Patient outcome according to the 2017 international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVE: We evaluated the usefulness of the 2017 definition of borderline pancreatic ductal adenocarcinoma (BR-PDAC) in fit patients (performance status 0-1) based on anatomical (A) and biological dimensions (B). METHODS: From 2011 to 2018, 139 resected patients with BR-PDAC according to the 2017 definition were included: 18 patients underwent upfront pancreatectomy (CA 19-9 > 500 U/mL and/or regional lymph node metastasis; BR-B group), and 121 received FOLFIRINOX (FX) induction chemotherapy and were divided into BR-A (CA 19-9 < 500 U/mL, no regional lymph node metastasis; n = 68) and BR-AB (CA 19-9 > 500 U/mL and/or regional lymph node metastasis; n = 53) groups. RESULTS: The 3 groups were comparable according to patient characteristics (except for back pain (P < .01) and CA 19-9 (P < .01)), intraoperative data, and postoperative courses. BR-AB patients required more venous resections (P < .01). The 3 groups were comparable on pathologic findings, except that BR-B patients had more lymph node invasions (P = .02). Median overall survival (OS) of the 121 patients was 45 months. In multivariate analysis, venous resection (P = .039) and R1 resection (P = .012) were poorly linked with OS, whereas BR-A classification (P < .01) independently favored OS. Median survival times of BR-A, BR-AB, and BR-B groups were undetermined, 27 months, and 20 months (P < .001), respectively. CONCLUSIONS: The 2017 definition was relevant for sub-classifying patients with BR-PDAC. The anatomical dimension (BR-A) was a favorable prognostic factor, whereas the biological dimension (BR-AB and BR-B) poorly impacted survival.

Has the non-resection rate decreased during the last two decades among patients undergoing surgical exploration for pancreatic adenocarcinoma?

PURPOSE: To determine if improvement in imaging reduces the non-resection rate (NRR) among patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: From 2000 to 2019, 751 consecutive patients with PDAC were considered eligible for a intention-to-treat pancreatectomy and entered the operating room. In April 2011, our institution acquired a dual energy spectral computed tomography (CT) scanner and liver diffusion weighted magnetic resonance imaging (DW-MRI) was included in the imaging workup. We consequently considered 2 periods of inclusion: period #1 (February 2000-March 2011) and period #2 (April 2011-August 2019). RESULTS: All patients underwent a preoperative CT scan with a median delay to surgery of 18 days. Liver DW-MRI was performed among 407 patients (54%). Median delay between CT and surgery decreased (21 days to 16 days, P < .01), and liver DW-MRI was significantly most prescribed during period #2 (14% vs 75%, P < .01). According to the intraoperative findings, the overall NRR was 24.5%, and remained stable over the two periods (25% vs 24%, respectively). While vascular invasion, liver metastasis, and carcinomatosis rates remained stable, para-aortic lymph nodes invasion rate (0.4% vs 4.6%; P < 0.001) significantly increased over the 2 periods. The mean size of the bigger extra pancreatic tumor significantly decrease (7.9 mm vs 6.4 mm (P < .01), respectively) when the resection was not done. In multivariate analysis, CA 19-9 < 500 U/mL (P < .01), and liver DW-MRI prescription (P < .01) favoured the resection. CONCLUSIONS: Due to changes in our therapeutic strategies, the NRR did not decrease during two decades despite imaging improvement.

'Peripheric' pancreatic cysts: performance of CT scan, MRI and endoscopy according to final pathological examination.

