Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care.

BACKGROUND: Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. METHODS: This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. RESULTS: Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. CONCLUSION: Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.

Whole blood transcriptome signature predicts severe forms of COVID-19: Results from the COVIDeF cohort study.

COVID-19 is associated with heterogeneous outcome. Early identification of a severe progression of the disease is essential to properly manage the patients and improve their outcome. Biomarkers reflecting an increased inflammatory response, as well as individual features including advanced age, male gender, and pre-existing comorbidities, are risk factors of severe COVID-19. Yet, these features show limited accuracy for outcome prediction. The aim was to evaluate the prognostic value of whole blood transcriptome at an early stage of the disease. Blood transcriptome of patients with mild pneumonia was profiled. Patients with subsequent severe COVID-19 were compared to those with favourable outcome, and a molecular predictor based on gene expression was built. Unsupervised classification discriminated patients who would later develop a COVID-19-related severe pneumonia. The corresponding gene expression signature reflected the immune response to the viral infection dominated by a prominent type I interferon, with IFI27 among the most over-expressed genes. A 48-genes transcriptome signature predicting the risk of severe COVID-19 was built on a training cohort, then validated on an external independent cohort, showing an accuracy of 81% for predicting severe outcome. These results identify an early transcriptome signature of severe COVID-19 pneumonia, with a possible relevance to improve COVID-19 patient management.

Predictive factors associated with pemetrexed acute toxicity.

PURPOSE: Pemetrexed has shown efficacy as monotherapy or in combination with platinum salts in the treatment of non-small cell lung cancer and mesothelioma. However, severe hematological toxicities induced by pemetrexed-based chemotherapy have been observed. Some studies have suggested that drug interactions may be associated with pemetrexed toxicity. The objective of this study was to determine predictive factors, including drug interactions, associated with pemetrexed toxicity. METHODS: This retrospective open monocentric study included patients consecutively treated with pemetrexed after a multidisciplinary risk assessment. Patients who experienced toxicity of grade 3 or 4 according to the Common Terminology Criteria for Adverse Events v5.0, or a grade 2 leading to a change in management, during the first four courses of pemetrexed, were assigned to the early limiting toxicities (ELT) group. Univariate and multivariable logistic regression models were used to test the association variables with the occurrence of ELT. RESULTS: Seventy-four patients were included in this study (median age: 67 years, with non-small cell lung cancer adenocarcinoma (88%), mesothelioma (7%), or others (5%). Thirty-six patients (49%) were assigned to the ELT group (27 grades 3 and 4; 9 grade 2 with management modification). Three baseline factors were associated with pemetrexed ELT in univariate and multivariate analysis: cystatin clearance (p = 0.0135), albumin level (p = 0.0333), and proton pump inhibitors use (p = 0.035). CONCLUSION: To conclude, ELT induced by pemetrexed-based treatments occur frequently in cancer patients in a real-world setting. A pretherapeutic assessment before pemetrexed initiation should include three major checkpoints: use of proton pump inhibitors, sarcopenia, and denutrition evaluation.

Pituitary surgery outcome in patients 75 years and older: a retrospective study.

BACKGROUND: As the population ages, the number of elderly patients with an indication for pituitary surgery is rising. Information on the outcome of patients aged over 75 is limited. This study reports a large series assessing the feasibility of surgical resection in this specific age range, focusing on surgical complications and postoperative results. METHODS: A retrospective cohort study of patients with pituitary adenomas and Rathke's cleft cysts was conducted. All patients were aged 75 years or over and treated by a single expert neurosurgical team. A control population included 2379 younger adult patients operated by the same surgeons during the same period. RESULTS: Between 2008 and 2022, 155 patients underwent surgery. Indication was based on vision impairment in most patients (79%). Median follow-up was 13 months (range: 3-96). The first surgery was performed with an endoscopic transsellar approach, an extended endonasal transtuberculum approach and a microscopic transcranial approach in 96%, 3%, and 1% of patients, respectively. Single surgery was sufficient to obtain volume control in 97% of patients. From Kaplan-Meier estimates, 2-year and 5-year disease control with a single surgery were 97.3% and 86.2%, respectively. Resection higher than 80% was achieved in 77% of patients. No vision worsening occurred. In acromegaly and Cushing's disease, endocrine remission was obtained in 90% of non-invasive adenomas. Surgical complications were noted in 5% of patients, with 30-day mortality, hematoma, cerebrospinal fluid leak, meningitis, and epistaxis occurring in 0.6%, 0.6%, 1.9%, 0.6%, and 1.3% respectively. New endocrine anterior deficits occurred in only 5%, while no persistent diabetes insipidus was noted. Compared with younger patients, the complication rate was not statistically different. CONCLUSIONS: Surgery beyond the age of 75, mainly relying on an endoscopic endonasal transsellar approach, is effective and safe, provided that patients are managed in tertiary centers.

