IL-8 levels were significantly higher than the blood levels, which was consistent with the results of a previous study [ 10 , 11 , 12 , 13 , 14 , 15 ], further suggesting that the cytokine storms induced by multiple elevated cytokines may increase BBB vascular permeability and contribute to the SFTSV invasion of the CNS. In patients with SFTS complicated by neurological involvement, protein and glucose levels in the CSF are normal and that an increase in leukocytes in the CSF may be uncommon. However, in the case of a high suspicion both on a clinical and epidemiological level in countries where the infection exists, in these patients the search for MCP-1 and IL-8 in the CSF and serum is indicated and CSF viral RNA detection are recommended.

According to the course of infection, SFTS can be divided into four periods: the incubation period, the febrile period, the MOF period, and the recovery period [ 1 , 2 , 3 , 16 ]. Patients with SFTS can present with neurological symptoms, which usually appear approximately 5 days after the onset of the disease (Table  3 ) and are often regarded as a complication of SFTS, which has been referred to as SFTS-associated encephalopathy/encephalitis (SFTSAE) [ 10 ]. SFTSAE mainly manifests as headache, seizures, mental abnormality, irritability, limb convulsions, cognitive impairment, and impaired consciousness, with an incidence of approximately 19.1-57.02% [ 4 , 5 , 11 , 17 ]. Most patients with SFTSAE develop impaired consciousness, such as coma, before their condition is taken seriously, which leads to a poor prognosis for the patients [ 4 , 18 ]. Most clinicians rely on the clinical manifestations to make the clinical diagnosis. SFTSV has rarely been isolated from CSF. We screened studies and case reports of SFTS with CNS involvement and found no reports of disease onset with CNS symptoms such as marked persistent involuntary shaking of the perioral area and extremities. In this case, the patient first presented with fever, followed by persistent involuntary tremors of the perioral area and limbs and mental behavioural abnormalities such as rambling, irritability and agitation; furthermore, the whole-genome sequence of SFTSV was found by mNGS of blood and CSF. The case reported here is a case of SFTS with CNS symptoms onset, accompanied by perioral and extremity persistent involuntary shaking, which has not been previously reported in the literature. It has been reported in the literature that SFTS patients can have tremors of limbs and muscles [ 8 , 17 , 19 ], but most of them occurred in the middle and late stages of the disease, and the tremor amplitude was small. In this case, the patient had large-amplitude involuntary shaking of the limbs that was persistent and intensified during agitation, which immediately attracted the clinician’s attention. An additional movie file shows this in more detail [see Additional file 1 ]. However, the specific underlying mechanism is not clear, and a description of similar symptoms of viral encephalitis and an analysis of the underlying mechanism have not been found before; therefore, further studies are needed. The course of the disease in this patient was consistent with the general pattern, with the clinical experience of the febrile period, the MOF period, and the recovery period. The febrile period lasted approximately 4 days, followed by MOF involving the liver, heart, lungs, kidneys, and pancreas, and then the recovery period began approximately 2 weeks after the disease onset, with clinical symptoms gradually returning to normal.

There are fewer reports on neurological-related ancillary investigations (CSF, cranial imaging, and EEG) in SFTS patients with CNS involvement, and we analyse this because SFTS patients rarely start with CNS symptoms and go directly to the neurology department and because such patients are generally more severely ill, making it difficult for them to cooperate in completing the relevant investigations. In a few previous studies, lumbar puncture CSF tests in SFTS patients with CNS symptoms were mostly normal, with few abnormal changes in leukocyte counts, sugars and proteins [ 10 , 20 ]. Park et al. [ 10 ] analysed head imaging and EEG in a series of SFTS patients presenting with CNS symptoms, and no new focal lesions were seen on imaging in any of the brain parenchyma, suggesting that the imaging was not specific and that the EEG in the majority of the patients showed a slow-wave background rhythm (δ-θ), a common feature of encephalitis/encephalopathy. In this patient, two lumbar punctures were performed successively, and no CSF leukocyte abnormalities were observed in any of them either; it was presumed that SFTSV infection was less likely to involve the meninges. We performed cranial MRI and EEG on the patient 12 and 16 days after admission, respectively, and slightly high signals were observed in the bilateral anterior temporal lobes, temporal lobe hook gyrus, insular cortex, and bilateral thalamus in the FLAIR and DWI sequences of cranial MRI, all of which were consistent with the general imaging manifestations of viral encephalitis and were presumed to be related to viral invasion. In addition, we should consider the similarities and differences between the above MRI changes and cortical laminar necrosis associated with hypoxia or hypotension. We found that both had MRI high signals distributed along the cortex. However, this patient’s cranial MRI showed cortical high signals only in FLAIR and DWI sequences, and no abnormal signal was found in T1WI, which was the most obvious difference from cortical laminar necrosis. Furthermore, the patient did not show hypotension or significant hypoxic injury, so the changes on cranial MRI were more likely to be inflammatory changes of viral encephalitis and less relevant to cortical laminar necrosis. The background rhythm of the EEG was an α rhythm, and the whole leads were in low amplitude, which was different from previous studies [ 10 ]. It was presumed that the patient’s brain inflammation had tended to recover at that time, but the suppression of cortical function was remained.

