The role of lidocaine in cancer progression and patient survival.

Since its development in 1943, lidocaine has been one of the most commonly used local anesthesia agents for surgical procedures. Lidocaine alters neuronal signal transmission by prolonging the inactivation of fast voltage-gated sodium channels in the cell membrane of neurons, which are responsible for action potential propagation. Recently, it has attracted attention due to emerging evidence suggesting its potential antitumor properties, particularly in the in vitro setting. Further, local administration of lidocaine around the tumor immediately prior to surgical removal has been shown to improve overall survival in breast cancer patients. However, the exact mechanisms driving these antitumor effects remain largely unclear. In this article, we will review the existing literature on the mechanism of lidocaine as a local anesthetic, its effects on the cancer cells and the tumor microenvironment, involved pathways, and cancer progression. Additionally, we will explore recent reports highlighting its impact on clinical outcomes in cancer patients. Taken together, there remains significant ambiguity surrounding lidocaine's functions and roles in cancer biology, particularly in perioperative setting.

Impact of environmental temperature on the survival outcomes of breast cancer: A SEER-based study.

BACKGROUND: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate and an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates will have better survival outcomes than patients living in colder climates. METHODS: A retrospective population-based analysis was conducted on 270,496 stage I-III breast cancer patients, who were retrieved from the Surveillance, Epidemiology and End Results (SEER) over the period from 1996 to 2017. The average annual temperature (AAT) was calculated based on city level data from the National Centers for Environmental Information. RESULTS: A total of 270, 496 patients were analyzed. Temperature as assessed in quartiles. After adjusting for potential confounders, patients who lived in the 3rd and 4th quartile temperature regions with AAT 56.7-62.5°F (3rd quartile) and > 62.5°F (4th quartile) had a 7% increase in the OS compared to patients living at AAT < 48.5°F (1st quartile) (HR 0.93, 95% CI 0.90-0.95 and HR 0.93, 95% CI 0.91-0.96, respectively). For DSS, When comparing AAT quartiles, patients living with AAT in the range of 56.7-62.5°F and > 62.5°F demonstrated a 7% increase each in DSS after adjustment (HR 0.93, 95% CI 0.90-0.96 and HR 0.93, 95% CI 0.90-0.96). CONCLUSIONS: Higher environmental temperatures are associated with significantly better OS and DSS in breast cancer patients. Future research is warranted to confirm this observation using large datasets to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

CD133 expression is associated with less DNA repair, better response to chemotherapy and survival in ER-positive/HER2-negative breast cancer.

Purpose: CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER+/HER2-) BC, the most abundant subtype, remains unknown. Methods: The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data. Results: Epithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER+/HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/ß-Catenin, Hedgehog, and Notchsignaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts. Conclusion: CD133-high ER+/HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.

Enhanced epithelial-mesenchymal transition signatures are linked with adverse tumor microenvironment, angiogenesis and worse survival in gastric cancer.

Epithelial-mesenchymal transition (EMT) is a crucial mechanism that facilitates cancer cell metastasis. Despite its importance, the clinical significance of EMT in gastric cancer (GC) patients has yet to be clearly demonstrated. For gauging the extent of EMT in GC, we employed gene set variation analysis to score 807 patient samples from two large cohorts: TCGA and GSE84437. In both cohorts, EMT high GC showed a significant association with worse overall survival (hazard ratio (HR) = 1.74, p = 0.011 and HR = 2.01, p < 0.001, respectively). This association was stronger when considering the EMT signature score compared to the individual expressions of EMT-related genes (CDH1, CDH2, VIM, and FN1). While the EMT signature level did not differ among various cancers, high EMT signature specifically correlated with survival in GC alone. Mucinous and diffuse histological types exhibited higher EMT levels compared to others (p < 0.001), and the EMT signature level was correlated with tumor depth and AJCC stage (all p < 0.001). Interestingly, the EMT score was an independent factor for overall and disease-specific survival (multivariate; p = 0.006 and 0.032, respectively). EMT high GC displayed a lower fraction of Th1 cells and a higher fraction of dendritic cells, M1 macrophages and several stromal cells. EMT high GC exhibited an inverse correlation with cell proliferation-related gene sets. While they significantly enriched multiple pro-cancerous gene sets, such as TGF-ß signaling, hypoxia, and angiogenesis. The presence of EMT signature in a bulk tumor was linked to TGF-ß signaling, hypoxia, and angiogenesis, and was also associated with poorer survival outcomes in GC patients.