KDM1A inactivation causes hereditary food-dependent Cushing syndrome.

PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.

Lean Body Mass and Endocrine Status But Not Age Are Determinants of Resting Energy Expenditure in Patients with Non-Small Cell Lung Cancer.

BACKGROUND: Cancer and aging are both frequently associated with malnutrition, a factor of poor prognosis. In adult cancer patients, this may be related in part to impaired energy metabolism, with higher than predicted resting energy expenditure (REE) in about 50% of patients. We hypothesized that frequently impaired energy metabolism in elderly patients could potentiate cancer-associated hypermetabolism, further promoting risk of malnutrition. OBJECTIVE: To study the hypermetabolic response to cancer in a predominantly aged population and the potential underlying determinants. METHODS: This was a cross-sectional exploratory study in patients with non-small-cell lung cancer. REE was measured by indirect calorimetry. Body composition was determined from a single CT scan imaging at L3 level. Endocrine, inflammatory, nutritional and metabolic status were evaluated. RESULTS: Twenty-seven patients, of median age 68 years (range 32-81) completed the study. In this population, mean measured REE was 7.5% higher than calculated REE. Sex and weight accounted for about 51% of REE variations, whereas age accounted only for 4%. However, these parameters did not explain the REE-to-lean body mass (LBM) ratio variations, suggesting that they influenced REE only through their effect on LBM. Among the other parameters evaluated, only the thyroid-stimulating hormone and interleukin-6 plasma levels appeared to have an influence on REE. The study of the consequences of this increase in REE-to-LBM ratio showed a growing inability of patients to meet their energy needs but showed no effect on nutritional markers such as transthyretin. CONCLUSIONS: The results of this pilot study suggest that in our population, age was not an important factor of REE. The elevated energy metabolism was associated with patients' failure to increase their energy intakes sufficiently, which can contribute to the development of cachexia. CLINICAL TRIAL: This trial is registered at clinicaltrials.gov under NCT0314.

Resting energy metabolism and anticancer treatments.

PURPOSE OF REVIEW: Cachexia is a multifactorial syndrome associated with morbidity and mortality in cancer patients and represents a major challenge in cancer management. Elevated energy expenditure is supposed to contribute to cachexia. The current article presents the recent findings on the resting energy expenditure (REE) in cancer and the clinical implications for anticancer treatments. RECENT FINDINGS: Half of cancer patients present with hypermetabolism (measured REE >110% of predicted REE). Hypermetabolism is associated with clinical and biological features of cachexia. Hypermetabolic patients - even those with normal nutritional status - have a high risk of severe acute toxicity and a poor prognosis. SUMMARY: Recent discoveries have highlighted the REE as an essential component of nutritional assessment in cancer patients. Multimodal care for cachexia should include REE measurements and dedicated pharmacologic interventions such as adrenoreceptor blockade in case of hypermetabolism.

Clinical parameters associated with anti-programmed death-1 (PD-1) inhibitors-induced tumor response in melanoma patients.

Background The identification of the melanoma patients sensitive to anti-PD-1 inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an urgent need. We hypothesized that the natural history of the disease might partly reflect the immune state of the patients. Methods We analyzed our cohort of melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our institution. Objective response was defined as a complete or partial response according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients, the overall response rate was 43%. Median time from diagnosis to anti-PD-1 initiation was longer among responders than non-responders (64 months vs. 35 months, p = 0.02). The response rate was 10% in patients starting anti-PD-1 within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status (PS) 0 was also associated with enhanced tumor response: 70% of responders were PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type BRAF status were significant predictors of progression free survival. Conclusion A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical features might reflect a potentially intact immune system of the host.

Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients.

Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m2) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney's tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m2 and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m2. For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m2; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.

NF1 mutations as biomarker of response to immune checkpoint blockades for lung adenocarcinoma patients.

Little is known about immune checkpoint inhibitors (ICI) response of NF1-mutated lung adenocarcinomas. 341/4,181 (8.2%) TCGA lung adenocarcinomas samples have a somatic NF1 mutation. NF1-mutated tumors have higher TMB (p < 0.0001), higher expression of immune genes ("hot phenotype") and higher CD8 + T cell (p = 0.03) and macrophage (p = 0.02) infiltrations compared to NF1 wild-type tumors. NF1 mutation status appears as a candidate predictive biomarker for ICI response in lung adenocarcinoma patients.

