Antigen Receptor T Cells (CAR-T) Effectively Control Tumor Growth in a Colorectal Liver Metastasis Model.

BACKGROUND: Effective treatment of solid tumors requires multi-modality approaches. In many patients with stage IV liver disease, current treatments are not curative. Chimeric antigen receptor T cells (CAR-T) are an intriguing option following success in hematological malignancies, but this has not been translated to solid tumors. Limitations include sub-optimal delivery and elevated interstitial fluid pressures. We developed a murine model to test the impact of high-pressure regional delivery (HPRD) on trafficking to liver metastases (LM) and tumor response. MATERIALS AND METHODS: CAR-T were generated from CD45.1 mice and adoptively transferred into LM-bearing CD45.2 mice via regional or systemic delivery (RD, SD). Trafficking, tumor growth, and toxicity were evaluated with flow cytometry, tumor bioluminescence (TB, photons/sec log2-foldover baseline), and liver function tests (LFTs). RESULTS: RD of CAR-T was more effective at controlling tumor growth versus SD from post-treatment days (PTD) 2-7 (P = 0.002). HPRD resulted in increased CAR-T penetration versus low-pressure RD (LPRD, P = 0.004), suppression of tumor proliferation (P = 0.03), and trended toward improved long-term control at PTD17 (TB=3.7 versus 6.1, P = 0.47). No LFT increase was noted utilizing HPRD versus LPRD (AST/ALT P = 0.65/0.84) while improved LFTs in RD versus SD groups suggested better tumor control (HPRD AST/ALT P = 0.04/0.04, LPRD AST/ALT P = 0.02/0.02). CONCLUSIONS: Cellular immunotherapy is an emerging option for solid tumors. Our model suggests RD and HPRD improved CAR-T penetration into solid tumors with improved short-term tumor control. Barriers associated with SD can be overcome using RD techniques to maximize therapeutic delivery and HPRD may further augment efficacy without increased toxicity.

Financial Well-Being for Thoracic Surgeons.

The authors provide a brief overview for thoracic surgeons in topics essential to achieving financial well-being as a student, trainee, practicing surgeon, and beyond. While broad in nature, the authors' article is comprehensive, and they cover topics including student loans, asset and wealth management, investment opportunities, financial and estate planning, and insurances. It is hoped that the information provided will allow thoracic surgeons to become more familiar with the financial topics that pertain to thoracic surgeons and provide an introduction to explore financial wellness and literacy more thoroughly.

First report of a post-pneumonectomy nocardia empyema.

Post-pneumonectomy empyema (PPE) is an uncommon but serious complication that carries significant therapeutic challenges. We present a late-onset PPE due to Nocardia nova in an immunocompetent individual. Nine years after a right pneumonectomy for non-small cell lung cancer, surveillance scans revealed new right pleural thickening and FDG avidity concerning for recurrence. Thoracoscopic pleural biopsies were negative for malignancy, but tissue cultures grew N. nova. Nocardia empyema is rare with few reported cases. Most occur in immunocompromised hosts, and all were associated with pulmonary or disseminated nocardiosis. Our case describes the first report of a PPE secondary to Nocardia.

Delayed cardiac tamponade secondary to blast injury from gunshot wound.

Penetrating injuries are recognized for the direct tissue damage, which is typically evident on physical examination. Secondary injuries resulting from kinetic energy transfer in the case of gunshot wounds (GSWs), often referred to as "blast injuries", may affect tissues distant to the ballistic trajectory and are often occult. We present a case of delayed cardiac tamponade resulting from secondary blast injury. The patient sustained a thoraco-abdominal GSW with entry adjacent to the cardiac box. An Advanced Trauma Life Support (ATLS)-guided assessment revealed intra-abdominal injuries necessitating operative intervention without evidence of cardiac injury. On post-operative day four, the patient developed chest pain, tachycardia, and shortness of breath. Imaging revealed a large pericardial effusion with cardiac tamponade. Emergent exploration revealed hemopericardium secondary to a bleeding epicardial hematoma without evidence of pericardial violation. Clinicians must maintain a high clinical suspicion for occult, indirect blast injuries which may be life-threatening.

Regional Delivery of Anti-PD-1 Agent for Colorectal Liver Metastases Improves Therapeutic Index and Anti-Tumor Activity.

Metastatic liver tumors have presented challenges with the use of checkpoint inhibitors (CPIs), with only limited success. We hypothesize that regional delivery (RD) of CPIs can improve activity in the liver and minimize systemic exposure, thereby reducing immune-related adverse events (irAE). Using a murine model of colorectal cancer liver metastases (LM), we confirmed high levels of PD-L1 expression on the tumor cells and liver myeloid-derived suppressor cells (L-MDSC). In vivo, we detected improved LM response at 3 mg/kg on PTD7 via portal vein (PV) regional delivery as compared to 3 mg/kg via tail vein (TV) systemic delivery (p = 0.04). The minimal effective dose at PTD7 was 5 mg/kg (p = 0.01) via TV and 0.3 mg/kg (p = 0.02) via PV. We detected 6.7-fold lower circulating CPI antibody levels in the serum using the 0.3 mg/kg PV treatment compared to the 5 mg/kg TV cohort (p < 0.001) without increased liver toxicity. Additionally, 3 mg/kg PV treatment resulted in increased tumor cell apoptotic signaling compared to 5 mg/kg TV (p < 0.05). Therefore, RD of an anti-PD-1 CPI therapy for CRCLM may improve the therapeutic index by reducing the total dose required and limiting the systemic exposure. These advantages could expand CPI indications for liver tumors.

