Forward-reverse mutation cycles in cancer cell lines under chemical treatments.

Spontaneous forward-reverse mutations were reported by us earlier in clinical samples from various types of cancers and in HeLa cells under normal culture conditions. To investigate the effects of chemical stimulations on such mutation cycles, the present study examined single nucleotide variations (SNVs) and copy number variations (CNVs) in HeLa and A549 cells exposed to wogonin-containing or acidic medium. In wogonin, both cell lines showed a mutation cycle during days 16-18. In acidic medium, both cell lines displayed multiple mutation cycles of different magnitudes. Genomic feature colocalization analysis suggests that CNVs tend to occur in expanded and unstable regions, and near promoters, histones, and non-coding transcription sites. Moreover, phenotypic variations in cell morphology occurred during the forward-reverse mutation cycles under both types of chemical treatments. In conclusion, chemical stresses imposed by wogonin or acidity promoted cyclic forward-reverse mutations in both HeLa and A549 cells to different extents.

Intraparenchymal breast leiomyoma and atypical leiomyoma.

BACKGROUND: Breast leiomyoma is a rare benign mesenchymal tumor, accounting for less than 1% of all breast neoplasms. Cases of breast atypical leiomyoma is even more rarely reported and its diagnostic criteria together with its clinical courses is not cleared defined. CASE PRESENTATION: We described two patients with breast leiomyomas. One has unilateral benign breast leiomyoma, the other one has bilateral breast leiomyomas. For the bilateral case, the left-side tumor was diagnosed as benign leiomyoma while the right-side tumor was diagnosed as atypical leiomyoma. The morphological features that lead to the diagnosis of atypical leiomyoma are its invasive growth pattern, mild nuclear atypia, and mitotic figures up to 3mitoses/10HPF. CONCLUSIONS: Atypical breast leiomyoma appears to behave like benign leiomyoma without recurrence in our study with nine-year follow-up. Due to the limited experience, cases presented as atypical intraparenchymal breast leiomyoma should be closely followed.

Gene expression trend changes in breast cancer populations over two decades: insights from The Cancer Genome Atlas database.

BACKGROUND: Breast cancer has remained the most common malignancy in women over the past two decades. As lifestyle and living environments have changed, alterations to the disease spectrum have inevitably occurred in this time. As molecular profiling has become a routine diagnostic and objective indicator of breast cancer etiology, we analyzed changes in gene expression in breast cancer populations over two decades using The Cancer Genome Atlas database. METHODS: We performed Heatmap and Venn diagram analyses to identify constantly up- and down-regulated genes in breast cancer patients of this cohort. We used Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to visualize associated functional pathways. RESULTS: We determined that three oncogenes, PD-L2, ETV5, and MTOR and 113 long intergenic non-coding RNAs (lincRNAs) were constantly up-regulated, whereas two oncogenes, BCR and GTF2I, one tumor suppression gene MEN1, and 30 lincRNAs were constantly down-regulated. Up-regulated genes were enriched in "focal adhesion" and "PI3K-Akt signaling" pathways, etc., and down-regulated genes were significantly enriched in "metabolic pathways" and "viral myocarditis". Eight up-regulated genes exhibited doubled or higher expression and the expression of three down-regulated genes was halved or lowered and correlated with long-term survival. CONCLUSIONS: In this study, we found that gene expression and molecular pathway enrichments are constantly changing with time, importantly, some altered genes were associated with prognostics and are potential therapeutic targets, suggesting that the current molecular subtyping system must be updated to keep pace with this dynamic change.

Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study.

Breast cancer (BC) is associated with hereditary components, and some deleterious germline variants have been regarded as effective therapeutic targets. We conducted a clinic-based, observational study to better understand the distribution of deleterious germline variants and assess any clinicopathological predictors related to the variants among Chinese BC patients using a 32 cancer-related genes next-generation sequencing panel. Between November 2020 and February 2022, a total of 700 BC patients were recruited, and 13.1% (92/700) of them carried deleterious germline variants in 15 cancer-related genes, including 37 (37/700, 5.3%) in BRCA2, 29 (29/700, 4.1%) in BRCA1, 8 (8/700, 1.1%) in PALB2, 4 (4/700, 0.6%) in NBN, 3 (3/700, 0.4%) in MRE11A, 3 (3/700, 0.4%) in TP53 and 12 (12/700, 1.7%) in other genes. There were 28 novel variants detected: 5 in BRCA1, 14 in BRCA2, and 9 in non-BRCA1/2 genes. The variants in panel genes, HRR (homologous recombination repair)-related genes, and BRCA1/2 were significantly associated with the following clinicopathological factors: age at the initial diagnosis of BC, family history of any cancer, molecular subtype, Ki-67 index, and hereditary risk. In conclusion, we further expanded the spectrum of germline deleterious variants in Chinese BC patients, and the clinicopathological predictors of variants were identified to facilitate clinical genetic testing and counseling for appropriate individuals.