Whole blood transcriptomic signature of Cushing's syndrome.

OBJECTIVE: Cushing's syndrome is characterized by high morbidity and mortality with high interindividual variability. Easily measurable biomarkers, in addition to the hormone assays currently used for diagnosis, could reflect the individual biological impact of glucocorticoids. The aim of this study is to identify such biomarkers through the analysis of whole blood transcriptome. DESIGN: Whole blood transcriptome was evaluated in 57 samples from patients with overt Cushing's syndrome, mild Cushing's syndrome, eucortisolism, and adrenal insufficiency. Samples were randomly split into a training cohort to set up a Cushing's transcriptomic signature and a validation cohort to assess this signature. METHODS: Total RNA was obtained from whole blood samples and sequenced on a NovaSeq 6000 System (Illumina). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore the transcriptome profile. Ridge regression was used to build a Cushing's transcriptome predictor. RESULTS: The transcriptomic profile discriminated samples with overt Cushing's syndrome. Genes mostly associated with overt Cushing's syndrome were enriched in pathways related to immunity, particularly neutrophil activation. A prediction model of 1500 genes built on the training cohort demonstrated its discriminating value in the validation cohort (accuracy .82) and remained significant in a multivariate model including the neutrophil proportion (P = .002). Expression of FKBP5, a single gene both overexpressed in Cushing's syndrome and implied in the glucocorticoid receptor signaling, could also predict Cushing's syndrome (accuracy .76). CONCLUSIONS: Whole blood transcriptome reflects the circulating levels of glucocorticoids. FKBP5 expression could be a nonhormonal marker of Cushing's syndrome.

Prognostic Impact of Hypothalamic Perforation in Adult Patients With Craniopharyngioma: A Cohort Study.

CONTEXT: Outcome of craniopharyngioma is related to its locoregional extension, which impacts resectability and the risk of surgical complications. To maximize resection and minimize complications, optic tract localization, temporal lobe extension, and hypothalamic involvement are essential factors for surgical management. OBJECTIVE: To assess the outcome of craniopharyngiomas depending on their relation to the hypothalamus location. METHODS: We conducted a retrospective analysis of 79 patients with a craniopharyngioma who underwent surgery from 2007 to 2022. Craniopharyngiomas were classified in 3 groups, depending on the type of hypothalamus involvement assessed by preoperative magnetic resonance imaging: infra-hypothalamic (type A, n = 33); perforating the hypothalamus (type B, n = 40); and supra-hypothalamic (type C, n = 6). Surgical strategy was guided by the type of hypothalamic involvement, favoring endonasal approaches for type A and type B, and transcranial approaches for type C. RESULTS: Long-term disease control was achieved in 33/33 (100%), 37/40 (92%), and 5/6 (83%) patients in type A, B, and C, respectively. In type B, vision was improved in 32/36 (89%) patients, while hypothalamic function was improved, stable, or worsened in 6/40 (15%), 32/40 (80%), and 2/40 (5%) patients, respectively. Papillary craniopharyngiomas were found in 5/33 (15%), 9/40 (22%), and 3/6 (50%) patients in types A, B, and C, respectively. In 4 patients, BRAF/MEK inhibitors were used, with significant tumor shrinkage in all cases. CONCLUSION: Craniopharyngiomas located below the hypothalamus or perforating it can be safely treated by transsphenoidal surgery. For supra-hypothalamic craniopharyngiomas, postoperative results are less favorable, and documenting a BRAF mutation may improve outcome, if targeted therapy was efficient enough to replace surgical debulking.

Differentiation between adrenocortical carcinoma and lipid-poor adrenal adenoma using a multiparametric MRI-based diagnostic algorithm.