Higher Inflammatory Response in Hepatocellular Carcinoma is Associated with Immune Cell Infiltration and a Better Outcome.

Background & Aims: Hepatocellular carcinoma (HCC) often develops from chronic liver inflammation. Inflammation within a tumor can either promote cancer progression or activate an immune response against it. This study aims to determine the clinical significance of enhanced inflammation in HCC. Methods: Data from 655 HCC patients across four cohorts (TCGA, GSE6764, GSE76427, GSE89377) were examined. Inflammatory response was quantified using a scoring system derived from the gene set variation analysis of the "INFLAMMATORY_RESPONSE" gene set. Results: A stepwise increase in inflammatory response was noted from normal liver to cirrhosis, with consistently lower levels in HCC across both GSE6764 and GSE89377 cohorts (both p<0.001). Similar trends were observed in interferon response, pathways such as IL6/JAK/STAT3 and complement signaling, coagulation cascade, and allograft rejection (all p<0.02). HCCs with high inflammatory response were associated with increased immune cell infiltrations (p<0.01) and cytolytic activity (p<0.001). Interestingly, these HCCs had reduced mutation rates, no relationship with cell proliferation, and displayed both immune responses and pro-cancerous signals including epithelial-mesenchymal transition, KRAS, and hypoxia. Further, a high inflammatory score correlated with improved disease-free survival in TCGA (p=0.034) and overall survival in GSE76427 (p=0.008). Conclusion: HCC with higher levels of inflammatory response demonstrated increased immune cell infiltration, enhanced immune-related and other pro-cancerous-related signaling, and better patient prognosis.

Racial and Ethnic Disparity in Preoperative Chemosensitivity and Survival in Patients With Early-Stage Breast Cancer.

Importance: It remains unclear what survival benefit is associated with preoperative chemosensitivity after receiving neoadjuvant chemotherapy (NACT) among patients with resectable breast cancer from diverse racial and ethnic backgrounds. Objective: To investigate racial and ethnic disparities in chemosensitivity and association with survival in patients with early-stage breast cancer. Design, Setting, and Participants: This retrospective cohort study queried data from the National Cancer Database (NCDB) between calendar years 2010 and 2018. Participants included patients with breast cancer with clinical stage I to III disease treated with NACT. Preoperative chemosensitivity was defined as very sensitive (ypT0N0), sensitive (pathologic TNM stage less than clinical stage, excluding ypT0N0), and refractory (pathologic stage greater than or equal to clinical stage). Data were analyzed in November 2022. Exposure: Receipt of NACT and clinicopathologic and treatment factors contributing to racial and ethnic disparities in survival. Main Outcomes and Measures: Overall survival of patients from diverse racial and ethnic backgrounds who received NACT. Results: This study included 103 605 patients (median age, 53 [IQR, 44-62] years, 99.5% [n = 103 060] women, and 68.7% [n = 71 203] White race). Among them, breast cancer was refractory in 43.2% (n = 44 796), sensitive in 34.4% (n = 35 638), and very sensitive in 22.4% (n = 23 171) of patients. In the hormone receptor-positive ERBB2 negative (formerly HER2 negative) group, patients had more refractory disease regardless of race or ethnicity (all races and ethnicities refractory: 54%-59%; P < .001). Among ERBB2 positive disease, Black patients had a lower percentage of very sensitive disease (32% vs 37%-40%; P < .001) and among triple-negative breast cancer, more refractory disease was seen among Black patients compared with other races and ethnicities (38% vs 30%-35%; P < .001). In refractory (hazard ratio [HR], 1.53; 95% CI, 1.47-1.60; P < .001) and sensitive (HR, 1.25; 95% CI, 1.17-1.33; P < .001) disease, Black patients had a higher mortality risk compared with White patients in the overall cohort. Asian patients had a lower mortality risk compared with White patients in refractory (HR, 0.71; 95% CI, 0.63-0.80; P < .001), sensitive (HR, 0.58; 95% CI, 0.49-0.69; P < .001), and very sensitive (HR, 0.60; 95% CI, 0.43-0.82; P < .001) disease groups in the overall cohort. Conclusions and Relevance: In this cohort study, Black patients had a higher mortality risk compared with White patients among those with residual disease after NACT. This highlights the need for personalized treatment strategies for Black patients to help them attain pathologic complete response.

