T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression.

Background: Almost half of the patients with metastatic melanoma obtain only short-term or no benefit at all from checkpoint inhibitor (CPI) immunotherapy. In this study, we investigated whether the immune system of patients progressing following CPI treatment was able to generate functional tumor-specific immune responses. Materials and methods: Tumor-infiltrating lymphocytes (TILs) were isolated and expanded from metastatic melanoma lesions which progressed during or after anti-programmed cell death protein 1 (PD)-1 and anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) treatment. Tumor-specific immune responses were assessed with co-culture assays of TILs and autologous tumor cells. Results: TILs from 23 metastases of individual patients could be assessed for T cells recognition of autologous tumor cells. All metastases were progressive on or following anti-PD-1 (23/23, 100%), and the majority also after anti-CTLA-4 (17/23, 74%). Functional antitumor immune responses were detected in 19/23 patients (83%). Both CD8+ (in 18/23 patients, 78%) and CD4+ (in 16/23 patients, 70%) TILs were able to recognize autologous tumors. A large fraction of CD8+ TILs (median 23%, range 1.0%-84%) recognized tumor cells. This is similar to the cohorts of unselected patient populations with metastatic melanoma presented in previous studies. The localization of intratumoral immune infiltrates was heterogeneous among samples. In a phase I/II clinical trial, TILs were administered with lymphodepleting chemotherapy, pegIFNα2b and interleukin-2 to 12 patients with CPI-resistant melanoma. Out of 12 patients who previously failed CPI therapy, treatment with TILs resulted in two partial responses, of which one is ongoing. Conclusions: Tumor-reactive T cells appear to heavily infiltrate the tumor microenvironment of patients who failed previous CPI treatment. These patients can still respond to an infusion of unselected autologous TILs. Our results warrant further testing of novel immune re-activation strategies in melanoma patients who failed multiple CPI therapy.

Endoscopic retrograde cholangiopancreatography causes reduced myocardial blood flow.

BACKGROUND AND STUDY AIMS: Previous studies have shown that up to 50% of healthy patients may develop ST-segment changes during upper gastrointestinal endoscopy. The aim of the study was to evaluate myocardial blood flow in patients during endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS AND METHODS: 11 patients scheduled for ERCP were monitored with a Holter tape recorder and underwent myocardial perfusion scintigraphies, to evaluate myocardial perfusion at rest and during ERCP. RESULTS: Ten patients completed the study. Eight patients had no sign of myocardial ischemia with either of the two methods, while two patients developed signs of ischemia during ERCP with both the Holter tape recording and on myocardial scintigraphy (P = 0.02). CONCLUSIONS: Patients undergoing ERCP may develop true myocardial ischemia with reduced myocardial blood flow. Although this is a small-scale study, these findings strongly support the use of alternative methods for diagnostic evaluation of the pancreatic duct and biliary tree.

Accelerated postoperative recovery programme after colonic resection improves physical performance, pulmonary function and body composition.

BACKGROUND: Postoperative organ dysfunction contributes to morbidity, hospital stay and convalescence. Multimodal rehabilitation with epidural analgesia, early oral feeding, mobilization and laxative use after colonic resection has reduced ileus and hospital stay. METHODS: Fourteen patients receiving conventional care (group 1) and 14 patients who had multimodal rehabilitation (group 2) were studied before and 8 days after colonic resection. Outcome measures included postoperative mobilization, body composition by whole-body dual X-ray absorptiometry, cardiovascular response to treadmill exercise, pulmonary function and nocturnal oxygen saturation. RESULTS: Defaecation occurred earlier (median day 1 versus day 4) and hospital stay was shorter (median 2 versus 12 days) in patients who had multimodal treatment. Lean body and fat mass decreased in group 1 but not in group 2. Exercise performance decreased by 44 per cent in group 1 but was unchanged in group 2. A postoperative increase in heart rate (HR) response to exercise was avoided in group 2. Pulmonary function decreased in group 1 but not in group 2. There was less nocturnal postoperative hypoxaemia in group 2. Cardiac demand-supply (HR/oxygen saturation ratio) increased in group 1 but not in group 2. CONCLUSION: Multimodal rehabilitation prevents reduction in lean body mass, pulmonary function, oxygenation and cardiovascular response to exercise after colonic surgery.

Fasting gall bladder volume and lithogenicity in relation to glucose tolerance, total and intra-abdominal fat masses in obese non-diabetic subjects.