AR Expression Correlates with Distinctive Clinicopathological and Genomic Features in Breast Cancer Regardless of ESR1 Expression Status.

Androgen receptor (AR) expression is frequently observed in breast cancer, but its association with estrogen receptor (ER) expression in breast cancer remains unclear. This study analyzed the clinicopathological and molecular features associated with AR negativity in both ER-positive and ER-negative breast cancer, trying to elucidate the molecular correlation between AR and ER. Our results showed that AR negativity was associated with different clinicopathological characteristics and molecular features in ER-positive and ER-negative breast cancer. Moreover, AR-positive breast cancer has better clinicopathological features than AR-negative breast cancer, especially in the ER-negative subtype. These results suggest that the role of AR in ER-negative breast cancer is distinctive from that in ER-positive breast cancer.

Protective effect of goserelin on ovarian reserve during (neo)adjuvant chemotherapy in young breast cancer patients: a prospective cohort study in China.

STUDY QUESTION: Does goserelin, a GnRH agonist, have a protective effect in young breast cancer patients in terms of ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) during chemotherapy? SUMMARY ANSWER: Compared with chemotherapy alone, concurrent goserelin is associated with a higher probability of ovarian reserve recovery at 1 year after chemotherapy. WHAT IS KNOWN ALREADY: Previous studies on the administration of goserelin to protect ovarian function during chemotherapy have produced conflicting results because of the endpoint used, namely, chemotherapy-induced amenorrhoea. Reproductive medicine specialists consider AMH and AFC as the most sensitive ovarian reserve markers; however, they have never been used as biomarkers to assess the potential protective effects on ovarian reserve of goserelin during chemotherapy. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study in which patients were assigned to receive (neo)adjuvant chemotherapy with goserelin (the goserelin group) or without goserelin (the control group) according to each patient's preference. Of 242 breast cancer patients enrolled between December 2015 and November 2019, 76 in control group and 73 in goserelin group were able to be assessed at 1 year after chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal patients with a regular menstrual cycle and aged 18-45 years were eligible for enrolment if they were newly diagnosed with stages I-III breast cancer for which treatment with adjuvant or neoadjuvant chemotherapy was planned. Each patient in the goserelin group was given a subcutaneous dose of 3.6 mg at least 1 week before the first cycle of chemotherapy and then every 4 weeks for the duration of chemotherapy. Ovarian reserve markers and menstrual status were evaluated before and after chemotherapy in the two treatment groups. The primary endpoint was the AMH recovery rate, the secondary endpoints were the recovery rates of AFC, estradiol (E2), follicle-stimulating hormone (FSH) and menstruation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 149 patients (76 in the control group and 73 in the goserelin group) with complete data at 1 year after chemotherapy, the adjusted recovery rate of AMH was 46.5% and 21.8% in the goserelin group and control group, respectively (odds ratio: 3.08; P = 0.002). The trends in AFC and FSH recovery rates were consistent with that in AMH recovery rate. Notably, AMH levels remained low in 41.3% of patients whose menstrual activity had resumed. LIMITATIONS, REASONS FOR CAUTION: Randomisation was not performed because of ethical considerations, so selection bias was inevitable, although propensity score weighting was done. The study was also underpowered because 21.5% (52/242) of enrolled patients received GnRH agonist-containing endocrine therapy and could not be analysed at 1 and 2 years after chemotherapy. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that co-administration of goserelin with chemotherapy provides obvious ovarian reserve protection in these young breast cancer patients. We expect that these results will be applicable in clinical practice for young breast cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Key R&D Program of China No. 2016YFC0901302, by the Research and Development Fund of Peking University People's Hospital No. RD2014-13, RDY2017-19 and by AstraZeneca. The authors have no disclosures. TRIAL REGISTRATION NUMBER: NCT02430103.

Classification of PR-positive and PR-negative subtypes in ER-positive and HER2-negative breast cancers based on pathway scores.