Emerging resistance vs. losing response to immune check point inhibitors in renal cell carcinoma: two differing phenomena.

The introduction of immune checkpoint inhibitor (ICI) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and has dramatically improved the outcomes of patients. The use of monotherapy or combinations of ICIs targeting PD-1/PD-L1 and CTLA-4, as well as the addition of ICIs with tyrosine kinase inhibitors, has significantly enhanced the overall survival of mRCC patients. Despite these promising results, there remains a subset of patients who either do not respond to treatment (primary resistance) or develop resistance to therapy over time (acquired resistance). Understanding the mechanisms underlying the development of resistance to ICI treatment is crucial in the management of mRCC, as they can be used to identify new targets for innovative therapeutic strategies. Currently, there is an unmet need to develop new predictive and prognostic biomarkers that can aid in the development of personalized treatment options for mRCC patients. In this review, we summarize several mechanisms of ICI resistance in RCC, including alterations in tumor microenvironment, upregulation of alternative immune checkpoint pathways, and genetic and epigenetic changes. Additionally, we highlight potential strategies that can be used to overcome resistance, such as combination therapy, targeted therapy, and immune modulation.

Oncotype Dx Score, HER2 Low Expression, and Clinical Outcomes in Early-Stage Breast Cancer: A National Cancer Database Analysis.

BACKGROUND: The interaction between HER2-low expression, oncotype recurrence score (RS), and their influence on the prognosis of HR+/HER2- breast cancer (BC) is not very well studied. METHODS: We conducted a retrospective cohort study of patients diagnosed with resectable HER2-low and HER2-zero BC from the National Cancer Database. The primary outcome was overall survival (OS), and the association of RS with the clinical outcomes in HR+/HER2- BC was analyzed as an exploratory endpoint. RESULTS: The distribution of RS was comparable between HER2-low and HER2-zero groups; however, the RSs of HER2-low tumors were more likely to be 16-25. Women with HER2-low tumors had longer 5-year OS than women with HER2-zero tumors in the HR-negative (84.3% vs. 83.9%; p < 0.001, HR: 0.87 (0.84-0.90), p < 0.001) but not in the HR-positive group (94.0% vs. 94.0%; p = 0.38, HR: 0.97 (0.95-0.99), p = 0.01). The survival advantage was observed in patients who received adjuvant/neoadjuvant chemotherapy (p-interaction (chemo vs. no chemo) < 0.001). Among those who received adjuvant chemotherapy in the group with higher RSs (26-100), those with HER2-low BC had higher 5-year OS than HER2-zero BC. CONCLUSIONS: Resectable HER2-low BC had a better prognosis than HER2-zero BC. Among those who received adjuvant chemotherapy in the higher oncotype RS group, those with HER2-low tumors had better survival.

Pancreatic ductal adenocarcinoma with a high expression of alcohol dehydrogenase 1B is associated with less aggressive features and a favorable prognosis.

Alcohol dehydrogenase (ADH) oxidizes alcohol into acetaldehyde (AA), which is a known carcinogen. Aldehyde dehydrogenase (ALDH) oxidizes AA into acetate. Therefore, pancreatic cancer that expresses a high level of ADH1B that generates more AA is expected to be associated with aggressive cancer. On the other hand, given that the differentiated cells that retain their cellular functions typically exhibit lower proliferation rates, it remains unclear whether pancreatic adenocarcinoma (PDAC) with high ADH1B gene expression is linked to aggressive features in patients. The Cancer Genome Atlas (n = 145) was used to obtain data of PDAC patients and GSE62452 cohort (n = 69) was used as a validation cohort. PDAC with high ADH1B expression was associated with less cancer cell proliferation as evidenced by lower MKI67 expression and lower histological grade; with a higher fraction of stromal cells consistent with less proliferative cancer. PDAC with high ADH1B expression also had lower homologous recombination deficiency and mutation rates, lower KRAS and TP53 mutation rates. ADH1B expression correlated with ALDH2 expression in PDAC, but not with DNA repair genes. High ADH1B expression PDAC was associated with high infiltration of anti-cancerous CD8+ T cells and pro-cancerous M2 macrophages but with lower levels of Th1 T cells, with a higher cytolytic activity. PDAC patients with a high ADH1B expression had better disease-specific survival (DSS) and overall survival (OS) and ADH1B was an independent prognostic biomarker for both DSS (HR = 0.89, 95% CI = 0.80-0.99, P = 0.045) and OS (HR = 0.90, 95% CI = 0.82-0.99, P = 0.044) in multivariate analysis. In conclusion, PDAC with high ADH1B expression had less cell proliferation and malignant features, along with higher immune cell infiltration, and had a better prognosis.