PURPOSE: The purpose of this study was to evaluate the capabilities of multiparametric magnetic resonance imaging (MRI) in differentiating between lipid-poor adrenal adenoma (LPAA) and adrenocortical carcinoma (ACC). MATERIALS AND METHODS: Patients of two centers who underwent surgical resection of LPAA or ACC after multiparametric MRI were retrospectively included. A training cohort was used to build a diagnostic algorithm obtained through recursive partitioning based on multiparametric MRI variables, including apparent diffusion coefficient and chemical shift signal ratio (i.e., tumor signal intensity index). The diagnostic performances of the multiparametric MRI-based algorithm were evaluated using a validation cohort, alone first and then in association with adrenal tumor size using a cut-off of 4 cm. Performances of the diagnostic algorithm for the diagnosis of ACC vs. LPAA were calculated using pathology as the reference standard. RESULTS: Fifty-four patients (27 with LPAA and 27 with ACC; 37 women; mean age, 48.5 ± 13.3 [standard deviation (SD)] years) were used as the training cohort and 61 patients (24 with LPAA and 37 with ACC; 47 women; mean age, 49 ± 11.7 [SD] years) were used as the validation cohort. In the validation cohort, the diagnostic algorithm yielded best accuracy for the diagnosis of ACC vs. LPAA (75%; 46/61; 95% CI: 55-88) when used without lesion size. Best sensitivity was obtained with the association of the diagnostic algorithm with tumor size (96%; 23/24; 95% CI: 80-99). Best specificity was obtained with the diagnostic algorithm used alone (76%; 28/37; 95% CI: 60-87). CONCLUSION: A multiparametric MRI-based diagnostic algorithm that includes apparent diffusion coefficient and tumor signal intensity index helps discriminate between ACC and LPAA with high degrees of specificity and accuracy. The association of the multiparametric MRI-based diagnostic algorithm with adrenal lesion size helps maximize the sensitivity of multiparametric MRI for the diagnosis of ACC.

Carney complex predisposes to breast cancer: prospective study of 50 women.

OBJECTIVE: Carney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors. DESIGN: The present study was designed to describe the characteristics of breast lesions in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. METHODS: A 3-year follow-up multicenter French prospective study of CNC patients included 50 women who were analyzed for CNC manifestations and particularly breast lesions, with breast imaging, genotyping, and hormonal settings. RESULTS: Among the 38 women with breast imaging, 14 (39%) had breast lesions, half of them bilateral. Ten women (26%) presented with benign lesions and six with breast carcinomas (16%): one had ductal carcinoma in situ at 54, and five had invasive cancer before 50 years old, whom one with contralateral breast cancer during follow-up. The occurrence of breast cancer was more frequent in women with PRKAR1A pathogenic variant odds ratio = 6.34 (1.63-17.91) than in general population of same age. The mean age at breast cancer diagnosis was 44.7 years old: 17 years younger than in the general population. Breast cancer patients had good prognosis factors. All breast carcinomas occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus in the 2 invasive breast carcinomas analyzed suggested a driver role of this tumor suppressor gene. CONCLUSIONS: As CNC could predispose to breast carcinoma, an adequate screening strategy and follow-up should be discussed in affected women. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT00668291.

PIT-EASY survey: validation of the European Pituitary Pathology Group proposal for reporting pituitary neuroendocrine tumors.

The aim of this multicenter prospective survey called PIT-EASY was to assess the relevance of the European Pituitary Pathology Group (EPPG) diagnostic tools for pituitary neuroendocrine tumors (PitNETs) to improve the quality of their histological diagnosis. Each center performed at least 30 histological cases of PitNETs using the EPPG tools and assessed their value using a scorecard with 10 questions. For each center, the histological cases were carried out by pathologists with varying levels of expertise in pituitary pathology defined as junior, intermediate, and expert. Two hundred and ninety histological cases were collected from six French and Italian centers. The three EPPG tools were validated and regarded as helpful for a more accurate and time-efficient diagnosis. The usefulness of level 2 and level 3 of the "EPPG's multi-step approach for immunohistochemistry" including pituitary transcription factors (PIT1, TPIT, and SF1) and chromogranin, SSTRs, and P53 respectively was higher in "other non-functioning" (silent plurihormonal PIT1, silent corticotroph, and null cell): 88% vs 32%, p < 10-6 and 42% vs 14%, p = 0.002, respectively. The diagnostic algorithm proved more useful for junior pathologists (p = 0.0001) and those with intermediate experience. PIT-EASY survey confirmed the importance of a standardized approach to PitNETs for an accurate and reproducible diagnosis and served as validation of the EPPG proposal. The tool appeared to be of practical value to junior participants and staff with intermediate experience for safe routine diagnostic reporting.

Artificial intelligence in adrenal imaging: A critical review of current applications.

In the elective field of adrenal imaging, artificial intelligence (AI) can be used for adrenal lesion detection, characterization, hypersecreting syndrome management and patient follow-up. Although a perfect AI tool that includes all required steps from detection to analysis does not exist yet, multiple AI algorithms have been developed and tested with encouraging results. However, AI in this setting is still at an early stage. In this regard, most published studies about AI in adrenal gland imaging report preliminary results that do not have yet daily applications in clinical practice. In this review, recent developments and current results of AI in the field of adrenal imaging are presented. Limitations and future perspectives of AI are discussed.