OBJECTIVE: To investigate whether total body fat mass or fat distribution and associated metabolic disturbances in glucose and lipid metabolism influence the well known gallstone pathogenetic factors in obese subjects in order to explain why some obese subjects develop gallstones and some do not. DESIGN: Cross sectional study of gallstone pathogenetic factors, body composition, fat distribution, glucose and lipid metabolism. SUBJECTS: 57 healthy overweight subjects (aged 26-64y, body mass index (BMI) 30-45 kg/m2). MEASUREMENTS: Total and intra-abdominal fat masses were measured by dual X-ray absorptiometry and abdominal CT scanning, respectively. The lithogenic index was measured in aspirated bile. The gallbladder volume was determined by ultrasound and the gallbladder ejection fraction% by dynamic cholescintigraphy. Plasma cholecystokinin (CCK) concentrations during a meal were measured with a specific radioimmunoassay. Insulin sensitivity was measured by the Minimal Model and glucose tolerance by an oral glucose tolerance test (OGTT). Serum lipid concentrations were measured by standard methods. RESULTS: The gallbladder volume in the fasting state increased with increasing intra-abdominal fat mass (P=0.006) and was increased in subjects with impaired glucose tolerance (41 vs 27 ml, P=0.001). The lithogenic index was > 1 in all subjects and correlated with total fat mass (P=0.04). CONCLUSION: Gallstone pathogenesis in obesity seems to be influenced by the total body fat mass and its regional distribution possibly via mutual association with the glucose tolerance.

Change in fat-free mass assessed by bioelectrical impedance, total body potassium and dual energy X-ray absorptiometry during prolonged weight loss.

A total of 16 obese women (body mass index (BMI) 30-43 kg m(-2)) participated in a weight reduction study. Before and after a weight loss of 11.7 +/- 7.4 kg (mean +/- SD), body composition was assessed by dual energy X-ray absorptiometry (DXA), and total body potassium counting (TBK). These measurements were compared with bioimpedance analysis (BIA) by applying 11 predictive BIA equations published in the literature. Predictive equations for the present study population were developed, with the use of fat-free mass (FFM) as assessed by TBK and DXA as references in multiple regression analysis. The results of the BIA equations varied widely; FFM was generally overestimated by BIA as compared with DXA and TBK before and after weight loss. During weight loss, the FFM did not change, as estimated by DXA (1.3 +/- 2.3 kg, p > 0.05) and TBK (0.9 +/- 2.9 kg, p > 0.05). The recorded change in impedance (R) was also insignificant. Three BIA equations from the literature, which were not specific for the degree of obesity in the present study group, predicted changes in FFM (from 0.5 + 3.6 to 2.4 +/- 4.4kg, p > 0.05) that were comparable with those estimated by the reference methods. Eight equations from the literature, which included equations specific for the degree of obesity in the study group, and the group specific equations developed for the present population predicted significant changes in FFM during weight loss (from 2.3 +/- 3.0 to 5.0 +/- 3.0 kg, p < 0.05). We conclude that in obesity most predictive equations are unable to predict static body composition and are not reproducible for individuals over time. However, a significant or insignificant change in R (without accompanying predictive equations) may be used to indicate whether FFM is lost or preserved in groups of obese subjects.

Body composition during weight loss in obese patients estimated by dual energy X-ray absorptiometry and by total body potassium.

OBJECTIVE: To validate the ability of DXA to measure total body composition before and after weight loss and the composition of the lost body mass. DESIGN: Cross sectional and follow-up study of body composition before and after a weight loss of 10.6 +/- 6.8 kg. SUBJECTS: 31 obese subjects with a mean body weight of 105.2 +/- 15.2 kg at baseline, and a mean body weight of 94.6 +/- 16.5 kg at follow-up. MEASUREMENTS: Body composition was measured by dual X-ray absorptiometry, total body potassium counting, and high precision scales before and after a weight loss. RESULTS: DXA and the scales showed a strong linear relation (r = 1). At baseline, however, DXA underestimated the body weight by a maximum of 3.2 kg because the subjects were too large for the scan table. After weight loss body weight measurements were accurate. Before and after weight loss the linear relations between DXA and TBK for FFM were strong (r = 0.92 and 0.93). Bland and Altman plots showed limits of agreement of +/-9 kg before and after weight loss; DXA underestimated FFM in women and overestimated FFM in men. DXA accounted for 80% of the lost body weight. The composition of the lost body mass did not differ from that estimated by TBK (7.6% FFM and 92.4% FM by TBK; 11% FFM and 89% FM by DXA). CONCLUSION: DXA estimates accurately the body composition and the composition of weight loss in groups of obese subjects. However, the scan table may be too small for patients weighing more than 95 kg.