Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.

OBJECTIVE: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures. DESIGN: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy. RESULTS: αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+ T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function. CONCLUSION: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.

A phase II trial of lanreotide for the prevention of postoperative pancreatic fistula.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) is a significant contributor to morbidity after pancreatectomy. Somatostatin analogues have shown variable efficacy in the prevention of CR-POPF. Lanreotide is a somatostatin analogue ideally suited for perioperative use due to its long half-life and favorable side effect profile. METHODS: We conducted a phase II single-arm trial of a single dose of preoperative lanreotide (120 mg) in patients undergoing either pancreaticoduodenectomy (PD) or distal pancreatectomy (DP). The primary outcome was development of CR-POPF or intra-abdominal abscess. Secondary outcomes included biochemical leak and overall morbidity. RESULTS: A total of 98 patients completed the study. Sixty-two underwent PD (63.3%) and 36 underwent DP (36.7%). The primary outcome was observed in eight (8%) patients in the overall cohort, one from the DP group and seven from the PD group. Biochemical leak was detected in 12 (12.2%) patients in the overall cohort. Twenty-seven (27.5%) patients developed complications, of which 14 (14.2%) were major complications. Drug-related adverse events were limited to mild skin reactions in two (2%) patients. CONCLUSION: Patients who received preoperative lanreotide developed CR-POPF at rates significantly lower than historical controls or published literature. This provides strong justification for a randomized controlled trial.

A novel rat model for the study of postoperative pancreatic fistula.

While over the past several decades mortality after pancreatic surgery has decreased to <5%, postoperative morbidity remains remarkably high, ranging from 15% to 65%. The development of a postoperative pancreatic fistula (POPF) is a significant contributor to morbidity in patients undergoing pancreatic surgery. POPF can lead to life-threatening conditions such as intra-abdominal abscess, uncontrolled hemorrhage, sepsis, and death. Rates of POPF have not significantly changed over time, despite the introduction of multiple technical and pharmacologic interventions aimed at their treatment and prevention. Unfortunately, there are few POPF experimental models that have been described in the literature and existing models are unable to reliably reproduce the clinical sequelae of POPF, limiting the development of new methods to prevent and treat POPF. Herein, we describe a new rat experimental model that reliably creates a POPF via transection of the common pancreatic duct.

Pancreatic paraganglioma mimicking pancreatic neuroendocrine tumor.

Extra-adrenal paragangliomas are rare tumors arising from the chromaffin cells of the autonomic nervous system. Retroperitoneal paragangliomas may present as a pancreatic mass. We present a case of a 61-year-old woman with an incidentally found pancreatic mass (7.2 × 6.5 cm) in the CT scan. EUS- guided FNA result was compatible with pancreatic neuroendocrine tumor. Patient underwent pancreaticoduodenectomy and histopathologic assessment revealed the mass was an extra-adrenal paraganglioma. Preoperative diagnosis of pancreatic paragangliomas can be challenging due to imaging and histopathologic similarities with pancreatic neuroendocrine tumors.

Emerging pathways for precision medicine in management of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the second most common biliary tract malignancy with a dismal prognosis. Surgical resection with a negative microscopic margin offers the only hope for long-term survival. However, the majority of patients present with advanced disease not amenable to curative resection, mainly due to late presentation and aggressive nature of the disease. Unfortunately, due to the heterogeneous nature of CCA as well as limitations of available chemotherapy medications, traditional chemotherapy regimens offer limited survival benefit. Recent advances in genomic studies and next-generation sequencing techniques have assisted in better understanding of cholangiocarcinogenesis and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in management of CCA with encouraging results in preclinical studies and early clinical trials. In this review, we present emerging therapies for precision medicine in CCA.

Current Advances in Minimally Invasive Surgical Management of Perihilar Cholangiocarcinoma.

