Treatment-related adverse events, including fatal toxicities, in patients with solid tumours receiving neoadjuvant and adjuvant immune checkpoint blockade: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Incorporating immune checkpoint blockade into perioperative cancer therapy has improved clinical outcomes. However, the safety of immune checkpoint blockade needs better evaluation, given the chances of more prolonged disease-free survival. We aimed to assess how adding immune checkpoint blockade to perioperative therapy affects treatment-related adverse events. METHODS: For this systematic review and meta-analysis, we searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library from database inception until Aug 8, 2023, for randomised controlled trials that assessed the addition of immune checkpoint blockade to neoadjuvant or adjuvant therapy for cancer, reported treatment-related deaths, and had a design in which the experimental group assessed immune checkpoint blockade in combination with the therapy used in the control group. Meta-analysis was done to pool odds ratios (ORs) of treatment-related deaths, any grade and grade 3-4 treatment-related adverse events, serious adverse events, and adverse events leading to treatment discontinuation. The protocol is registered with PROSPERO, CRD42022343741. FINDINGS: 28 randomised controlled trials with 16 976 patients were included. The addition of immune checkpoint blockade was not significantly associated with increased treatment-related deaths (OR 1·76, 95% CI 0·95-3·25; p=0·073), consistent across immune checkpoint blockade subtype (I2=0%). 40 fatal toxicities were identified across 9864 patients treated with immune checkpoint blockade, with pneumonitis being the most common (six [15·0%]); 13 fatal toxicities occurred among 7112 patients who were not treated with immune checkpoint blockade. The addition of immune checkpoint blockade increased the incidence of grade 3-4 treatment-related adverse events (OR 2·73, 95% CI 1·98-3·76; p<0·0001), adverse events leading to treatment discontinuation (3·67, 2·45-5·51; p<0·0001), and treatment-related adverse events of any grade (2·60 [1·88-3·61], p<0·0001). The immune checkpoint blockade versus placebo design primarily used as adjuvant therapy was associated with increased incidence of treatment-related deaths (4·02, 1·04-15·63; p=0·044) and grade 3-4 adverse events (5·31, 3·08-9·15; p<0·0001), whereas the addition of immune checkpoint blockade in the neoadjuvant setting was not associated with increased incidence of treatment-related death (1·11, 95% CI 0·38-3·29; p=0·84) or grade 3-4 adverse events (1·17, 0·90-1·51; p=0·23). INTERPRETATION: The addition of immune checkpoint blockade to perioperative therapy was associated with an increase in grade 3-4 treatment-related adverse events and adverse events leading to treatment discontinuation. These findings provide safety insights for further clinical trials assessing neoadjuvant or adjuvant immune checkpoint blockade therapy. Clinicians should closely monitor patients for treatment-related adverse events to prevent treatment discontinuations and morbidity from these therapies in earlier-stage settings. FUNDING: None.

First-line therapy for elderly patients with advanced renal cell carcinoma in the immuno-oncology era: a network meta-analysis.

BACKGROUND: Tyrosine kinase inhibitors (TKI) or immune checkpoint blockade (ICB), either alone or in combination, confers a significant overall survival (OS) benefit for metastatic RCC in the first-line setting. However, guidance for optimal treatment selection in elderly patients remains limited. METHODS: A database search was performed to identify eligible randomized controlled trials (RCTs) evaluating first-line regimens for patients with advanced RCC older than 65 years old. The primary outcomes were progression-free survival (PFS) and OS. Indirect comparisons of available regimens were estimated using a random-effects network meta-analysis. RESULTS: A total of 14 and five RCTs were eligible for PFS and OS analyses. Compared with sunitinib, pembrolizumab plus axitinib (HR 0.68, 95% CI 0.48-0.97) and pembrolizumab plus lenvatinib (HR 0.61, 95% CI 0.4-0.94) were associated with improved OS. Pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and cabozantinib alone each showed improved PFS over sunitinib. Among these, pembrolizumab plus lenvatinib showed better PFS than pembrolizumab plus axitinib (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared to nivolumab plus cabozantinib (HR 0.63, 95% CI 0.39-1.03) and cabozantinib alone (HR 0.84, 95% CI 0.40-1.77). Network ranking showed pembrolizumab plus lenvatinib provided the favored OS and PFS benefit for elderly patients. CONCLUSIONS: The combination of ICB with TKI such as pembrolizumab plus lenvatinib needs to be considered over monotherapy in the elderly population, but further validation using real-world data or prospective trials is necessary to confirm the efficacy and safety of first-line regimens for the geriatric population with advanced RCC.