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitides During Rituximab Maintenance Therapy.

OBJECTIVE: Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes. METHODS: Patients included in the MAINRITSAN2 trial (ClinicalTrials.gov identifier: NCT01731561) were randomized to receive a 500-mg fixed-schedule rituximab infusion or an individually tailored regimen. Rituximab plasma concentrations at month 3 (CM3) were assessed. DNA samples (n = 53) were genotyped for single-nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models. RESULTS: One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 µg/ml) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% versus 18.0%; P = 0.02, respectively). Low rituximab plasma concentration at 3 months (CM3 <4 µg/ml) was an independent risk factor for major relapse (odds ratio 6.56 [95% confidence interval (95% CI) 1.26-34.09]; P = 0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 µg/ml as an independent risk factor for major relapse (hazard ratio [HR] 4.81 [95% CI 1.56-14.82]; P = 0.006) and relapse (HR 2.70 [95% CI 1.02-7.15]; P = 0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28. CONCLUSION: These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase.

Impact of sarcopenia indexes on survival and severe immune acute toxicity in metastatic non-small cell lung cancer patients treated with PD-1 immune checkpoint inhibitors.

BACKGROUND & AIMS: Sarcopenia has long been associated with higher toxicity induced by anti-cancer treatments and shorter survival in patients with solid tumors. The creatinine-to-cystatin ratio (CC ratio, serum creatinine/cystatin C × 100) and the sarcopenia index (SI, serum creatinine × cystatin C (CysC)-based glomerular filtration rate (eGFRCysC)) are have been reported to be correlated with skeletal muscle mass. The aim of this study is to assess primarily whether the CC ratio and the SI could predict mortality in metastatic non-small cell lung cancer (NSCLC) patients treated with PD-1 inhibitors, and secondarily their impact on severe immune-related adverse effects (irAEs). METHODS: From the prospective CERTIM cohort, we analyzed retrospectively stage IV NSCLC patients, who received PD-1 inhibitors between June 2015 and November 2020 in Cochin Hospital (Paris, France). We assessed sarcopenia measuring skeletal muscle area (SMA) by computed tomography and handgrip strength (HGS) by a hand dynamometer. RESULTS: In total, 200 patients were analyzed. The CC ratio and the IS were significantly correlated with SMA and HGS: rCC/SMA = 0.360, rSI/SMA = 0.407, rCC/HGS = 0.331, rSI/HGS = 0.370. In multivariate analysis of overall survival, a lower CC ratio (HR 1.73, P = 0.033) and a lower SI (HR 1.89, P = 0.019) were independent predictors of poor prognosis. In univariate analysis of severe irAEs, CC ratio (OR 1.01, P = 0.628) and SI (OR 0.99, P = 0.595) were not associated with a higher risk of severe irAEs. CONCLUSIONS: In metastatic NSCLC patients treated with PD-1 inhibitors, a lower CC ratio and a lower SI are independent predictors of mortality. However, they are not associated with severe irAEs.

Closure strategy for endoscopic pituitary surgery: Experience from 3015 patients.

Introduction: Effective strategies are required to ensure optimal management of the crucial closure step in endoscopic pituitary surgery. Many surgical techniques have been reported but no significant consensus has been defined. Methods: Between January 2006 and March 2022, 3015 adult patients with pituitary adenomas were operated on by a single expert neurosurgical team, using a mononostril endoscopic endonasal approach. Based of preoperative risk factors of and operative findings, a detailed closure strategy was used. Body mass index >40, sellar floor lysis, number of surgeries>2, large skull base destruction, prior radiotherapy were considered as preoperative risk factors for closure failure. All patients treated with an expanded endonasal approach were excluded. Results: Patients were mostly women (F/M ratio: 1.4) with a median age of 50 (range: 18 -89). Intraoperative CSF leak requiring specific surgical management was observed in 319/3015 (10.6%) of patients. If intraoperative leak occurred, patients with predictive risk factors were managed using a Foley balloon catheter in case of sellar floor lysis or BMI>40 and a multilayer repair strategy with a vascularized nasoseptal flap in other cases. Postoperative CSF leak occurred in 29/3015 (1%) of patients, while meningitis occurred in 24/3015 (0.8%) of patients. In patients with intraoperative leak, closure management failed in 11/319 (3.4%) of cases. Conclusion: Based on our significant 16-year experience, our surgical management is reliable and easy to follow. With a planned and stepwise strategy, the closure step can be optimized and tailored to each patient with a very low failure rate.