Accelerated glycolysis in tumor microenvironment is associated with worse survival in triple-negative but not consistently with ER+/HER2- breast cancer.

Metabolic reprogramming to sustain immortality is a hallmark of cancer and glycolysis is an important way to attain this. Thus, we investigate the association of glycolysis and associated pathways in the survival of breast cancer. A total of 5,176 breast cancer patients from multiple independent cohorts were analyzed. We determined the glycolytic signaling score by the degree of enrichment by Gene Set Variant Analysis and the median was used to divide each cohort into high vs low score groups. Glycolysis high breast cancer significantly enriched the hallmark cell proliferation-related gene sets (E2F targets, G2M checkpoint, and MYC targets v1 and v2) and was associated with high MKI67 expression. In all cohorts, triple-negative breast cancer (TNBC) was associated with the highest glycolysis score. It was found that in TNBC, glycolysis high breast cancer was associated with worse survival but in ER-positive/HER2-negative breast cancer this was not observed consistently. The glycolysis high TNBC enriched multiple pro-cancerous gene sets and was infiltrated with a low level of B-cells and anti-cancerous immune cells, and significantly associated with a decreased level of cytolytic activity. It was also observed that the glycolysis was higher in the metastatic sites than in the primary breast cancer and the survival was not affected by the metastatic sites. In conclusion, accelerated glycolysis is associated with cancer cell proliferation and worse survival in TNBC.

Effect of neighborhood deprivation index on breast cancer survival in the United States.

PURPOSE: To analyze the association between the Neighborhood Deprivation Index (NDI) and clinical outcomes of locoregional breast cancer (BC). METHODS: Surveillance, Epidemiology and End Results (SEER) database is queried to evaluate overall survival (OS) and disease-specific survival (DSS) of early- stage BC patients diagnosed between 2010 and 2016. Cox multivariate regression was performed to measure the association between NDI (Quintiles corresponding to most deprivation (Q1), above average deprivation (Q2), average deprivation (Q3), below average deprivation (Q4), least deprivation (Q5)) and OS/DSS. RESULTS: Of the 88,572 locoregional BC patients, 27.4% (n = 24,307) were in the Q1 quintile, 26.5% (n = 23,447) were in the Q3 quintile, 17% (n = 15,035) were in the Q2 quintile, 13.5% (n = 11,945) were in the Q4 quintile, and 15.6% (n = 13,838) were in the Q5 quintile. There was a predominance of racial minorities in the Q1 and Q2 quintiles with Black women being 13-15% and Hispanic women being 15% compared to only 8% Black women and 6% Hispanic women in the Q5 quintile (p < 0.001). In multivariate analysis, in the overall cohort, those who live in Q2 and Q1 quintile have inferior OS and DSS compared to those who live in Q5 quintile (OS:- Q2: Hazard Ratio (HR) 1.28, Q1: HR 1.2; DSS:- Q2: HR 1.33, Q1: HR 1.25, all p < 0.001). CONCLUSION: Locoregional BC patients from areas with worse NDI have poor OS and DSS. Investments to improve the socioeconomic status of areas with high deprivation may help to reduce healthcare disparities and improve breast cancer outcomes.

The extracellular matrix in hepatocellular carcinoma: Mechanisms and therapeutic vulnerability.

The tumor microenvironment (TME) is influenced by a "disorganized" extracellular matrix (ECM) that sensitizes cancer cells toward mechanical stress, signaling, and structural alterations. In hepatocellular carcinoma (HCC), lack of knowledge about key ECM proteins driving the TME refractory to targeted therapies poses a barrier to the identification of new therapeutic targets. Herein, we discuss the contributions of various ECM components that impact hepatocytes and their surrounding support network during tumorigenesis. In addition, the underpinnings by which ECM proteins transduce mechanical signals to the liver TME are detailed. Finally, in view of the bidirectional feedback between the ECM, transformed hepatocytes, and immune cells, we highlight the potential role of the ECM disorganization process in shaping responses to immune checkpoint inhibitors and targeted therapies. Our comprehensive characterization of these ECM components may provide a roadmap for innovative therapeutic approaches to restrain HCC.

