Outcomes After Curative Metastasectomy for Patients with Malignant Melanoma: A Systematic Review and Meta-analysis.

BACKGROUND: Evidence on the role of curative metastasectomy (CM) for malignant melanoma (MM) patients is limited, especially in the current era of effective systemic therapy. A systematic review and meta-analysis were performed to ascertain the role of CM compared with incomplete or nonsurgical treatment for patients with MM. METHODS: Medline, Embase, and Scopus databases were searched for studies investigating CM for MM until 30 September 2021. The review included studies that compared CM with no-CM and reported a hazard ratio (HR) after multivariate analysis for overall survival. A random-effects model with inverse variance was used to calculate pooled HR. The Newcastle-Ottawa Scale was used to assess the risk of bias. RESULTS: For the final analysis, 40 studies including 31,282 patients (CM, 9958; no-CM, 21,324) were considered. Compared with no-CM, CM was associated with a significantly lower risk of death (HR, 0.42; 95% confidence interval [CI], 0.38-0.47; p < 0.00001). Subgroup analysis showed that the outcome was independent of the effective systemic therapy and anatomic location of metastasis. An unfavorable prognosis was associated with advancing age, elevated lactate dehydrogenase (LDH), male gender, prior stage 3 disease, multiple metastases and organ sites, and shorter disease-free interval. CONCLUSION: Curative metastasectomy for MM is associated with a lower risk of death than non-curative treatment methods. Selection bias and underlying weakness of studies reduced the strength of evidence in this review. However, CM should be a part of the multimodality treatment of MM whenever technically feasible.

Evaluation of Eighth AJCC TNM Sage for Lung Cancer NSCLC: A Meta-analysis.

INTRODUCTION: The AJCC 8th edition TNM classification for lung cancer was released in 2017. This edition has made major changes in many tumor descriptors including sites of metastasis. The new staging system has been a subject of multiple validation studies, of which many have had mixed results. The present study is designed to critically evaluate the results of these external validation studies. METHODS: A metaanalysis of these external validation studies was performed to critically evaluate the new staging system. Out of 12 studies, 8 were found to fulfill the eligibility criteria, with 654,185 patients being included in the analysis. Hazard ratios (HRs) and associated 95% confidence intervals (CI) extracted from these studies were utilized for analysis. The primary outcomes were survival discrimination and prognostic ability of the 8th edition compared with the 7th edition. RESULTS: The HRs for the 8th edition staging system were 1.41 in IB, 1.64 in IIA, 1.24 in IIB, 1.95 in IIIA, 3.96 in IIIB, and 4.82 in IIIC compared with IA. The new edition fared better than the 7th edition in survival discrimination in all but stage IIA and IIB. The C-index of the 8th and 7th editions was 0.690 and 0.688, respectively, suggesting almost similar prognostic values. CONCLUSIONS: This study shows that the survival discrimination of the 8th edition fared better than the 7th edition in all but stage IIA and IIB. The prognostic value of the two staging systems is similar, with no added advantage of the new edition.

Left Upper Lobectomy for Lung Cancer as a Risk Factor for Cerebral Infarction: A Systematic Review and Meta-Analysis.

BACKGROUND: There is limited evidence on the role of the type of lobectomy after primary lung cancer with postoperative cerebral infarction (CI). The purpose of this review was to evaluate the role of left upper lobectomy (LUL) in pulmonary vein thrombosis (PVT) and eventual CI. METHODS: A search was performed on MEDLINE, Embase, and Web of Science from inception to January 2021. Prospective and retrospective cohort studies investigating the association between types of lobectomies for primary lung cancer with PVT and/or CI were included. Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. A random-effect model meta-analysis was utilized if significant heterogeneity was observed. RESULTS: Twelve studies, including 5266 patients were included. The majority of studies were having a low risk of bias. LUL was associated with higher likelihood of CI (ORfixed 6.27, 95% Confidence Interval (CI) 3.12-12.56; p < 0.00001) and PVT (ORfixed 13.46, 95% CI 5.97-30.33; p < 0.00001) as compared to other lobectomies. Sensitivity analysis showed an independent role of LUL without underlying PVT in CI (ORfixed 2.44, 95% CI 1.25-4.74; p = 0.009). Male and diabetic patients were at a higher risk, while Video-Assisted Thoracoscopic Surgery (VATS) was protective from CI. CONCLUSION: The results of this review indicate that LUL after lung cancer is an independent risk factor for developing CI without underlying PVT. In addition, the risk of CI increases significantly when PVT develops after LUL. LUL is also a risk factor for PVT. A more frequent follow-up may be beneficial in lung cancer patients after LUL, especially in those with diabetes or undergoing adjuvant systemic therapy.

