Urinary detection of early responses to checkpoint blockade and of resistance to it via protease-cleaved antibody-conjugated sensors.

Immune checkpoint blockade (ICB) therapy does not benefit the majority of treated patients, and those who respond to the therapy can become resistant to it. Here we report the design and performance of systemically administered protease activity sensors conjugated to anti-programmed cell death protein 1 (αPD1) antibodies for the monitoring of antitumour responses to ICB therapy. The sensors consist of a library of mass-barcoded protease substrates that, when cleaved by tumour proteases and immune proteases, are released into urine, where they can be detected by mass spectrometry. By using syngeneic mouse models of colorectal cancer, we show that random forest classifiers trained on mass spectrometry signatures from a library of αPD1-conjugated mass-barcoded activity sensors for differentially expressed tumour proteases and immune proteases can be used to detect early antitumour responses and discriminate resistance to ICB therapy driven by loss-of-function mutations in either the B2m or Jak1 genes. Biomarkers of protease activity may facilitate the assessment of early responses to ICB therapy and the classification of refractory tumours based on resistance mechanisms.

Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control.

Treating solid malignancies with chimeric antigen receptor (CAR) T cells typically results in poor responses. Immunomodulatory biologics delivered systemically can augment the cells' activity, but off-target toxicity narrows the therapeutic window. Here we show that the activity of intratumoural CAR T cells can be controlled photothermally via synthetic gene switches that trigger the expression of transgenes in response to mild temperature elevations (to 40-42 °C). In vitro, heating engineered primary human T cells for 15-30 min led to over 60-fold-higher expression of a reporter transgene without affecting the cells' proliferation, migration and cytotoxicity. In mice, CAR T cells photothermally heated via gold nanorods produced a transgene only within the tumours. In mouse models of adoptive transfer, the systemic delivery of CAR T cells followed by intratumoural production, under photothermal control, of an interleukin-15 superagonist or a bispecific T cell engager bearing an NKG2D receptor redirecting T cells against NKG2D ligands enhanced antitumour activity and mitigated antigen escape. Localized photothermal control of the activity of engineered T cells may enhance their safety and efficacy.

Meta-analysis of warmed versus standard temperature CO2 insufflation for laparoscopic cholecystectomy.

BACKGROUND: There is conflicting evidence for the use of warmed, humidified carbon dioxide (CO2) for creating pneumoperitoneum during laparoscopic cholecystectomy. Few studies have reported less post-operative pain and analgesic requirement when warmed CO2 was used. AIM: This systematic review and meta-analysis aims to analyse the literature on the use of warmed CO2 in comparison to standard temperature CO2 during laparoscopic cholecystectomy. METHODS: Systematic review and meta-analysis carried out in line with the PRISMA guidelines. Primary outcomes of interest were post-operative pain at 6 h, day 1 and day 2 following laparoscopic cholecystectomy. Secondary outcomes were analgesic usage and drop in intra-operative core body temperature. Standard Mean Difference (SMD) was calculated for continuous variables. RESULTS: Six randomised controlled trials (RCTs) met the inclusion criteria (n = 369). There was no significant difference in post-operative pain at 6 h [3 RCTs; SMD = -0.66 (-1.33, 0.02) (Z = 1.89) (P = 0.06)], day 1 [4 RCTs; SMD = -0.51 (-1.47, 0.44) (Z = 1.05) (P = 0.29)] and day 2 [2 RCTs; SMD = -0.96 (-2.30, 0.37) (Z = 1.42) (P = 0.16)] between the warmed CO2 and standard CO2 group. There was no difference in analgesic usage between the two groups, but pooled analysis was not possible. Two RCTs reported significant drop in intra-operative core body temperature, but there were no adverse events related to this. CONCLUSIONS: This review showed no difference in post-operative pain and analgesic requirements between the warmed and standard CO2 insufflation during laparoscopic cholecystectomy. Currently there is not enough high quality evidence to suggest routine usage of warmed CO2 for creating pneumoperitoneum during laparoscopic cholecystectomy.

Transomental defects as a cause of chronic abdominal pain, the role of diagnostic laparoscopy: a case series.