A review of treatment options in HER2-low breast cancer and proposed treatment sequencing algorithm.

The expansion of the spectrum of human epidermal growth factor receptor 2 (HER2)-status to HER2-low, defined as HER2 expression of 1+ by immunohistochemistry (IHC) or 2+ by IHC without gene amplification, has made a major impact in the field of oncology. The HER2-low expression has emerged as a targetable biomarker, and anti-HER2 antibody-drug conjugate trastuzumab deruxtecan has shown significant survival benefit in pretreated metastatic HER2-low breast cancer (BC). With these recent data, the treatment algorithm for hormone receptor-positive and triple-negative BC needs to be reconsidered, as approximately half of these BCs are HER2-low. Although there are different therapeutic agents for hormone receptor-positive and hormone receptor-negative HER2-low BCs, there is no consensus regarding the sequencing of these agents. In this article, the treatment options for HER2-low BC are enumerated and a treatment sequencing algorithm based on the current clinical evidence proposed.

E2F target score is associated with cell proliferation and survival of patients with hepatocellular carcinoma.

BACKGROUND: E2F target genes are essential for the cell cycle. A score that quantifies its activity is expected to reflect the aggressiveness and prognosis of hepatocellular carcinoma. METHODS: Cohorts of hepatocellular carcinoma patients (total n = 655) from The Cancer Genome Atlas, GSE89377, GSE76427, and GSE6764 were analyzed. The cohorts were divided into high versus low by the median. RESULTS: All the Hallmark cell proliferation-related gene sets were consistently enriched in hepatocellular carcinoma with high E2F targets score, and E2F score was associated with grade, tumor size, American Joint Committee on Cancer staging, proliferation score, and MKI67 expression, as well as with less abundance of hepatocytes and stromal cells. E2F targets enriched DNA repair, mTORC1 signaling, glycolysis, and unfolded protein response gene sets and were significantly associated with the higher intratumoral genomic heterogeneity, homologous recombination deficiency, and progression of hepatocellular carcinoma. On the other hand, there was no relationship between E2F targets and mutation rates or neoantigens. High E2F hepatocellular carcinoma did not enrich any of the immune-response-related gene sets but was associated with high infiltration of Th1, Th2 cells, and M2 macrophage; however, there was no difference in cytolytic activity. In both early (I and II) and late (III and IV) stages of hepatocellular carcinoma, a high E2F score was associated with worse survival and was an independent prognostic factor for overall and disease-specific survival in patients with hepatocellular carcinoma. CONCLUSION: The E2F target score, associated with cancer aggressiveness and worse survival, could be used as a prognostic biomarker in patients with hepatocellular carcinoma.

Effect of Neighborhood Deprivation Index on Breast Cancer Survival in the United States.

Purpose To analyze the association between the Neighborhood Deprivation Index (NDI) and clinical outcomes of early-stage breast cancer (BC). Methods Surveillance, Epidemiology and End Results (SEER) database is queried to evaluate overall survival (OS) and disease-specific survival (DSS) of early- stage BC patients diagnosed between 2010-2016. Cox multivariate regression was performed to measure the association between NDI (Quintiles corresponding to most deprivation (Q1), above average deprivation (Q2), average deprivation (Q3), below average deprivation (Q4), least deprivation (Q5)) and OS/DSS. Results Of the 88,572 early-stage BC patients, 27.4% (n = 24,307) were in the Q1 quintile, 26.5% (n = 23,447) were in the Q3 quintile, 17% (n = 15,035) were in the Q2 quintile, 13.5% (n = 11,945) were in the Q4 quintile, and 15.6% (n = 13,838) were in the Q5 quintile. There was a predominance of racial minorities in the Q1 and Q2 quintiles with Black women being 13-15% and Hispanic women being 15% compared to only 8% Black women and 6% Hispanic women in the Q5 quintile (p < 0.001). In multivariate analysis, in the overall cohort, those who live in Q2 and Q1 quintile have inferior OS and DSS compared to those who live in Q5 quintile (OS:- Q2: Hazard Ratio (HR) 1.28, Q1: HR 1.2; DSS:- Q2: HR 1.33, Q1: HR 1.25, all p < 0.001). Conclusion Early-stage BC patients from areas with worse NDI have poor OS and DSS. Investments to improve the socioeconomic status of areas with high deprivation may help to reduce healthcare disparities and improve breast cancer outcomes.