OBJECTIVE: To assess the accuracy of pre-operative staging in patients with peripheral pancreatic cystic neoplasms (pPCNs). METHODS: From 2005 to 2011, 148 patients underwent a pancreatectomy for pPCNs. The pre-operative examination methods of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) were compared for their ability to predict the suggested diagnosis accurately, and the definitive diagnosis was affirmed by pathological examination. RESULTS: A mural nodule was detected in 34 patients (23%): only 1 patient (3%) had an invasive pPCN at the final histological examination. A biopsy was performed in 79 patients (53%) during EUS: in 55 patients (70%), the biopsy could not conclude a diagnosis; the biopsy provided the correct and wrong diagnosis in 19 patients (24%) and 5 patients (6%), respectively. A correct diagnosis was affirmed by CT, EUS and pancreatic MRI in 60 (41%), 103 (74%) and 80 (86%) patients (when comparing EUS and MRI; P = 0.03), respectively. The positive predictive values (PPVs) of CT, EUS and MRI were 70%, 75% and 87%, respectively. CONCLUSIONS: Pancreatic MRI appears to be the most appropriate examination to diagnose pPCNs accurately. EUS alone had a poor PPV. Mural nodules in a PCN should not be considered an indisputable sign of pPCN invasiveness.

Patient-derived precision cut tissue slices from primary liver cancer as a potential platform for preclinical drug testing.

BACKGROUND: The exploitation of anti-tumour immunity, harnessed through immunomodulatory therapies, has fundamentally changed the treatment of primary liver cancer (PLC). However, this has posed significant challenges in preclinical research. Novel immunologically relevant models for PLC are urgently required to improve the translation from bench to bedside and back, explore and predict effective combinatorial therapies, aid novel drug discovery and develop personalised treatment modalities. METHODS: We used human precision-cut tissue slices (PCTS) derived from resected tumours to create a patient-specific immunocompetent disease model that captures the multifaceted and intricate heterogeneity of the tumour and the tumour microenvironment. Tissue architecture, tumour viability and treatment response to single agent and combination therapies were assessed longitudinally over 8 days of ex vivo culture by histological analysis, detection of proliferation/cell death markers, ATP content via HPLC. Immune cell infiltrate was assessed using PCR and immunofluorescence. Checkpoint receptor expression was quantified via Quantigene RNA assay. FINDINGS: After optimising the culture conditions, PCTS maintained the original tissue architecture, including tumour morphology, stroma and tumour-infiltrated leukocytes. Moreover, PCTS retained the tumour-specific immunophenotype over time, suggesting the utility of PCTS to investigate immunotherapeutic drug efficacy and identify non-responsiveness. INTERPRETATION: Here we have characterised the PCTS model and demonstrated its effectiveness as a robust preclinical tool that will significantly support the development of successful (immuno)therapeutic strategies for PLC. FUNDING: Foundation for Liver Research, London.

Exposure to Contaminated River Water is Associated with Early Hatching and Dysregulation of Gene Expression in Early Life Stages of the Endangered Copper Redhorse (Moxostoma hubbsi).

The copper redhorse (Moxostoma hubbsi) is an endangered fish that spawns exclusively in the Richelieu River (Quebec, Canada). Tributaries of the Richelieu are contaminated with high levels of current-use pesticides, which may impact early-life stage (ELS) copper redhorse and other native fishes. We assessed the effects of exposure to contaminated river water on ELS copper redhorse and river redhorse (Moxostoma carinatum), a related fish that shares the copper redhorse's spawning grounds and nursery habitat. A riverside flow-through system was used to expose copper and river redhorse embryos (1000 each) to Richelieu River water or laboratory water as a control. Fish were maintained until 14 days posthatch, and water samples were taken daily for chemical analysis. Following a heavy rain event, concentrations of two neonicotinoid pesticides, clothianidin and thiamethoxam, exceeded water quality guidelines for aquatic life (20 ng/L). Using nontargeted screening, we tentatively identified an additional 24 pharmaceutical and personal care products and 23 pesticides in river water. Effects of river water on ELS fish were observed in both species, but the copper redhorse appeared to be more sensitive. Fish exposed to river water hatched 10.7 (copper redhorse) and 2.4 (river redhorse) cumulative degree days earlier than controls. Copper redhorse survival was significantly lower in river water (73 ± 16%) compared to laboratory water (93 ± 3%), whereas river redhorse survival was similar between treatments (84 ± 6% and 89 ± 4%, respectively). Sequencing of copper redhorse larvae RNA revealed 18 differentially expressed genes (DEGs) following 14 days of exposure to river water. Eight up-regulated DEGs were linked to immune function and injury response, and seven down-regulated DEGs were involved with digestion and nutrient absorption. The present study provided valuable data on the effects of ELS exposure to a real-world mixture of contaminants in two fish species of concern. Environ Toxicol Chem 2022;41:1950-1966. © 2022 SETAC.