SMARCA4 alterations in non-small cell lung cancer: a systematic review and meta-analysis.

AIMS: A mutation in the SMARCA4 gene which encodes BRG1, a common catalytic subunit of switch/sucrose non-fermentable chromatin-remodelling complexes, plays a vital role in carcinogenesis. SMARCA4 mutations are present in approximately 10% of non-small cell lung cancers (NSCLC), making it a crucial gene in NSCLC, but with varying prognostic associations. To explore this, we conducted a systematic review and meta-analysis on the prognostic significance of SMARCA4 mutations in NSCLC. METHODS: Electronic database search was performed from inception to December 2022. Study characteristics and prognostic data were extracted from each eligible study. Depending on heterogeneity, pooled HR and 95% CI were derived using the random-effects or fixed-effects models. RESULTS: 8 studies (11 cohorts) enrolling 8371 patients were eligible for inclusion. Data on overall survival (OS) and progression-free survival (PFS) were available from 8 (10 cohorts) and 1 (3 cohorts) studies, respectively. Comparing SMARCA4-mutated NSCLC patients with SMARCA4-wild-type NSCLC patients, the summary HRs for OS and PFS were 1.49 (95% CI 1.18 to 1.87; I2=84%) and 3.97 (95% CI 1.32 to 11.92; I2=79%), respectively. The results from the trim-and-fill method for publication bias and sensitivity analysis were inconsistent with the primary analyses. Three studies reported NSCLC prognosis for category I and II mutations separately; category I was significantly associated with OS. CONCLUSION: Our findings suggest that SMARCA4 mutation negatively affects NSCLC OS and PFS. The prognostic effects of SMARCA4-co-occurring mutations and the predictive role of SMARCA4 mutation status in immunotherapy require further exploration.

Clinical significance of combined tumour-infiltrating lymphocytes and microsatellite instability status in colorectal cancer: a systematic review and network meta-analysis.

BACKGROUND: Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating the combination of TIL and MSI status identified distinct colorectal cancer subtypes with unique prognostic associations. However, these studies were often limited by sample size, particularly for MSI-high (MSI-H) tumours, and there is no comprehensive summary of the available evidence. We aimed to review the literature to compare the survival outcomes associated with the subtypes derived from the integrated MSI-TIL classification in patients with colorectal cancer. METHODS: In this systematic review and network meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library without language restrictions, for articles published between Jan 1, 1990, and March 13, 2024. Patient cohorts comparing different combinations of TIL (high or low) and MSI status (MSI or microsatellite stable [MSS]) in patients with surgically resected colorectal cancer were included. Studies were excluded if they focused on neoadjuvant therapy or on other immune markers such as B cells or macrophages. Methodological quality assessment was done with the Newcastle-Ottawa scale; data appraisal and extraction was done independently by two reviewers. Summary estimates were extracted from published reports. The primary outcomes were overall survival, disease-free survival, and cancer-specific survival. A frequentist network meta-analysis was done to compare hazard ratios (HRs) and 95% CI for each outcome. The MSI-TIL subgroups were prognostically ranked based on P-score, bias, magnitude, and precision of associations with each outcome. The protocol is registered with PROSPERO (CRD42023461108). FINDINGS: Of 302 studies initially identified, 21 studies (comprising 14 028 patients) were included in the systematic review and 19 (13 029 patients) in the meta-analysis. Nine studies were identified with a low risk of bias and the remaining ten had a moderate risk of bias. The MSI-TIL-high (MSI-TIL-H) subtype exhibited longer overall survival (HR 0·45, 95% CI 0·34-0·61; I2=77·7%), disease-free survival (0·43, 0·32-0·58; I2=61·6%), and cancer-specific survival (0·53, 0·43-0·66; I2=0%), followed by the MSS-TIL-H subtype for overall survival (HR 0·53, 0·41-0·69; I2=77·7%), disease-free survival (0·52, 0·41-0·64; I2=61·6%), and cancer-specific survival (0·55, 0·47-0·64; I2=0%) than did patients with MSS-TIL-low tumours (MSS-TIL-L). Patients with the MSI-TIL-L subtype had similar overall survival (0·88, 0·66-1·18; I2=77·7%) and disease-free survival (0·93, 0·69-1·26; I2=61·6%), but a modestly longer cancer-specific survival (0·72, 0·57-0·90; I2=0%) than did the MSS-TIL-L subtype. Results from the direct and indirect evidence were strongly congruous. INTERPRETATION: The findings from this network meta-analysis suggest that better survival was only observed among patients with TIL-H colorectal cancer, regardless of MSI or MSS status. The integrated MSI-TIL classification should be further explored as a predictive tool for clinical decision-making in early-stage colorectal cancer. FUNDING: German Research Council (HO 5117/2-2).