Incidence of hepatotoxicity associated with addition of immune checkpoint blockade to systemic solid tumor therapy: a meta-analysis of phase 3 randomized controlled trials.

Hepatotoxicity is a major immune-related adverse event that may become life-threatening. The impact of adding immune checkpoint blockade (ICB) to systemic therapy on the incidence of hepatotoxicity remains unknown. We performed a systematic review and meta-analysis to compare the incidence of hepatotoxicity among patients with cancer who received therapy with and without addition of ICB. PubMed, Embase, Web of Science, and Cochrane Library were searched to select phase 3 randomized controlled trials (RCTs) evaluating the effect of adding ICB to systemic therapy, placebo, or supportive care. The odds ratio (OR) of any grade and grade 3-5 hepatitis, elevations in aspartate aminotransferase (AST), and alanine aminotransferase (ALT) was pooled for meta-analysis. 43 RCTs with 28,905 participants were analyzed. Addition of ICB increased the incidence of hepatitis (any grade: OR, 2.13, 95% confidence interval [CI] 1.52-2.97, grade 3-5: OR, 2.66, 95% CI 1.72-4.11), elevated AST (any grade: OR, 2.16, 95% CI 1.73-2.70, grade 3-5: OR, 2.72, 95% CI 1.86-3.99), and elevated ALT (any grade: OR, 2.01, 95% CI 1.59-2.54, grade 3-5: OR, 2.40, 95% CI 1.62-3.55). Subgroup analysis based on the ICB mechanism revealed no significant heterogeneity among each mechanism for hepatitis (any Grade: I2 = 11.1%, p for heterogeneity = 0.32, grade 3-5: I2 = 0%, p = 0.48). Adding ICB to systemic therapy increases the incidence of hepatotoxicity regardless of the mechanism of ICB. Hepatotoxicity is common and vigilant monitoring of liver function is required during ICB therapy for patients with cancer.

[Traumatic Neuroma Mimicking Lymph Node Metastasis of Pancreatic Neuroendocrine Neoplasms Developed after Pancreatoduodenectomy-A Case Report].

A traumatic neuroma is a benign tumor consisting of a non-neoplastic growth of injured nerves as a result of trauma or surgery. It is rarely found in an abdominal cavity, but some reports showed that it occurred around the bile duct. We report a case of a 72-year-old man who underwent subtotal stomach-preserving pancreatoduodenectomy for pancreatic neuroendocrine neoplasms 4 years ago. An abdominal contrast-enhanced CT follow-up examination revealed a growing nodule on the dorsal surface of the portal vein. The lesion showed a mild increase in fluorodeoxyglucose uptake in FDG-PET⊘CT. A lymph node metastasis of pancreatic neuroendocrine neoplasms was suspected. Nodule resection was performed for purpose of diagnosis and treatment. The final pathological diagnosis was traumatic neuroma with no evidence of recurrence. Traumatic neuromas developed after pancreatoduodenectomy have not been reported. Postoperative masses around the bile ducts should also be considered traumatic neuromas.

Self-assessment of health status among lesbian, gay, and bisexual cancer survivors in the United States.