PURPOSE: PR loss in ER+/HER2- breast cancer indicates worse prognosis and insensitivity to anti-estrogen therapy, while the mechanisms of PR loss in ER+/HER2- breast cancer remain unrevealed. METHODS: In this study, ER+/PR+/HER2- and ER+/PR-/HER2- breast cancer cases from TCGA were used. 1387 pathways were analyzed and used as variables for classifying the two groups with LASSO regression. RESULTS: ER+/PR+/HER2- and ER+/PR-/HER2- breast cancer groups can be classified by a combination of 13 pathways using their activity score. Among the 13 pathways, those involving growth factors and ion-channel transporters were most significant in the distinction, followed by pathways involving immune modulation and cell metabolism. Two growth factor pathways, EGF and IGF-1, were deferentially regulated in ER+/PR+/HER2- and ER+/PR-/HER2- groups. CONCLUSIONS: In conclusion, this study indicated in ER+/HER2- breast cancers the various status of PR expression can be an indication of molecular variation, particularly for the growth factor pathway activation.

Genomic subtyping of liver cancers with prognostic application.

BACKGROUND: Cancer subtyping has mainly relied on pathological and molecular means. Massively parallel sequencing-enabled subtyping requires genomic markers to be developed based on global features rather than individual mutations for effective implementation. METHODS: In the present study, the whole genome sequences (WGS) of 110 liver cancers of Japanese patients published with different pathologies were analyzed with respect to their single nucleotide variations (SNVs) comprising both gain-of-heterozygosity (GOH) and loss-of-heterozygosity (LOH) mutations, the signatures of combined GOH and LOH mutations, along with recurrent copy number variations (CNVs). RESULTS: The results, obtained based on the WGS sequences as well as the Exome subset within the WGSs that covered ~ 2.0% of the WGS and the AluScan-subset within the WGSs that were amplifiable by Alu element-consensus primers and covered ~ 2.1% of the WGS, indicated that the WGS samples could be employed with the mutational parameters of SNV load, LOH%, the Signature α%, and survival-associated recurrent CNVs (srCNVs) as genomic markers for subtyping to stratify liver cancer patients prognostically into the long and short survival subgroups. The usage of the AluScan-subset data, which could be implemented with sub-micrograms of DNA samples and vastly reduced sequencing analysis task, outperformed the usage of WGS data when LOH% was employed as stratifying criterion. CONCLUSIONS: Thus genomic subtyping performed with novel genomic markers identified in this study was effective in predicting patient-survival duration, with cohorts of hepatocellular carcinomas alone and those including intrahepatic cholangiocarcinomas. Such relatively heterogeneity-insensitive genomic subtyping merits further studies with a broader spectrum of cancers.

Forward and reverse mutations in stages of cancer development.

BACKGROUND: Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. METHODS: In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published "nontumor"-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined. RESULTS: Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in "nontumor" tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in "paratumor" tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from "nontumor" to "paratumor" and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. CONCLUSIONS: These findings suggest that developing cancer cells undergo sequential changes that enable the "nontumor" cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the "paratumor" cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

Characteristics and Prognostic Factors of Patients With Osteosarcoma Older Than 60 Years From the SEER Database.

Osteosarcoma is predominant in the adolescent and the elderly population, but few studies have described the characteristics and prognostic factors of patients older than 60 years. In this study, the Surveillance, Epidemiology, and End Results registry database was used to identify all patients diagnosed with primary osteosarcoma from 1973 to 2014. We utilized Cox proportional hazards regression analysis to evaluate the association between patient overall survival and relevant characteristics, including gender, race, disease stage, treatment methods, primary tumor site, differentiation grade, and histologic subtype. In the data set, a total of 1139 patients with osteosarcoma older than 60 years old were identified. The overall rate of distant metastatic cases was 28.6%. Osteosarcoma occurred equally in men and women (49.5% vs 50.5%). Of all, 41.3% of tumors were located in axial location (pelvis, spine, and ribs), 34.1% of tumors were located in extremity (long or short bones of the upper or lower extremity), and 24.6% in other location (mandible, skull, and other atypical locations). Male (hazard ratio [HR] = 1.201; 95% confidence interval [CI]: 1.056-1.366), axial location (HR = 1.342; 95% CI: 1.157-1.556), distant metastasis (HR = 2.369; 95% CI: 2.015-2.785), non-surgery perform (HR = 2.108; 95% CI: 1.814-2.451) were independent risk factors for 5-year overall survival. This study revealed distinct clinicopathological features of patients with osteosarcoma older than 60 years. Male gender, tumor in axial site, nonsurgery perform, and distant metastasis indicated worse prognosis survival. Performing surgery is still an effective and reliable treatment method for patients older than 60 years.