Large-scale external validation and meta-analysis of gene methylation biomarkers in tumor tissue for colorectal cancer prognosis.

BACKGROUND: DNA methylation biomarkers in colorectal cancer (CRC) tissue hold potential as prognostic indicators. However, individual studies have yielded heterogeneous results, and external validation is largely absent. We conducted a comprehensive external validation and meta-analysis of previously suggested gene methylation biomarkers for CRC prognosis. METHODS: We performed a systematic search to identify relevant studies investigating gene methylation biomarkers for CRC prognosis until March 2024. Our external validation cohort with long-term follow-up included 2303 patients with CRC from 22 hospitals in southwest Germany. We used Cox regression analyses to assess associations between previously suggested gene methylation biomarkers and prognosis, adjusting for clinical variables. We calculated pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) using random-effects models. FINDINGS: Of 151 single gene and 29 multiple gene methylation biomarkers identified from 121 studies, 37 single gene and seven multiple gene biomarkers were significantly associated with CRC prognosis after adjustment for clinical variables. Moreover, the directions of these associations with prognosis remained consistent between the original studies and our validation analyses. Seven single biomarkers and two multi-biomarker signatures were significantly associated with CRC prognosis in the meta-analysis, with a relatively strong level of evidence for CDKN2A, WNT5A, MLH1, and EVL. INTERPRETATION: In a comprehensive evaluation of the so far identified gene methylation biomarkers for CRC prognosis, we identified candidates with potential clinical relevance for further investigation. FUNDING: The German Research Council, the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, the German Federal Ministry of Education and Research.

PD-1/PD-L1 inhibitors in treatment-naïve, advanced non-small cell lung cancer patients with < 1% PD-L1 expression: a meta-analysis of randomized controlled trials.

BACKGROUND: PD-1/PD-L1 inhibitors prolong survival in treatment-naïve, locally advanced, and metastatic non-small cell lung cancer (NSCLC) with positive PD-L1 expression (> 1%/ > 50%). Recent evidence has suggested that tumors with < 1% PD-L1 expression may also be predictive of PD-1/PD-L1 inhibiting agents. METHODS: Systematic review and meta-analysis were conducted of randomized controlled trials (RCTs) evaluating PD-1/PD-L1 inhibitors that have assessed tumors with < 1% PD-L1 expression (negative PD-L1 expression). PD-1/PD-L1 inhibitors-chemotherapy combinations (PC) were compared with histology-selected chemotherapy with respect to overall survival (OS) and progression-free survival (PFS). RESULTS: Twelve RCTs comprising 5410 participants (PD-1/PD-L1 inhibitors-chemotherapy: 3051; chemotherapy: 2359) met the inclusion criteria. Tumors with PD-L1 expression < 1% were evident in 38.9% of the pooled study population. A significant OS [hazard ratio (HR) 0.71 95% confidence interval (CI) 0.63-0.80, p < 0.00001] and PFS [HR 0.65 95% CI 0.58-0.72, p < 0.00001] benefit of PC was evident in tumors with negative PD-L1 expression. PD-1/PD-L1 inhibitors-chemotherapy combinations were more likely to achieve an objective response than chemotherapy [odds ratio, 1.86; 95% CI, 1.46-2.38, p < 0.00001]. Histologic subtypes and diagnostic assays did not modify the OS and PFS treatment effects for PC compared to chemotherapy. CONCLUSION: Tumors harboring < 1% PD-L1 expression are likely to benefit from PD-1/PD-L1 inhibitor-chemotherapy regimens in advanced NSCLC.