There are no specific drugs for the treatment of CNS symptoms in SFTS, and symptomatic supportive treatment is the mainstay. In vitro and ex vivo studies have found that nifedipine or benidipine hydrochloride can inhibit SFTSV replication, reduce viral load, increase platelet counts, and reduce morbidity and mortality, as confirmed in a retrospective clinical study [ 21 , 22 ]. Glucocorticoids can inhibit the cytokine storms caused by the overproduction of cytokines and reduce patient mortality [ 12 , 13 , 23 ], and a Japanese report documented that three SFTS patients with impaired consciousness recovered without any neurological sequelae after short-term glucocorticoid treatment. However, the authors also suggested that the dosage should be minimized and the duration of administration should be shortened to inhibit cytokine storms and provide systemic benefit, rather than high doses or prolonged use, to avoid side effects [ 24 ]. Gamma globulin, which triggers complement activation and viral neutralization and influences the differentiation process of Schwann cells to increase their regenerative potential [ 25 ], has been used to treat other virus-induced encephalitides and can be used for the treatment of CNS symptoms in SFTS. Two successful cases of combined glucocorticoid and IVIG therapy were reported in Korea [ 26 ]. Two case reports documented that plasma exchange therapy reduced cytokine levels but not viral load, presumably making plasma exchange more effective at an early stage [ 27 , 28 ]. However, these are case reports, and the findings should be confirmed by large-scale randomized controlled studies. In this case, the patient was given the broad-spectrum antiviral drug foscarnet sodium, intravenous infusion of dexamethasone and IVIG to regulate the immune function of the body and inhibit the inflammatory storm, nifedipine and benidipine hydrochloride to inhibit viral replication and reduce the viral load, and other symptomatic treatments. The patient’s clinical manifestations and laboratory indicators gradually improved.

The prognosis of patients with SFTS is related to numerous factors, and studies have shown that advanced age; significant elevations in ALT, AST, CK, CK-MB, LDH, γ-GT, and BUN; low platelet count; persistent lowering of blood calcium; and the presence of CNS symptoms are all important influences that can lead to a poor prognosis [ 29 , 30 , 31 , 32 , 33 , 34 ]. Most of these are commonly used to monitor cardiac, hepatic and renal function, and significant abnormalities in their results indicate more severe organ damage and dysfunction. In addition, there is a statistically significant difference in serum viral copy number between deceased and non-dead patients. The mean viral copy number was higher in deceased patients than in surviving patients, and patients with higher copy numbers had higher mortality rates [ 35 , 36 ]. It was shown that the serum viral load detected by polymerase chain reaction (PCR) on admission was higher in SFTSAE patients than in non-encephalitis patients [ 11 ]. The above suggests a relationship between patient serum number of SFTSV RNA copies and encephalitis CNS symptoms and mortality in SFTS patients. CNS symptoms are often considered to be associated with fatal outcomes in patients with SFTS [ 33 ], and early diagnosis and treatment of neurological symptoms can help reduce mortality. Advanced age; long intervals between onset and admission; comorbid diabetes mellitus or subcutaneous haemorrhage; pulmonary rales; low platelet count; elevated neutrophil percentages and LDH, CK, and C-reactive protein (CRP) levels; and decreased chloride concentrations are significantly associated with the development of CNS symptoms and should be taken into consideration in clinical practice [ 11 , 17 ]. We believe that changes in platelet count and CK-MB should be monitored in patients with SFTSAE. As shown in previous, decreased platelet counts and high CK-MB levels are risk factors for poor prognosis in patients with SFTS. The presence of encephalitis is evidence of a more critical condition. Monitoring changes in platelet counts may provide an initial indication of the direction of the patient’s regression. It has been found that in cardiac enzyme profiles, patients presenting with CNS symptoms have elevated CK levels earlier than LDH and AST levels, and elevated liver enzyme levels later than cardiac enzymes [ 17 ]. Therefore, early monitoring of CK-MB levels may have a predictive effect on the development of CNS symptoms in patients. Although the mortality rate of SFTS patients presenting with CNS symptoms is significantly higher [ 11 ], several studies have found [ 11 , 37 , 38 ] that the long-term prognosis of surviving patients is good, with no obvious sequelae after active treatment. In this case, the patient’s laboratory indicators were consistent with the factors leading to a poor prognosis, and the CNS symptoms were prominent, suggesting that the condition was critical, but with timely administration of treatment, the patient’s condition eventually returned to normal.