INTRODUCTION: Transomental herniation is a rare but recognised clinical condition, which usually presents as an emergency with bowel obstruction. It accounts for 1-4% of intra-abdominal herniations. We reviewed 3 patients found to have a transomental defect during elective diagnostic laparoscopy performed for chronic abdominal pain. To our knowledge, there is no case series reported in the literature on transomental defect in the non-emergency situation. CASE PRESENTATION: A retrospective case note analysis of 3 patients, found to have transomental defect during elective diagnostic laparoscopy, was undertaken. Data were gathered with respect to clinical presentation, investigations performed, transomental defect size and outcome of surgery. All patients were followed up for 6 months post-operatively. Three females (age range 18-35 years) were referred with a 3-10 year history of chronic intermittent abdominal pain, often postprandial. Blood tests, radiological investigations (ultrasound, magnetic resonance imaging/computed tomography, small bowel studies) and endoscopy were all normal. In each case, diagnostic laparoscopy revealed the presence of a peripheral defect in the greater omentum, but no actual small bowel herniation. No other pathology was found. These defects were resected, which subsequently led to complete resolution of the patients' symptoms. CONCLUSION: Chronic abdominal pain of unknown aetiology with normal radiological findings may be caused by intermittent obstruction due to small bowel herniation through a transomental defect. This should be considered during elective diagnostic laparoscopy, in the absence of any other obvious pathology. The omentum should be thoroughly inspected as a discrete entity and any such defects should be closed or resected.

Biliary peritonitis caused by a leaking T-tube fistula disconnected at the point of contact with the anterior abdominal wall: a case report.

INTRODUCTION: Operations on the common bile duct may lead to potentially serious complications such as biliary peritonitis. T-tube insertion is performed to reduce the risk of this occurring postoperatively. Biliary leakage at the point of insertion into the common bile duct, or along the fistula, can sometimes occur after T-tube removal and this has been reported extensively in the literature. We report a case where the site at which the T-tube fistula leaked proved to be the point of contact between the fistula and the anterior abdominal wall, a previously unreported complication. CASE PRESENTATION: A 36-year-old sub-Saharan African woman presented with gallstone-induced pancreatitis and, once her symptoms settled, laparoscopic cholecystectomy was performed, common bile duct stones were removed and a T-tube was inserted. Three weeks later, T-tube removal led to biliary peritonitis due to the disconnection of the T-tube fistula which was recannulated laparoscopically using a Latex drain. CONCLUSION: This case highlights a previously unreported mechanism for bile leak following T-tube removal caused by detachment of a fistula tract at its contact point with the anterior abdominal wall. Hepatobiliary surgeons should be aware of this mechanism of biliary leakage and the use of laparoscopy to recannulate the fistula.

Laparoscopic management of difficult recurrent choledocholithiasis.

The management of common bile duct stones has traditionally required open laparotomy and bile duct exploration. With the advent of endoscopic and laparoscopic technology in the latter half of the last century, endoscopic retrograde cholangiopancreatography and laparoscopic common bile duct exploration has become the mainstream treatment for common bile duct stones in most medical centers around the world. However, in some patients, endoscopic retrograde cholangiopancreatography is difficult and laparoscopy is challenging because of previous surgery. These facts are highlighted in this report.

Pneumonitis following grease gun injury.

Grease gun trauma often involves subcutaneous injection of the grease because of the high pressures required for its industrial application. The case is presented of a man who developed a pneumonitis shortly after sustaining a grease gun injury, with injection of grease into his upper thigh associated with significant vascular damage. Pneumonitis has not previously been reported with this type of injury, and is likely to represent a systemic reaction to the local inflammatory response. Management of these injuries should incorporate early debridement with anticipation of underlying vascular trauma, and also an awareness of the potential systemic complications.

Postoperative taste and smell deficit after upper gastrointestinal cancer surgery--an unreported complication.

BACKGROUND AND OBJECTIVES: Patients undergoing upper gastrointestinal cancer surgery were noted to suffer loss of taste and/or smell, a previously unreported problem. Our aim was to investigate the extent of this phenomenon, quantify recovery time, and identify potentially associated factors. METHODS: In this retrospective study, a postal questionnaire was sent to all patients still alive after oesophagectomy or gastrectomy, with a minimum 1-year follow-up and no clinical or radiological evidence of recurrence. Data were analysed for prevalence of deficit in relation to operation, age, sex, respiratory complications, and disease stage. RESULTS: A total of 109/119 (92%) patients completed the questionnaire: 50 gastrectomies and 69 oesophagectomies. Ten patients were excluded with prior sensory deficit. Overall, 45/99 patients (45%) suffered deficit (M:F = 1.6:1). No association was found with type of surgery: deficits for subtotal gastrectomy, total gastrectomy, and oesophagectomy were 44, 46 and 46% respectively (chi(2) = 0.355, 2 df P > 0.5). No other parameter was associated, and full recovery occurred in 30 patients (67%) within a mean of 6 months. CONCLUSIONS: Loss of taste and smell occurs in nearly one-half of all cases after upper gastrointestinal surgery. The pathophysiology is unknown, but it resolves in most patients within 6-12 months. This complication should be discussed as part of informed consent for patients undergoing oesophagogastric cancer surgery.