BACKGROUND: Research is lacking for understanding the health disparities in cancer survivorship in the lesbian, gay, and bisexual (LGB) population in the United States. Self-reported health status is used as a predictor of health disparities. METHODS: This secondary data analysis study used 2018 Behavioral Risk Factor Surveillance System data to analyze cancer survivorship characteristics by sexual orientation and sex through the use of logistic regressions. RESULTS: Overall, 17,656,329 US cancer survivors were included in this study after weighting, with percentage estimates of 1.52% for gays/lesbians and 1.41% for bisexuals. LGB participants were younger and more ethnically diverse. Significantly, bisexuals had current smoking (32.3% vs 13.6%) and binge drinking rates (17.1% vs 9.1%) twice those of heterosexuals; 16.6% of bisexuals versus 4.1% of heterosexuals reported no health insurance coverage (P < .0001). After adjustments for socioeconomic, health-related behavioral risk, and health care access factors, bisexual females reported poorer general health (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.31-1.36) as well as mental health (OR, 2.43; 95% CI, 2.39-2.46) than their heterosexual peers (P < .0001). Bisexual males were 5.14 times more likely to be told that they had depressive disorders than their heterosexual counterparts (95% CI, 5.05-5.23), whereas bisexual females were 3.23 times more likely for the same outcome (95% CI, 3.18-3.28). All LGB groups reported significantly more inadequate sleep than their heterosexual counterparts (especially lesbians: OR, 2.14; 95% CI, 2.10-2.18). CONCLUSIONS: This study indicates that LGB cancer survivors have worse survivorship than their heterosexual peers with heterogeneity in subgroups. Future studies should use larger sample sizes, further investigate disparities, and promote survivorship in LGB populations. LAY SUMMARY: It has been observed that lesbian, gay, and bisexual (LGB) cancer survivors may face challenges in cancer survivorship that are not as prevalent in the heterosexual community. This cross-sectional study has found that LGB cancer survivors, especially bisexuals, have overall poorer physical and mental health, are more likely to be told that they have depressive disorders, and have worse sleep quality in comparison with their heterosexual counterparts. These results also differ by sex, and this can provide rationales for future studies and guide interventions to relocate resources to better promote equality.

Clinical features and outcomes of metastatic pheochromocytoma treated by cytotoxic chemotherapy.

Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983-2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10-42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21-74%) and median overall survival was 4.4 years (95% CI, 2.4 years-not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.

Tumor growth rate as a prognostic factor for metastatic or recurrent adenoid cystic carcinoma of the head and neck patients treated with carboplatin plus paclitaxel.

PURPOSE: Large prospective studies of chemotherapy for metastatic or recurrent adenoid cystic carcinoma (ACC) of the head and neck are lacking due to the rarity of ACC. The aim of this study is to evaluate the efficacy of carboplatin plus paclitaxel toward ACC and perform an exploratory investigation of the prognostic factors to investigate the optimal strategy for metastatic or recurrent ACC. METHODS: We retrospectively analyzed recurrent or metastatic ACC patients treated with carboplatin plus paclitaxel between April 2007 and September 2019 in our hospital. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated, and an exploratory analysis of the prognostic factors was conducted. RESULTS: A total of 26 ACC patients were enrolled. ORR and DCR were 11.5 and 76.9%; the median PFS and OS were 8.1 and 22.3 months, respectively. From the results of the multivariate analysis, higher (≥ 6%/month) tumor growth rate (TGR) was associated with worse PFS (hazard ratio [HR] 7.00, 95% CI 1.34-36.53, p = 0.02) and OS (HR 29.33, 95% CI 3.38-254.80, p < 0.01). The median PFS (10.6 vs. 6.6 months, log-rank p < 0.05) and OS (48.5 vs. 16.9 months, log-rank p < 0.01) were significantly shorter in patients with higher TGR. CONCLUSIONS: Carboplatin plus paclitaxel showed modest efficacy for recurrent or metastatic ACC patients. Watchful waiting may be optimal for ACC patients with lower TGR. Systemic chemotherapy should be considered when TGR increases during active surveillance.

Synthesis of Oligodiacetylene Derivatives from Flexible Porous Coordination Frameworks.

Oligodiacetylenes (ODAs) with alternating ene-yne conjugated structure are significant materials for optical and electronic properties. Due to the low solubility of ODAs in common solvents, the synthetic approaches are limited. Here we disclose a new synthetic approach of ODAs without a side alkyl chain using a porous coordination polymer (PCP) as a sacrificial template. 1,2-Bis(4-pyridyl)butadiyne, which works as a monomer, was embedded in the flexible framework of the PCP, and ODAs were synthesized via utilization of the anisotropic thermal expansion of the PCP crystal. The oligomeric state of ODAs depends on the metal ion and coligand of the precursor.

