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Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF -mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAF V600E mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability ( F ) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/ F ) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75–300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug–drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.

Background Cachexia, characterized by involuntary muscle mass loss, negatively impacts survival outcomes, treatment tolerability, and functionality in cancer patients. However, there is a limited appreciation of the true prevalence of low muscle mass due to inconsistent diagnostic methods and limited oncologist awareness. Methods Twenty-nine French healthcare establishments participated in this cross-sectional study, recruiting patients with those metastatic cancers most frequently encountered in routine practice (colon, breast, kidney, lung, prostate). The primary outcome was low skeletal muscle mass prevalence, as diagnosed by estimating the skeletal mass index (SMI) in the middle of the third-lumbar vertebrae (L3) level via computed tomography (CT). Other objectives included an evaluation of nutritional management, physical activity, and toxicities related to ongoing treatment. Results Seven hundred sixty-six patients (49.9% males) were enrolled with a mean age of 65.0 years . Low muscle mass prevalence was 69.1%. Only one-third of patients with low skeletal muscle mass were receiving nutritional counselling and only 28.4% were under nutritional management (oral supplements, enteral or parenteral nutrition). Physicians highly underdiagnosed those patients identified with low skeletal muscle mass, as defined by the primary objective, by 74.3% and 44.9% in obese and non-obese patients, respectively. Multivariate analyses revealed a lower risk of low skeletal muscle mass for females (OR: 0.22, P  <  0.01 ) and those without brain metastasis (OR: 0.34, P  <  0.01 ). Low skeletal muscle mass patients were more likely to have delayed treatment administration due to toxicity (11.9% versus 6.8%, P  =  0.04 ). Conclusions There is a critical need to raise awareness of low skeletal muscle mass diagnosis among oncologists, and for improvements in nutritional management and physical therapies of cancer patients to curb potential cachexia. This calls for cross-disciplinary collaborations among oncologists, nutritionists, physiotherapists, and radiologists.

Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment.

A woman with lung cancer in whom the usual toxicities from erlotinib did not develop at the standard dose had a tumor response and side effects when the erlotinib dose was increased. Furthermore, the erlotinib dose had to be reduced when fenofibrate was stopped. To the Editor: A 78-year-old nonsmoking woman with a history of depression and dyslipidemia presented with a stage IV lung adenocarcinoma, harboring an activating mutation of the epidermal growth factor receptor (EGFR) (exon 19 deletion). Erlotinib was started at the recommended dose of 150 mg per day. Her other medications included escitalopram (15 mg per day), alprazolam (0.5 mg three times a day), and fenofibrate (200 mg per day). Two months later, progressive disease with chest pain developed, but neither diarrhea nor skin rash, both expected side effects of erlotinib, was observed. The plasma trough concentration for erlotinib, determined with . . .

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2–3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

Pancreatic exocrine insufficiency and a reduction in the volume of the pancreas on computed tomography developed in two patients after more than 24 months of sorafenib therapy. To the Editor: Sorafenib is an oral multitargeted tyrosine kinase inhibitor with potent antiangiogenic activity. It was first approved to treat renal-cell carcinoma, 1 but it is also active in other solid tumors, such as hepatocellular and thyroid carcinomas. Prolonged use of sorafenib may cause cumulative, serious, and life-threatening late toxic effects due to the long-term effect of antiangiogenic therapies on the microvessels. We report reproducible evidence of irreversible pancreatic atrophy in two patients after long-term treatment with sorafenib. The first patient received sorafenib for 2.5 years; during the treatment period, the patient had a complete tumor response for 1 year. . . .

Lean body mass (LBM) is an important prognostic factor in patients with cancer. Although the L3–computed tomography (CT) scan is considered a reference method for assessment, a convenient and easily available method for longitudinal follow-up is required. Although bioelectrical impedance analysis (BIA) is widely used, its accuracy is questioned; plasma creatinine-to-cystatin C (CC) ratio could be an attractive alternative. The aim of this study was to evaluate the ability of the CC ratio and BIA to detect myopenia in patients with cancer compared with the use of the CT scan as a standard. Patients with any kind of cancer had body composition evaluation by CT scan, BIA, and CC. Statistical analysis included correlation test, Bland–Altman, and receiver operating characteristic curve analysis. Forty-four patients (14 women) were included. Of the participants, 59% had myopenia on CT scan. Both BIA LBM and CC ratio were well correlated with CT scan LBM (r = 0.763 and 0.648, respectively) but concordance analysis revealed a 3-kg constant bias toward BIA compared with CT scan. In terms of ability to detect myopenia, areas under the curve (AUC) for BIA were 0.675 and 0.388 for men and women, respectively. For CC ratio, AUCs were 0.813 and 0.673. This study demonstrated that LBM assessed by the CC ratio or BIA is well correlated with that determined by L3-CT scan. The ability of the CC ratio to detect myopenia was better than that of BIA. Findings from the present study demonstrated that CC ratio can be conveniently used in patients with cancer as a reliable biomarker of muscularity. •L3–computed tomography scan is most widely used for body composition evaluation in oncology.•L3–computed tomography scan for body composition in oncology has some shortcomings.•Bioimpedance analysis has a good correlation but poor agreement with L3–computed tomography scan.•The ratio of creatinine to cystatin C can be an alternative for the diagnosis of myopenia.

Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown. To study the impact of COPD on the immune contexture of non-small cell lung cancer. We performed in-depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patient survival (n = 435). Tumor-infiltrating T lymphocyte (TIL) exhaustion by flow cytometry (n = 50) was also investigated. The effectiveness of an anti-PD-1 (programmed cell death-1) treatment (nivolumab) was evaluated in 39 patients with advanced-stage non-small cell lung cancer. All data were analyzed according to patient COPD status. Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD patients. Interestingly, a negative prognostic value of PD-L1 (programmed cell death ligand 1) expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD patients. Finally, data obtained on 39 patients with advanced-stage non-small cell lung cancer treated by an anti-PD-1 antibody showed longer progression-free survival in COPD patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD patients. COPD is associated with an increased sensitivity of CD8 tumor-infiltrating T lymphocytes to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.

Erlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non–small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were to describe the pharmacokinetic profile of erlotinib in unselected patients with NSCLC, to quantify and explain its variability, to challenge the standard recommended dose in older patients, and to propose clinical recommendations for the therapeutic management of patients taking erlotinib. : A population pharmacokinetic model was developed using erlotinib plasma concentrations collected from patients with NSCLC participating in a routine therapeutic drug monitoring program (with the nonlinear mixed effect modeling program NONMEM). Relevant demographic characteristics, clinical factors, and co-medications were tested as potential covariates. An independent dataset was used for model validation. Simulations based on the final model allowed comparison of expected erlotinib concentrations under standard and alternative dosing regimens for smokers and for several age groups. A total of 481 erlotinib plasma concentrations from 91 patients with NSCLC were used for model building and 239 plasma drug concentrations from 107 patients for model validation. A one-compartment model with first-order absorption and elimination provided the best fit. Average erlotinib CL/F with interindividual variability (%CV) was 3.8 L/h (41.5%), and V/F was 166 L (53.8%). The absorption rate constant was 1.48 h−1. The external validation showed a negligible bias of −4% (95% CI, −7 to −1) in the individual predictions, with a precision of 23%. Current smoking and use of proton pump inhibitors were associated with higher CL/F, whereas age was associated with lower CL/F. Simulations suggest that a lower dose in older patients would decrease the risk of overexposure. This large cohort study confirms the substantial interindividual variability in erlotinib plasma exposure and the impact of smoking and proton pump inhibitor intake. This large variability in erlotinib pharmacokinetics indicates that the standard recommended dose of 150 mg once daily is likely not appropriate to reach the expected concentrations in each patient. Concentration monitoring should be performed to individually adjust the erlotinib dosing regimen. The observed decrease in erlotinib CL/F with age suggests that a lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent overexposure and potential toxicity in older frail patients with co-morbidities. •Smoking, intake of proton pump inhibitors and age can influence erlotinib clearance.•Older patients are more subject to toxicities compared to younger patients at the standard recommended dose, which may lead to treatment interruption.•A lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent the risk of overexposure and potential toxicity in older frail patients with comorbidities.

Background Cancer‐associated weight loss (WL) associates with increased mortality. International consensus suggests that WL is driven by a variable combination of reduced food intake and/or altered metabolism, the latter often represented by the inflammatory biomarker C‐reactive protein (CRP). We aggregated data from Canadian and European research studies to evaluate the associations of reduced food intake and CRP with cancer‐associated WL (primary endpoint) and overall survival (OS, secondary endpoint). Methods The data set included a total of 12,253 patients at risk for cancer‐associated WL. Patient‐reported WL history (% in 6 months) and food intake (normal, moderately, or severely reduced) were measured in all patients; CRP (mg/L) and OS were measured in N = 4960 and N = 9952 patients, respectively. All measures were from a baseline assessment. Clinical variables potentially associated with WL and overall survival (OS) including age, sex, cancer diagnosis, disease stage, and performance status were evaluated using multinomial logistic regression MLR and Cox proportional hazards models, respectively. Results Patients had a mean weight change of −7.3% (±7.1), which was categorized as: ±2.4% (stable weight; 30.4%), 2.5–5.9% (19.7%), 6.0–10.0% (23.2%), 11.0–14.9% (12.0%), ≥15.0% (14.6%). Normal food intake, moderately, and severely reduced food intake occurred in 37.9%, 42.8%, and 19.4%, respectively. In MLR, severe WL (≥15%) (vs. stable weight) was more likely (P < 0.0001) if food intake was moderately [OR 6.28, 95% confidence interval (CI 5.28–7.47)] or severely reduced [OR 18.98 (95% CI 15.30–23.56)]. In subset analysis, adjusted for food intake, CRP was independently associated (P < 0.0001) with ≥15% WL [CRP 10–100 mg/L: OR 2.00, (95% CI 1.58–2.53)] and [CRP > 100 mg/L: OR 2.30 (95% CI 1.62–3.26)]. Diagnosis, stage, and performance status, but not age or sex, were significantly associated with WL. Median OS was 9.9 months (95% CI 9.5–10.3), with median follow‐up of 39.7 months (95% CI 38.8–40.6). Moderately and severely reduced food intake and CRP independently predicted OS (P < 0.0001). Conclusions Modelling WL as the dependent variable is an approach that can help to identify clinical features and biomarkers associated with WL. Here, we identify criterion values for food intake impairment and CRP that may improve the diagnosis and classification of cancer‐associated cachexia.