Determinants of humoral immune response to SARS-CoV-2 vaccines in solid cancer patients: A systematic review and meta-analysis.

IMPORTANCE: Solid cancer patients following SARS-CoV-2 vaccination are likely to have a lower seroconversion rate than healthy adults. Seroconversion between those with and without cancer is likely to vary moderately or to be restricted to specific subgroups. Therefore, we sought to conduct a systematic review and meta-analysis to identify risk factors for diminished humoral immune responses in solid cancer patients. METHODS: MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were used to search literature through May 1, 2022. Prospective or retrospective studies comparing responders with non-responders against SARS-CoV-2 spike (S) protein receptor-binding domain (RBD) following COVID-19 vaccination were included. Pooled Odds Ratios (pORs) with 95% CIs for binary variables and differences in means (with SDs) for continuous variables were calculated to determine the pooled effect estimates of risk factors for poor antibody response. RESULTS: Fifteen studies enrolling 3593 patients were included in the analysis. Seroconversion was seen in 84% of the pooled study population. Male gender, age >65 years, and recent chemotherapy were all factors in a poor immune response. Patients under follow-up, those who received immunotherapy or targeted therapy, were more likely to be seropositive. Cancer subtypes, vaccine types, and timing of antibody testing from the 2nd dose of vaccine did not correlate with seroconversion. CONCLUSION: Cytotoxic therapy for solid cancer may portend poor immune response following 2 doses of COVID-19 vaccines suggesting a need for booster doses in these patients. Immunotherapy and targeted therapy are likely to be associated with seropositive status, and thus can be considered as an alternative to cytotoxic agents in cases where both therapies are equally efficacious.

The prognostic value of TMB in early-stage non-small cell lung cancer: a systematic review and meta-analysis.

Background: Tumor mutation burden (TMB) has been validated as a predictive biomarker for immunotherapy response and survival in numerous cancer types. Limited data is available on the inherent prognostic role of TMB in early-stage tumors. Objective: To evaluate the prognostic role of TMB in early-stage, resected non-small cell lung cancer (NSCLC). Design: Systematic review and meta-analysis of pertinent prospective and retrospective studies. Data sources and methods: Publication search was performed in PubMed, Embase, Cochrane Library, and Web of Science databases. Based on the level of heterogeneity, a random- or fixed-effects model was used to calculate pooled effects of hazard ratio (HR) for overall survival (OS) and disease-free survival (DFS). The source of heterogeneity was investigated using sensitivity analysis, subgroup analysis, and publication bias assessment. Results: Ten studies comprising 2520 patients were included in this analysis. There was no statistically significant difference in OS (HR, 1.18, 95% CI, 0.70, 1.33; p 0.53, I2 = 80%; phet < 0.0001) and DFS (HR, 1.18, 95% CI, 0.91, 1.52; p = 0.53, I2 = 75%; phet = 0.0001) between the high-TMB and low-TMB group. Subgroup analyses indicated that East Asian ethnicity, and TMB detected using whole exome sequencing, and studies with <100 patients had poor DFS in the high-TMB group. Conclusion: The inherent prognostic role of TMB is limited in early-stage NSCLC. Ethnic differences in mutation burden must be considered while designing future trials on neoadjuvant immunotherapy. Further research in the harmonization and standardization of panel-based TMB is essential for its widespread clinical utility.Registration: CRD42023392846.

Prognostic Role of KRAS G12C Mutation in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

KRAS G12C mutation (mKRAS G12C) is the most frequent KRAS point mutation in non-small cell lung cancer (NSCLC) and has been proven to be a predictive biomarker for direct KRAS G12C inhibitors in advanced solid cancers. We sought to determine the prognostic significance of mKRAS G12C in patients with NSCLC using the meta-analytic approach. A protocol is registered at the International Prospective Register for systematic reviews (CRD42022345868). PubMed, EMBASE, The Cochrane Library, and Clinicaltrials.gov.in were searched for prospective or retrospective studies reporting survival data for tumors with mKRAS G12C compared with either other KRAS mutations or wild-type KRAS (KRAS-WT). The hazard ratios (HRs) for overall survival (OS) or Disease-free survival (DFS) of tumors were pooled according to fixed or random-effects models. Sixteen studies enrolling 10,153 participants were included in the final analysis. mKRAS G12C tumors had poor OS [HR, 1.42; 95% CI, 1.10-1.84, p = 0.007] but similar DFS [HR 2.36, 95% CI 0.64-8.16] compared to KRAS-WT tumors. Compared to other KRAS mutations, mKRAS G12C tumors had poor DFS [HR, 1.49; 95% CI, 1.07-2.09, p < 0.0001] but similar OS [HR, 1.03; 95% CI, 0.84-1.26]. Compared to other KRAS mutations, high PD-L1 expression (>50%) [OR 1.37 95% CI 1.11-1.70, p = 0.004] was associated with mKRAS G12C tumors. mKRAS G12C is a promising prognostic factor for patients with NSCLC, negatively impacting survival. Prevailing significant heterogeneity and selection bias might reduce the validity of these findings. Concomitant high PD-L1 expression in these tumors opens doors for exciting therapeutic potential.