Combinatory use of central venous catheter and ethanol lock for a patient with X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome.

X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome is a disorder associated with severe intellectual disability and intractable epilepsy. Intractable diarrhea is also observed frequently. At present, pathogenic background of diarrhea is not revealed and the essential treatment has not yet established. We encountered a patient with XLAG, who showed intractable diarrhea. Lactose removed hypoallergenic milk and somatostatin analogs were ineffective. For enteral nutrition was impossible, a tunneled central venous catheters was inserted to obtain a sustained parenteral nutrition management. However, catheter-related bloodstream infections were repeated in a short period of time. Thus, we introduced ethanol lock therapy for infectious disease prevention purposes. As a result, we succeeded continuous treatments with preserving the catheter.

Formation of Foam-like Microstructural Carbon Material by Carbonization of Porous Coordination Polymers through a Ligand-Assisted Foaming Process.

Porous carbon material with a foam-like microstructure has been synthesized by direct carbonization of porous coordination polymer (PCP). In situ generation of foaming agents by chemical reactions of ligands in PCP during carbonization provides a simple way to create lightweight carbon material with a foam-like microstructure. Among several substituents investigated, the nitro group has been shown to be the key to obtain the unique foam-like microstructure, which is due to the fast kinetics of gas evolution during carbonization. Foam-like microstructural carbon materials showed higher pore volume and specific capacitance compared to a microporous carbon.

Evolution of Precision Oncology, Personalized Medicine, and Molecular Tumor Boards.

With multiple molecular targeted therapies available for patients with cancer that correspond to a specific genetic alteration, the selection of the best treatment is essential to ensure therapeutic efficacy. Molecular tumor boards (MTBs) play a key role in this process to deliver personalized medicine to patients with cancer in a multidisciplinary manner. Historically, personalized medicine has been offered to patients with advanced cancer, but the incorporation of molecular targeted therapies and immunotherapy into the perioperative setting requires clinicians to understand the role of the MTB. Evidence is accumulating to support feasibility and survival benefit in patients treated with matched therapy.

Endocrine adverse events in patients with cancer receiving perioperative immune checkpoint blockade: a meta-analysis of randomized controlled trials.

Background: Perioperative use of immune checkpoint blockade (ICB) improves survival in patients with early-stage cancer. Treatment-related adverse events (AEs), frequently involve the endocrine system which may increase perioperative complications and affect quality of life. Objective: We conducted a meta-analysis to elucidate the impact of adding ICB to conventional neoadjuvant/adjuvant therapy on the incidence of endocrine AEs. Design: A systematic review and meta-analysis of randomize-controlled trials (RCTs). Data sources and methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed for RCTs comparing groups with and without the addition of ICB to conventional perioperative therapy in patients with cancer. Outcomes included all-grade and grade 3-5 thyroiditis, hyperthyroidism, hypothyroidism, adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, and hyperglycemia. The odds ratios (ORs) of all-grade and grade 3-5 endocrine were pooled using the random-effect model meta-analysis. Results: Twenty-four RCTs comprising 12,199 patients were identified for meta-analysis. The addition of ICB was associated with higher incidence of thyroiditis [all grade: OR = 3.53 (95% confidence interval (CI): 1.88-6.64)], hyperthyroidism [all-grade: 7.18 (4.30-12.01); grade 3-5: 3.93 (1.21-12.82)], hypothyroidism [all-grade: 5.39 (3.68-7.90); grade 3-5: 3.63 (1.18-11.11)], adrenal insufficiency [all-grade: 3.82 (1.88-7.79); grade 3-5: 5.91 (2.36-14.82)], hypophysitis [all-grade: 10.29 (4.97-21.3); grade 3-5: 5.80 (1.99-16.92)], and type 1 diabetes mellitus [all-grade: 2.24 (1.06-4.74); grade 3-5: 3.49 (1.21-10.08)]. The cumulative incidence of each grade 3-5 endocrine AE was low (<1.3%). No grade 5 AEs leading to death were observed. Conclusion: The addition of neoadjuvant/adjuvant ICB to conventional therapy was associated with an increased incidence of several endocrine AEs. Clinicians should be aware of the risk of endocrinopathy from the perioperative ICB use to facilitate risk-benefit discussion with patients with early-stage cancer. Trial registration: The protocol of this research was registered in PROSPERO (CRD42022332624).