Challenges in assessing solid tumor responses to immunotherapy.

With the advent of immunotherapy as an integral component of multidisciplinary solid tumor treatment, we are confronted by an unfamiliar and novel pattern of radiographic responses to treatment. Enlargement of tumors or even new lesions may not represent progression, but rather reflect what will ultimately evolve into a clinically beneficial response. In addition, the kinetics of radiographic changes in response to immunotherapy treatments may be distinct from what has been observed with cytotoxic chemotherapy and radiation. The phenomenon of pseudoprogression has been documented in patients receiving immunotherapeutic agents, such as checkpoint inhibitors and cellular therapies. Currently, there are no clinical response guidelines that adequately account for pseudoprogression and solid tumor responses to immunotherapy in general. Even so, response criteria have evolved to account for the radiographic manifestations of novel therapies. The evolution of World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST), along with the emergence of immune-related response criteria (irRC) and the immune Response Evaluation Criteria in Solid Tumors (iRECIST) reflect the need for new frameworks. This review evaluates the relationship between pseudoprogression, clinical outcomes, and our current understanding of the biology of pseudoprogression. To achieve our goal, we discuss unusual response patterns in patients receiving immunotherapy. We seek to develop a deeper understanding of radiographic responses to immunotherapy such that clinical benefit is not underappreciated in individual patients and during clinical investigation.

Pressure-enabled delivery of gemcitabine in an orthotopic pancreatic cancer mouse model.

BACKGROUND: We describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment. METHODS: Murine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion. RESULTS: Baseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm3; P < .01). CONCLUSION: Pancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway.

Choledochoplasty with Gallbladder Wall Free Flap: A Novel Technique for Large Bile Duct Defects from Mirizzi Syndrome in High-Risk Patients-A Case Report and Literature Review.

BACKGROUND: Cholecystectomies are almost universally performed laparoscopically with complication rates similar to open surgery. Possible complications include bleeding and damage to surrounding structures. These often require intervention to repair the damage immediately when recognized intraoperatively or postoperatively. These injuries can cause significant morbidity and mortality, and additional interventions further compound this, especially for high-risk patients. All attempts should be made to a lower risk while performing the safest operation and addressing complications appropriately. We present a case of a surgically high-risk patient who underwent an attempted laparoscopic, converted to open, cholecystectomy for Mirizzi syndrome, during which a biliary defect was found and repaired with a novel technique of choledochoplasty with a gallbladder wall free flap. CASE: An 82-year-old female with abdominal pain was diagnosed with a cholecystocholedochal fistula from chronic cholecystitis and Mirizzi syndrome. During cholecystectomy, a large common bile duct defect was noted, and given intraoperative instability, the repair was completed using a gallbladder wall free flap. Postoperatively, the patient recovered well through a 4.5-year follow-up. CONCLUSION: Complications from laparoscopic cholecystectomy are rare but may result in additional interventions. For patients who are high-risk surgical candidates, gallbladder wall free flap choledochoplasty should be considered to avoid additional morbidity and mortality.

Pneumoscrotum: Value as an early diagnostic sign of tension pneumothorax in blunt thoracic trauma.

Pneumoscrotum is a rare complication that can result from various etiologies and can be essential in the diagnosis of those causative factors, especially life-threatening ones such as infection or trauma. We present here a case of a patient who presented in posttraumatic cardiac arrest and an extensive, grossly obvious, and rapidly expanding pneumoscrotum. Based on our patient's clinical presentation and a history of a high-speed mechanism with obvious torso trauma, a diagnosis of tension pneumothorax was quickly made resulting in immediate treatment. We review the existing literature and highlight the importance of pneumoscrotum in aiding with differential diagnosis. The presence of pneumoscrotum is often benign; however, in the right clinical setting, it can be an extremely important and useful clinical tool for the early identification and timely treatment of life-threatening diagnoses, such as tension pneumothorax.

Taking the Lead: A Case Report of a Leiomyoma Causing Duodeno-Duodenal Intussusception and Review of Literature.

Background: Duodenal masses are rare entities and symptomatic presentation generally is due to abdominal pain or the presence of gastrointestinal bleeding. A number of published case reports in the literature have detailed various neoplasms that have caused an intussusception isolated to the duodenum. This is a particularly unusual phenomenon due to the location and fixation of this portion of the proximal small bowel to the retroperitoneum. We present here a case of duodeno-duodenal intussusception secondary to a leiomyoma. Case: A 65-year-old Caucasian male presented with intermittent bloody stools and syncope over a 9-month period secondary to a duodenal leiomyoma causing intussusception, which was treated through a pancreaticoduodenectomy. Conclusion: Intussusception of the duodenum is an uncommon entity and the diagnosis of a leiomyoma should be considered in the setting of a potential mass in the small intestine.