Bridging Discoveries and Treatments: The New Landscape of Breast Cancer Research.

Welcome to our Special Issue, "Advances in Breast Cancer Research and Treatment" of Life, where we have embarked on a comprehensive exploration of groundbreaking studies that advance our understanding and management of breast cancer [...].

cascAGS: Comparative Analysis of SNP Calling Methods for Human Genome Data in the Absence of Gold Standard.

The development of third-generation sequencing has accelerated the boom of single nucleotide polymorphism (SNP) calling methods, but evaluating accuracy remains challenging owing to the absence of the SNP gold standard. The definitions for without-gold-standard and performance metrics and their estimation are urgently needed. Additionally, the possible correlations between different SNP loci should also be further explored. To address these challenges, we first introduced the concept of a gold standard and imperfect gold standard under the consistency framework and gave the corresponding definitions of sensitivity and specificity. A latent class model (LCM) was established to estimate the sensitivity and specificity of callers. Furthermore, we incorporated different dependency structures into LCM to investigate their impact on sensitivity and specificity. The performance of LCM was illustrated by comparing the accuracy of BCFtools, DeepVariant, FreeBayes, and GATK on various datasets. Through estimations across multiple datasets, the results indicate that LCM is well-suitable for evaluating callers without the SNP gold standard, and accurate inclusion of the dependency between variations is crucial for better performance ranking. DeepVariant has a higher sum of sensitivity and specificity than other callers, followed by GATK and BCFtools. FreeBayes has low sensitivity but high specificity. Notably, appropriate sequencing coverage is another important factor for precise callers' evaluation. Most importantly, a web interface for assessing and comparing different callers was developed to simplify the evaluation process.

CellSAM: Advancing Pathologic Image Cell Segmentation via Asymmetric Large-Scale Vision Model Feature Distillation Aggregation Network.

Segment anything model (SAM) has attracted extensive interest as a potent large-scale image segmentation model, with prior efforts adapting it for use in medical imaging. However, the precise segmentation of cell nucleus instances remains a formidable challenge in computational pathology, given substantial morphological variations and the dense clustering of nuclei with unclear boundaries. This study presents an innovative cell segmentation algorithm named CellSAM. CellSAM has the potential to improve the effectiveness and precision of disease identification and therapy planning. As a variant of SAM, CellSAM integrates dual-image encoders and employs techniques such as knowledge distillation and mask fusion. This innovative model exhibits promising capabilities in capturing intricate cell structures and ensuring adaptability in resource-constrained scenarios. The experimental results indicate that this structure effectively enhances the quality and precision of cell segmentation. Remarkably, CellSAM demonstrates outstanding results even with minimal training data. In the evaluation of particular cell segmentation tasks, extensive comparative analyzes show that CellSAM outperforms both general fundamental models and state-of-the-art (SOTA) task-specific models. Comprehensive evaluation metrics yield scores of 0.884, 0.876, and 0.768 for mean accuracy, recall, and precision respectively. Extensive experiments show that CellSAM excels in capturing subtle details and complex structures and is capable of segmenting cells in images accurately. Additionally, CellSAM demonstrates excellent performance on clinical data, indicating its potential for robust applications in treatment planning and disease diagnosis, thereby further improving the efficiency of computer-aided medicine.

MSGM: An Advanced Deep Multi-Size Guiding Matching Network for Whole Slide Histopathology Images Addressing Staining Variation and Low Visibility Challenges.

Matching whole slide histopathology images to provide comprehensive information on homologous tissues is beneficial for cancer diagnosis. However, the challenge arises with the Giga-pixel whole slide images (WSIs) when aiming for high-accuracy matching. Learning-based methods are difficult to generalize well with large-size WSIs, necessitating the integration of traditional matching methods to enhance accuracy as the size increases. In this paper, we propose a multi-size guiding matching method applicable high-accuracy requirements. Specifically, we design learning multiscale texture to train deep descriptors, called TDescNet, that trains 64 × 64 × 256 and 256 × 256 × 128 size convolution layer as C64 and C256 descriptors to overcome staining variation and low visibility challenges. Furthermore, we develop the 3D-ring descriptor using sparse keypoints to support the description of large-size WSIs. Finally, we employ C64, C256, and 3D-ring descriptors to progressively guide refined local matching, utilizing geometric consistency to identify correct matching results. Experiments show that when matching WSIs of size 4096 × 4096 pixels, our average matching error is 123.48 µm and the success rate is 93.02 % in 43 cases. Notably, our method achieves an average improvement of 65.52 µm in matching accuracy compared to recent state-of-the-art methods, with enhancements ranging from 36.27 µm to 131.66 µm. Therefore, we achieve high-fidelity whole-slice image matching, and overcome staining variation and low visibility challenges, enabling assistance in comprehensive cancer diagnosis through matched WSIs.