BACKGROUND: While the safety of minimally invasive surgery (MIS) has been reported for several liver malignancies, the role of MIS in the management of perihilar cholangiocarcinoma (pCCA) has been poorly defined. METHODS: A systematic review of the literature was performed utilizing MEDLINE/PubMed and Web of Science databases up to January 2020 to assess the safety and feasibility of MIS in the management of patients with pCCA. RESULTS: Limited data exist on the MIS approach to treat pCCA. Staging laparoscopy carries a low diagnostic yield and typically is used only in select patients with high suspicion of metastatic disease. Data on the use of MIS approach for resection of pCCA have largely been limited to case reports or small case series. A MIS approach to pCCA resection has been demonstrated to be feasible and safe, yet in most series the surgeon failed to include resection of the caudate lobe. Given that caudate lobe involvement occurs in 31-98% of patients with pCCA, incomplete resection of the caudate lobe may be associated with higher local recurrence. More recently, several surgeons have reported complete R0 surgical with removal of the caudate lobe using a MIS approach. While patients may have a shorter length-of-stay, the true benefit of the MIS approach for pCCA needs to be better defined. CONCLUSIONS: MIS may be a safe and feasible approach at high-volume centers with robust expertise in the management of patients with pCCA. Further studies with larger number of patients are required prior to universal application of MIS for pCCA.

Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8+ T cells. We hypothesized that tumor-infiltrating CD8+ T cells harbor latent antitumor activity that can be reactivated using combination immunotherapy. EXPERIMENTAL DESIGN: Preserved human PDA specimens were analyzed using multiplex IHC (mIHC) and T-cell receptor (TCR) sequencing. Fresh tumor was treated in organotypic slice culture to test the effects of combination PD-1 and CXCR4 blockade. Slices were analyzed using IHC, flow cytometry, and live fluorescent microscopy to assess tumor kill, in addition to T-cell expansion and mobilization. RESULTS: mIHC demonstrated fewer CD8+ T cells in juxtatumoral stroma containing carcinoma cells than in stroma devoid of them. Using TCR sequencing, we found clonal expansion in each tumor; high-frequency clones had multiple DNA rearrangements coding for the same amino acid binding sequence, which suggests response to common tumor antigens. Treatment of fresh human PDA slices with combination PD-1 and CXCR4 blockade led to increased tumor cell death concomitant with lymphocyte expansion. Live microscopy after combination therapy demonstrated CD8+ T-cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis. CONCLUSIONS: Endogenous tumor-reactive T cells are present within the human PDA tumor microenvironment and can be reactivated by combined blockade of PD-1 and CXCR4. This provides a new basis for the rational selection of combination immunotherapy for PDA.See related commentary by Medina and Miller, p. 3747.

Role of associating liver partition and portal vein ligation in staged hepatectomy (ALPPS)-strategy for colorectal liver metastases.

Colorectal carcinoma (CRC) is the third leading cause of cancer-related death in the United States. The liver is the most frequent site of metastasis and a key determinant of survival in patients with isolated colorectal liver metastasis (CRLM). Surgical resection remains the only hope for prolonged survival in patients with CRLM. However, most patients are deemed to be unresectable at presentation due to a small future liver remnant (FLR) and fear of post-hepatectomy liver failure. Procedures such as portal vein ligation or embolization (PVL/PVE) followed by hepatectomy have been established as standard methods to increase FLR volume, but have limitations dependent upon extent of disease and patient's ability to grow the liver remnant. Recently, associating liver partition and portal vein ligation in staged hepatectomy (ALPPS) has been introduced as a technique to induce liver hypertrophy over a shorter time period. Being a complex two-stage surgical procedure, initial reports of higher ALPPS-associated complications and mortality limited its worldwide adoption by hepatobiliary surgeons. However, recent studies have showed ALPPS superiority over conventional procedures in terms of feasibility and inducing liver hypertrophy, with comparable morbidity and mortality. We herein review the role of ALPPS in management of patients with CRLM.

Hepatic Hemodynamic Changes Following Stepwise Liver Resection.