C-reactive protein (CRP) as a prognostic biomarker in patients with urothelial carcinoma: A systematic review and meta-analysis.

C-reactive protein (CRP) may reflect a pro-inflammatory tumor microenvironment and could represent a biomarker to select patients with urothelial carcinoma more likely to benefit from therapies directed at modulating tumor-promoting inflammation. We performed a systematic review to evaluate survival outcomes based on pre-treatment CRP values in urothelial carcinoma. The hazard ratios (HRs) of survival such as overall survival (OS) and progression-free survival (PFS) between groups with high versus low CRP values were pooled by the random-effect model meta-analyses. Overall, 28 studies comprising 6789 patients were identified for meta-analyses. High CRP levels were associated with shorter OS (HR=1.96 [95% CI: 1.64-2.33], p < 0.01), particularly in advanced disease treated with immune checkpoint blockade (ICB, HR=1.78 [1.47-2.15], p < 0.01). Similar findings were observed in ICB-treated patients with PFS. These findings suggest that CRP could be an attractive biomarker to select patients with urothelial carcinoma for strategies seeking to modulate tumor-promoting inflammation.

High indoleamine 2,3-dioxygenase transcript levels predict better outcome after front-line cancer immunotherapy.

Indoleamine 2,3-dioxygenase 1 (IDO1), which catabolizes tryptophan, is a potential target to unlock the immunosuppressive tumor microenvironment. Correlations between IDO1 and immune checkpoint inhibitor (ICI) efficacy remain unclear. Herein, we investigated IDO1 transcript expression across cancers and clinical outcome correlations. High IDO1 transcripts were more frequent in uterine (54.2%) and ovarian cancer (37.2%) but varied between and within malignancies. High IDO1 RNA expression was associated with high expression of PD-L1 (immune checkpoint ligand), CXCL10 (an effector T cell recruitment chemokine), and STAT1 (a component of the JAK-STAT pathway) (all multivariable p < 0.05). PIK3CA and CTCF alterations were more frequent in the high IDO1 group. High IDO1 expression was an independent predictor of progression-free survival (adjusted HR = 0.44, 95% CI 0.20-0.99, p = 0.049) and overall survival (adjusted HR = 0.31, 95% CI 0.11-0.87, p = 0.026) after front-line ICIs. IDO1 expression warrants further exploration as a predictive biomarker for immunotherapy. Moreover, co-expressed immunoregulatory molecules merit exploration for co-targeting.

Consolidation Osimertinib Versus Durvalumab Versus Observation After Concurrent Chemoradiation in Unresectable EGFR-Mutant NSCLC: A Multicenter Retrospective Cohort Study.

INTRODUCTION: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown. METHODS: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used. RESULTS: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3). CONCLUSIONS: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.

The Geriatric Nutritional Risk Index as a prognostic factor in older adult patients with locally advanced head and neck cancer receiving definitive chemoradiotherapy with tri-weekly cisplatin.