Impact of Environmental Temperature on the Pathological Complete Response and Survival Outcomes of Breast Cancer: A NCDB and SEER study.

Background: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate with an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates have higher odds of achieving pathologic complete response (pCR) and better survival outcomes than patients living in colder climates. Methods: A retrospective population-based analysis was conducted on Stage I-III breast cancer patients utilizing data from National Cancer Database (NCDB) from 2010-2018 with 892,092 patients and Surveillance, Epidemiology and End Results (SEER) from 1996-2017 with 270,496 patients. The average annual temperature (AAT) was calculated based on data from the National Centers for Environmental Information. Results: In the SEER cohort, patients residing at AAT ≥47.5°F had a 16% higher overall survival (OS) (HR 0.84, 95% CI 0.81-0.88, p <0.001) and 15% higher disease specific survival (DSS) (HR 0.85, 95% CI 0.80 - 0.90; p <0.001). Similarly, 4% higher OS (HR 0.96, 95% CI 0.95-0.97, p <0.001) and DSS (HR 0.96, 95% CI 0.94-0.97, p <0.001) was noted with every 5°F increment in AAT. In the NCDB cohort, patients in regions with AAT ≥ 60.9°F had 9% greater odds of achieving a pCR, odds ratio (OR 1.09, 95% CI 1.05, 1.13, p <0.001) and a 5% higher OS (HR 0.95, 95% CI 0.93 - 0.97, p<0.001). Conclusions: Higher environmental temperatures are associated with significantly better OS and DSS, as well as higher odds of achieving pCR in these patients. Future research is warranted to confirm this observation using large datasets, to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

Management of immune-mediated toxicities and their implications in the outcomes of advanced kidney cancer.

Plain language summary Targeted immunotherapy refers to a new class of drugs that boost the body's immune system to fight against cancer. Studies have shown that immunotherapy increases the survival of kidney cancer patients, but it has certain side effects that can affect any organ in the body, including the heart, lungs, skin, bowel and thyroid. Most side effects can be managed with drugs that can suppress the immune system, such as steroids; however, some side effects can be fatal if not diagnosed in a timely manner. It is vital to have a proper understanding of the side effects of immunotherapy drugs when making decisions about treatment for kidney cancer.

Targeted immunotherapy refers to a new class of drugs that boost the body's immune system to fight against cancer. Studies have shown that immunotherapy increases the survival of kidney cancer patients, but it has certain side effects that can affect any organ in the body, including the heart, lungs, skin, bowel and thyroid. Most side effects can be managed with drugs that can suppress the immune system, such as steroids; however, some side effects can be fatal if not diagnosed in a timely manner. It is vital to have a proper understanding of the side effects of immunotherapy drugs when making decisions about treatment for kidney cancer.

Immunotherapy in malignant peritoneal mesothelioma (Review).

Over the last decade, there has been a movement in cancer treatment away from cytotoxic therapies toward strategies that enhance the immune system against cancer. Immune checkpoint inhibitors (ICIs) have been incorporated into the treatment regimens for patients with various solid tumors. Mesothelioma trials revealed encouraging efficacy; however, patients with peritoneal mesothelioma are usually excluded, slowing the progress of improving the treatment of this aggressive cancer and compelling oncologist to rely on retrospective studies despite their flaws and limitations. Currently, there is no consensus on the role of ICIs in the treatment of malignant peritoneal mesothelioma (MPeM). The present review discusses data from clinical studies that examined immunotherapy in MPeM and evaluates what is known about the relevance of the tumor microenvironment and clinically validated biomarkers for ICIs efficacy. Furthermore, a proposed strategy for utilizing immunotherapy in treating MPeM is discussed.

Facing the conundrum: which first-line therapy should be used for patients with metastatic triple-negative breast cancer carrying germline BRCA mutation?

Pembrolizumab combined with chemotherapy has been established as the preferred first-line therapy for treating metastatic triple-negative breast cancer (mTNBC) with programmed cell death ligand-1 (PD-L1)-positive disease since its approval for that indication. However, the optimal sequencing of therapy remains an unanswered question for a subset of mTNBC patients who harbor germline breast cancer gene 1/2 (BRCA1/2; gBRCA1/2) mutation. This article aims to offer insights into the optimal therapy sequencing for mTNBC patients with gBRCA1/2 mutations and its impact on clinical decision-making. The perspective offered is based on the best currently available data and propose a practical algorithm to guide the management of this subgroup in the frontline setting.