AIM: Extended liver resection has increased during the last decades. However, hepatic hemodynamic changes after resection and the consequent complications like post hepatectomy liver failure are still a challenging issue. The aim of this study was to systematically evaluate the role of stepwise liver resection on hepatic hemodynamic changes. METHODS: To evaluate this effect we performed 25, 50, and 75 % sequential liver resections in 10 pigs. Before and after each resection, the hepatic artery flow and portal vein flow in relation to the remnant liver volume (RLV) as well as hepatic vascular pressures were measured and compared between the groups. RESULTS: Following sequential liver resection, the hepatic artery flow /100 g decreases and the portal vein flow increases up to 17 and 167 % following extended liver resection (75 %), respectively. Also, during stepwise liver resection, the portal vein pressure increases gradually up to 33 % following extended hepatectomy (75 %). CONCLUSION: Sequential decrease in the RLV decreases the hepatic artery flow /100 g and increases the portal vein flow /100 g and portal vein pressure. As the consequence, the liver goes under more poor-oxygenated blood supply and higher pressure. This may be one of the most important mechanisms of the post hepatectomy liver failure in case of extended liver resection.

A novel approach to lower rectal anastomosis: technique innovation and the preliminary report of twenty cases / Uma nova abordagem para a anastomose retal mais baixa: inovação técnica e relatório preliminar de cinte casos

Background and aims: To describe a practical technique innovation (transanal 'Pull-through' approach) as a feasible, safe and effective alternative to the conventional transabdominal stapler low rectal anastomosis in lesions of minimal anatomical distinction from the adjacent intact mucosa. Material and methods: Prospective case-series of patients with low rectal cancers, familial adenomatous polyposis (FAP) and ulcerative colitis undergoing Pull-through transection and very low rectal anastomosis using linear TA-90 noncutting stapler and circular stapler-cutter. Results: In this series, twenty patients (11 men and 9 women) underwent proctectomy by the transanal Pull-through technique. Barring one of the patients that developed a pelvic abscess in the immediate postop follow-up, surgical procedure and the long-term follow-up period was uncomplicated with no critical findings of leakage, stenosis and bleeding. The postop rate of infection and fecal incontinence was not significantly different between genders and different age groups of the study. The mean operative time was calculated 169.9 ± 11.1 minutes. Conclusion: Pull-through transection procedure using the TA-90 non-cutting stapler is a safe, efficient and economically sound technique implicated in low-lying rectal lesions. The transanal 'Pull-through' approach is particularly helpful in situations where the direct visualization of lower rectal mucosa changes the prognosis through determining the marginal extent of intact/involved mucosa (e.g., FAP, villous adenomas, rectal polyps and post-neoadjuvant chemoradiotherapy tumors).

Experiência e objetivos: Descrever uma inovação técnica prática (abordagem transanal pull-through) como uma alternativa viável, segura e eficaz à anastomose transabdominal retal baixa convencional com grampos em lesões com mínima diferenciação anatômica com respeito à mucosa intacta adjacente. Material e métodos: Estudo prospectivo de série de casos de pacientes com cânceres retais baixos, polipose adenomatosa familiar e colite ulcerativa submetidos à transecção pull-through e a uma anastomose retal muito baixa com o uso de um grampeador linear não cortante TA-90 e um grampeador cortante circular. Resultados: Nesta série, 20 pacientes (11 homens, 9 mulheres) foram submetidos a uma proctectomia pela técnica transanal pull-through. À exceção de um dos pacientes, que apresentou um abcesso pélvico no seguimento pós-operatório imediato, não ocorreram complicações com o procedimento cirúrgico e ao longo do prolongado período de seguimento, nem houve achados críticos de vazamento, estenose ou sangramento. O percentual de infecção e incontinência fecal no pós-operatório não foi significativamente diferente entre gêneros e nas diferentes faixas etárias dos pacientes envolvidos no estudo. O tempo cirúrgico médio foi de 169,9 ± 11,1 minutos. Conclusão: O procedimento de transecção pull-through com o uso do grampeador não cortante TA-90 é técnica segura, eficaz e economicamente confiável para uso em lesões retais baixas. A abordagem transanal pull-through tem particular utilidade em situações nas quais a visualização direta de alterações na mucosa retal mais baixa muda o prognóstico, mediante a determinação da extensão marginal da mucosa intacta/envolvida (p. ex., FAP, adenomas vilosos, pólipos retais e tumores pós-quimiorradioterapia neoadjuvante).