INTRODUCTION: Concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced head and neck cancer (LAHNC) in the definitive setting. The Geriatric Nutritional Risk Index (GNRI) is a screening tool to predict the risk of morbidity and mortality in the older adult. Nutritional management is key during CCRT but the association between prognosis and initial nutritional status in older adults with LAHNC undergoing CCRT remains unknown. MATERIALS AND METHODS: Patients ≥65 years old with LAHNC who received definitive CCRT with cisplatin (80 mg/m2 or 100 mg/m2, every three weeks, three times) between 2012 and 2018 were included. Patients without completion of radiotherapy were excluded. Patients were stratified into two groups based on the GNRI (≦98 or > 98). Overall survival (OS) and event-free survival (EFS) were analyzed by the Kaplan-Meier method and the log-rank test. The Cox proportional hazards model was adopted to identify prognostic factors. GNRI, sex, T and N categories were prespecified as variables for multivariable analysis. RESULTS: The median age of 111 patients (88 male, 79%) was 69 years (interquartile range: 67-71), among which 23 patients had low GNRI (20 male, 87%) and 88 patients had high GNRI (68 male, 77%). Baseline clinical characteristics were not statistically different between the two groups. OS was significantly worse in the low GNRI group than in the high GNRI group (p = 0.048). There was no statistical difference in EFS between the two groups (p = 0.12). Multivariable analysis revealed that low GNRI (hazard ratio [HR]: 3.17, 95% confidence interval [95%CI]: 1.12-8.96, p = 0.029) and higher N category (HR: 4.37, 95% CI: 1.58-12.06, p = 0.004) were associated with worse OS. For EFS, the higher N category was significantly associated with a worse outcome (HR: 2.54, 95% CI: 1.16-5.59, p = 0.02). DISCUSSION: Poorer nutritional status before initiation of CCRT was associated with worse OS in older adults with LAHNC in the definitive setting. The GNRI is a convenient tool for predicting OS in older adult patients with LAHNC treated with CCRT.

Targeting KRAS: Crossroads of Signaling and Immune Inhibition.

Mutations of RAS are commonly seen in human cancers, especially in lung, colorectal, and pancreatic adenocarcinoma. Despite huge effort for decades, targeting RAS mutations has been "undruggable" because of the molecular instability of RAS protein inhibition. However, the recent discovery of the KRAS G12C inhibitor paved the way to expand therapeutic options for patients with cancer harboring the KRAS G12C mutation. At the same time, the successful development of immune checkpoint inhibitors (ICIs) drastically changed the paradigm of cancer treatment and resulted in a better understanding of the tumor immune microenvironment in patients with KRAS-mutant cancer. This review describes the following: the clinical characteristics of cancer with KRAS mutation; successful development of the KRAS G12C inhibitor and its impact on the tumor immune microenvironment; and potential new avenues such as the combination strategy using KRAS inhibitor and ICI, with preclinical and clinical rationales for overcoming resistance to inhibition of KRAS to improve therapeutic efficacy for patients with cancer harboring KRAS mutations.

Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: a systematic review and meta-analysis.

BACKGROUND: Platinum-doublet chemotherapy has been conventionally used for patients with advanced gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) but evidence of chemotherapy is based on studies with small sample sizes and remains scarce. Thus, we conducted a systematic review and meta-analysis to elucidate the efficacy of platinum-doublet chemotherapy for advanced GEP-NEC. METHODS: We performed a database search in PubMed/MEDLINE and EMBASE. Eligible studies were prospective and retrospective studies documenting the efficacy of platinum plus etoposide (EP) and platinum plus irinotecan (IP) for advanced GEP-NEC. Overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were pooled and weighted using generic inverse variance in a random-effects meta-analysis model. RESULTS: Nineteen studies including 1157 patients were identified. The ORR of the platinum-doublet regimen, EP, and IP was 49.1% (95% confidence interval [CI], 41.8-56.5), 44.4% (95% CI: 35.9-53.0), and 59.4% (95% CI: 48.0-70.8). The pooled median OS of the platinum-doublet regimen, EP, and IP was 12.9 months (95% CI:10.9-15.3), 12.9 months (95% CI: 10.8-15.4), and 12.9 months (95% CI: 6.0-27.8), and the pooled median PFS of the platinum-doublet regimen, EP, and IP was 5.4 months (95% CI: 4.5-6.4), 5.4 months (95% CI 4.5-6.5), and 4.0 months (95% CI: 1.4-11.7), respectively. CONCLUSION: Considerable response rate and survival time of the platinum-doublet regimen for advanced GEP-NEC were observed. IP and EP regimens can be reasonably applicable and these results provide a reference for oncologists in deciding the suitable regimen for patients with advanced GEP-NEC.