Circulating Tumor Cells as a Predictive Biomarker in Resectable Lung Cancer: A Systematic Review and Meta-Analysis.

Background: In breast, prostate, and other epithelial tumors, circulating tumor cells (CTC) in peripheral blood may predict survival. Our study evaluated the prognostic significance of baseline and postoperative CTC in patients with early non-small cell lung cancer (NSCLC) through a meta-analytic approach. Methods: Prospective studies comparing survival outcomes between positive (CTC+) and negative CTC (CTC−) patients were systematically searched. Primary outcomes were overall (OS) and disease-free survival (DFS) with hazard ratio (HR) and 95% confidence interval (CI) as the effect measure. Pooled HR determined the prognostic role under a fixed-effect or random-effect model depending on heterogeneity. Results: Eighteen studies with 1321 patients were eligible. CTC+ patients were associated with an increased risk of death (HR 3.53, 95% CI 2.51−4.95; p < 0.00001) and relapse (HR 2.97, 95% CI 2.08−4.22; p < 0.00001). Subgroup analysis results were consistent in different subsets, including time points (baseline and postoperative) and sources (peripheral and pulmonary vein) of blood collection, detection methods (label-free, label-dependent, and RT-PCR), and follow-up duration. Conclusion: Our meta-analysis revealed that CTC is a promising predictive biomarker for stratifying survival outcomes in patients with early-stage NSCLC. However, future studies are required to validate these findings and standardize detection methods.

Vulvar cancer: surgical management and survival trends in a low resource setting.

BACKGROUND: This study aims to analyze risk factors, clinical profiles, treatment protocols, and disease outcomes in histologically proven resectable vulvar cancer (VC) patients according to tumor stage. This is a retrospective analysis of a prospectively collected database of 20 VC patients from May 2014 to June 2019. RESULTS: The mean age of VC diagnosis was 55 years, with a range of 38-84 years. The incidence was four cases per year. The disease incidence was significantly more in post-menopausal (65%) and multiparous (90%) women. According to FIGO staging of vulvar cancer, stages I, II, and III were assigned to 6, 1, and 11 patients respectively. Two patients suffered from stage IVa vulvar melanoma. All patients had undergone surgical interventions. Patients treated with only nonsurgical (chemotherapy/radiotherapy/chemo-radiotherapy) treatment modalities were excluded from the study. Fifteen patients were treated with wide local excision (WLE), bilateral inguinofemoral dissection (B/L IFLND), and primary repair. Four and one patients were treated with radical vulvectomy (RV) and modified radical vulvectomy (MRV) [with or without B/L IFLND and PLND] respectively. Reconstruction with V-Y gracilis myocutaneous and local rotation advancement V-Y fasciocutaneous flaps were done in two patients. Therapeutic groin nodal dissection was performed in 19 patients except in one patient who was treated by palliative radical vulvectomy. In the final histopathology reports, tumor size varies from 0.5 to 6.5 cm (mean 3.35 cm) with the predominance of squamous cell carcinoma (18 out of 20 patients). Only 10 out of 18 eligible patients received adjuvant treatment. Poor patient compliance has been one of the major reasons for adjuvant treatment attrition rate. Systemic and loco-regional metastasis occurred in 3 patients each arm respectively. Poor follow up of patients is the key limitation of our study. CONCLUSION: Vulvar cancer incidence was significantly high in post-menopausal and multiparous women. The most important prognostic factors were tumor stage and lymph node status. Oncological resection should be equated with functional outcome. The multidisciplinary team approach should be sought for this rare gynecological malignancy.