Loss of Human Epidermal Receptor 2 Expression in Formalin-Fixed Paraffin-Embedded Breast Cancer Samples and the Rescuing Effect of Enhanced Antigen Retrieval and Signal Amplification.

As an important therapeutic target in breast cancer, HER2 expression assessed by immunohistochemistry plays a critical role in breast cancer treatment. Recent advances in HER2 antibody-drug conjugate therapy have enabled patients with HER2-low expression breast cancer to benefit from the drugs. However, it is not known whether the HER2-low expression in breast cancer FFPE blocks would be lost as storage time increased. In this study, we aimed to assess the loss of HER2 antigenicity in stored FFPE blocks of breast cancer and the rescue effect of modifying the protocol of antigen staining. We selected archived HER2-low breast cancer FFPE blocks with stored time ranging from 1 year to over 15 years and re-detected the expression of HER2. Our study showed that HER2 antigenicity loss increased with storage time and could cause false negativity in HER2-low detection. Moreover, we showed that by either increasing the antigen retrieval time or applying the tyramide signal amplification (TSA) kit, the HER2 signal can be rescued and detected in about half of the cases with HER2-low loss without causing false positivity.

An orientation-free ring feature descriptor with stain-variability normalization for pathology image matching.

Comprehensively analyzing the corresponding regions in the images of serial slices stained using different methods is a common but important operation in pathological diagnosis. To help increase the efficiency of the analysis, various image registration methods are proposed to match the corresponding regions in different images, but their performance is highly influenced by the rotations, deformations, and variations of staining between the serial pathology images. In this work, we propose an orientation-free ring feature descriptor with stain-variability normalization for pathology image matching. Specifically, we normalize image staining to similar levels to minimize the impact of staining differences on pathology image matching. To overcome the rotation and deformation issues, we propose a rotation-invariance orientation-free ring feature descriptor that generates novel adaptive bins from ring features to build feature vectors. We measure the Euclidean distance of the feature vectors to evaluate keypoint similarity to achieve pathology image matching. A total of 46 pairs of clinical pathology images in hematoxylin-eosin and immunohistochemistry straining to verify the performance of our method. Experimental results indicate that our method meets the pathology image matching accuracy requirements (error ¡ 300µm), especially competent for large-angle rotation cases common in clinical practice.

Mechanism and effect of stress granule formation in cancer and its potential roles in breast cancer therapy.

Stress granules are non-membranous cytoplasmic foci induced by various stress conditions. It is a protective strategy used by cells to suppress overall translation during stress. In cancer cells, it was thought that the formation of stress granules could protect them from apoptosis and induces resistance towards anti-cancer drugs or radiation treatment which makes the stress granules a potential target for cancer treatment. However, most of our understanding of stress granules are still in the stage of molecular and cell biology, and a transitional gap for its actual effect on clinical settings remains. In this review, we summarize the mechanism and effect of stress granules formation in cancer and try to illuminate its potential applications in cancer therapy, using breast cancer as an example.

Modeling effective tumor burden of primary lesion and metastatic lymph node in breast cancer patients from the SEER database.

BACKGROUND: Characterizing the role of the primary tumor and axillary lymph nodes (ALNs) in metastasis progression can provide a rational basis for effective local control and systemic treatments. METHODS: We employed data from the Surveillance, Epidemiology, and End Results (SEER) database to perform survival analysis and modeling to estimate breast cancer (BC) progression in both untreated and treated patients. Effective tumor burden was defined as the number of cancer cells that can lead to distant metastasis. Quantified analysis was conducted for primary lesion and metastatic nodes, respectively. A tumor growth model was built based on mathematical modeling: N ( t ) = m N T ( t ) + n N N ( t ) . In this model, the parameters "m" and "n" represent the contributions of the primary lesion and metastatic lymph nodes (LNs) to distant metastasis, respectively. RESULTS: We found that both the primary lesion and the metastatic LNs contribute to the effective tumor burden. Through fitting the built tumor growth model, "m" in treated groups was determined to be 1, and "n" was determined to be 1.5; while in the untreated group, "m" was determined to be 1, and "n" was 0.15, which was 10 times smaller than in treated groups. CONCLUSIONS: Our study revealed that the prognostic value of the anatomic stage in BC progression varied in different historical periods, due to the development of oncological treatments. While tumor size was a significant prognostic factor in both untreated and treated patients, the prognostic value of nodal status was only significant in patients who received locoregional treatment and systemic treatment.