In summary, we report a case of SFTS in a patient who started with CNS symptoms accompanied by marked persistent involuntary perioral and extremity shaking, and the whole-genome sequence of SFTSV was found by mNGS of both serum and CSF (It is important to note that hospitals where mNGS analysis is unavailable should use real-time fluorescent quantitative PCR to detect SFTS-specific nucleic acids in serum and CSF.). This has given us great insight into the fact that SFTS should be considered a possible cause when patients present with common CNS symptoms of viral encephalitis, such as mental behavioural abnormalities, convulsions, and cognitive deficits, or rare symptoms, such as persistent involuntary shaking of the perioral area and limbs in the rare case of this patient, combined with thrombocytopenia and leukopenia. Prompt lumbar puncture examination for SFTSV should be performed, and appropriate treatment should be given aggressively to reduce mortality.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

severe fever with thrombocytopenia syndrome

severe fever with thrombocytopenia syndrome virus

multiple-organ failure

disseminated intravascular coagulation

central nervous system

metagenomic next-generation sequencing

cerebrospinal fluid

alanine aminotransferase

aspartate aminotransferase

gamma-glutamyl transpeptidase

electrocardiogram

blood urea nitrogen

prothrombin time

thrombin time

fibrinogen degradation products

creatine kinase

lactate dehydrogenase

alpha-hydroxybutyrate dehydrogenase

interleukin

immunoglobulin

intravenous immunoglobulin

magnetic resonance imaging

fluid attenuated inversion recovery

diffusion weighted imaging

electroencephalogram

tumour necrosis factor

monocyte chemotactic protein

blood-brain barrier

severe fever with thrombocytopenia syndrome -associated encephalopathy/ encephalitis

polymerase chain reaction

C-reactive protein

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This project was supported by National Key Research and Development Program of China (2020YFC2005403), and by China Association for Promotion of Health Science and Technology (JKHY2023001).

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Dawei Shan and Yan Zhang contributed to the conception and design of the manuscript. Dawei Shan collected the data and drafted the manuscript. Yan Zhang, Weibi Chen, Gang Liu, Huimin Zhang and Shuting Chai reviewed and modified the manuscript. All authors contributed to manuscript revision and read and approved the final submitted version.

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12883_2024_3664_MOESM1_ESM.mp4

Supplementary Material 1. File name: Additional file 1. File format: mp4. Title of data: Video of patient with persistent involuntary shaking of the perioral area and limbs. Description of data: We took this video on day 2 after the patient was admitted to the hospital. The patient develops persistent involuntary shaking of the perioral area and limbs, especially in the perioral area and distal limbs, which is aggravated by agitation and is accompanied by slurred speech.

Supplementary Material 2. CARE Checklist of information to include when writing this case report.

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Shan, D., Chen, W., Liu, G. et al. Severe fever with thrombocytopenia syndrome with central nervous system symptom onset: a case report and literature review. BMC Neurol 24 , 158 (2024). https://doi.org/10.1186/s12883-024-03664-6

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Received : 30 November 2023

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DOI : https://doi.org/10.1186/s12883-024-03664-6

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• Severe fever with thrombocytopenia syndrome
• Novel bunyaviruses
• Central nervous system
• Encephalitis
• Involuntary shaking

BMC Neurology

ISSN: 1471-2377

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