Two-Dose Vaccination Significantly Prolongs the Duration from Symptom Onset to Death: A Retrospective Study Based on 173,894 SARS-CoV-2 Cases in Khyber Pakhtunkhwa, Pakistan.

This research was carried out to quantify the duration from symptom onset to recovery/death (SOR/SOD) during the first four waves and the Alpha/Delta period of the epidemic in Khyber Pakhtunkhwa, Pakistan, and identify the associated factors. A total of 173,894 COVID-19 cases were admitted between 16 March 2020 and 30 November 2021, including 458 intensive care unit (ICU) cases. The results showed that the case fatality rate (CFR) increased with age, and females had a higher CFR. The median SOR of ICU cases was longer than that of non-ICU cases (27.6 vs. 17.0 days), while the median SOD was much shorter (6.9 vs. 8.4 days). The SOR and SOD in the Delta period were slightly shortened than the Alpha period. Age, cardiovascular diseases, chronic lung disease, diabetes, fever, breathing issues, and ICU admission were risk factors that were significantly associated with SOD (p < 0.001). A control measure, in-home quarantine, was found to be significantly associated with longer SOD (odds ratio = 9.49, p < 0.001). Infected vaccinated individuals had longer SOD than unvaccinated individuals, especially for cases that had received two vaccine doses (p < 0.001). Finally, an advice on getting full-dose vaccination is given specifically to individuals aged 20-59 years.

Adverse Events of PD-1 or PD-L1 Inhibitors in Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis.

(1) Background: This study aimed to develop a comprehensive understanding of the treatment-related adverse events when using PD-1 or PD-L1 inhibitors in triple-negative breast cancer (TNBC). (2) Methods: We conducted a meta-analysis of Phase II/III randomized clinical trials. Studies were searched for using PubMed, Embase, and Cochrane Library from 1 March 1980 till 30 June 2022. Data on adverse events were mainly extracted from ClinicalTrials.gov and published articles. A generalized linear mixed model with the logit transformation was employed to obtain the overall incidence of adverse events across all studies. For serious adverse events with low incidences, the Peto method was used to calculate the odds ratio (OR) and 95% confidence interval (95%CI) in the PD-1 or PD-L1 inhibitors groups compared to the control groups. (3) Results: Nine studies were included in the meta-analysis, including a total of 2941 TNBC patients treated with PD-1 or PD-L1 inhibitors (including atezolizumab, pembrolizumab and durvalumab) and 2339 patients in the control groups. Chemotherapy alone was the control group in all studies. The average incidences of all serious immune-related adverse events of interest (hypothyroidism, hyperthyroidism, pneumonitis, pruritus, rash) were less than 1%, except for adrenal insufficiency (1.70%, 95%CI: 0.50-5.61%) in the PD-1 or PD-L1 groups. PD-1 or PD-L1 inhibitors significantly increased the risk of serious pneumonitis (OR = 2.52, 95%CI: 1.02-6.26), hypothyroidism (OR = 5.92, 95%CI: 1.22-28.86), alanine aminotransferase (ALT) elevation (OR = 1.66, 95%CI: 1.12-2.45), and adrenal insufficiency (OR = 18.81, 95%CI: 3.42-103.40). For non-serious adverse events, the patients treated with PD-1 or PD-L1 inhibitors had higher risk of aspartate aminotransferase (AST) elevation (OR =1.26, 95%CI: 1.02-1.57), hypothyroidism (OR = 3.63, 95%CI: 2.92-4.51), pruritus (OR = 1.84, 95%CI: 1.30-2.59), rash (OR = 1.29, 95%CI: 1.08-1.55), and fever (OR = 1.77, 95%CI: 1.13-2.77), compared with chemotherapy alone. (4) Conclusions: The incidence of serious immune-related adverse events in PD-1 or PD-L1 inhibitors groups is low but significantly higher than in chemotherapy groups. When using PD-1 or PD-L1 inhibitors for the treatment of TNBC, serious pneumonitis, hypothyroidism, ALT elevation, and adrenal insufficiency should be considered. Non-serious adverse events, such as AST elevation, rash, and fever, should also be taken into consideration.