Outcomes of pancreatic adenocarcinoma that was not resected because of isolated para-aortic lymph node involvement.

PURPOSE: Survival appears to be poor in cases of pancreatic ductal adenocarcinoma (PDAC) with para-aortic lymph node involvement (PALN+). However, resection is still performed in these cases because the prognostic impact of PALN+remains controversial. METHODS: PALN+was intraoperatively found in 14 patients (4.8%) with resectable PDAC who consequently did not undergo pancreatectomy. RESULTS: The median overall survival time after laparotomy was 21 months. The 1- and 3-year overall survival rates were 58.3% and 25%, respectively. CONCLUSIONS: We support the advisability of reconsidering pancreatectomy in patients with intraoperatively detected PALN+because the reported survival of such patients who undergo pancreatectomy is poorer than the survival observed for patients in our series.

Targeting senescent cells alleviates obesity-induced metabolic dysfunction.

Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.

Resectable pancreatic head adenocarcinoma: Is R0 resection an illusion? Genetic evaluation of venous resection margin affirmed unrecognized disease.

PURPOSE: To assess the K-ras gene mutation in the histologically negative venous margin of a pancreaticoduodenectomy (PD) specimen and its impact on survival. METHOD: From 2007 to 2010, 22 patients underwent R0 PD for resecable pancreatic adenocarcinoma. All specimens were stained and the portal vein (PV) bed was identified by blue ink; a 2mm3 sample (including the blue ink) was cut from a microscopic free-tumor block. DNA was extracted and assessed by quantitative real time polymerase chain reaction to detect the K-ras gene mutation. Twelve specimens (55%) (kras+ group) were identified with a K-ras mutation in the venous margin resection, and 10 specimens (kras- group) did not have K-ras mutation detected in the venous margin resection. RESULTS: The two groups were comparable. Overall 3years survival of patients of kras+ group versus patients of kras- group was 0 and 17% (P=0.03), respectively. Median survival time of patients of kras+ group versus patients of kras- group was 16months vs 25months (P=0.04; 95% confidence interval [1,11-1,88]), respectively. CONCLUSION: Genetic evaluation of venous resection margin affirmed unrecognized disease with strong impact on survival in more than 50% of patients with histologically R0 resection.

New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463.

Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturally-occurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-XL inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.

Body composition during long-term treatment of uremia with amino acid supplemented low-protein diet.

The influence on body composition of prolonged treatment with low-protein diet (20 g/day) supplemented with the essential amino acids and histidine was studied in 49 patients with chronic renal failure and uremic symptoms. Total body potassium (TBK) was measured with 40K in a whole-body counter. Total body water was determined with dilution of tritiated water. Predicted values for TBK and total body water were obtained from a reference population of 476 healthy subjects. In 38 patients investigated before treatment body weight was normal while mean TBK was 91% of predicted in men and 100% in women. Mean total body water was 104% of predicted in both men and women. Thirty-one patients were investigated at 3-month intervals during treatment for up to 12 months. No significant changes in mean body weight, TBK, or total body water were found. However, in 10/13 patients TBK decreased significantly, presumably due to increased catabolism in connection with intercurrent disease or insufficient energy intake. In the absence of complications long-term treatment with a low-protein diet and essential amino acids in renal failure seems to maintain body cell mass reflected in unchanged TBK.

Centrorhynchus aluconis (Acanthocephala) and other helminth species in tawny owls (Strix aluco) in Great Britain.

Observations on the distribution of Centrorhynchus aluconis (Acanthocephala) and 6 other species of helminths in the definitive host Strix aluco, in tawny owl, are presented. Infected owls were collected from 16 sites ranging from Tarbet, Strathclyde, Scotland, to Ewhurst, Surrey, in the south of England. In addition, unidentified cyclophyllidean cestodes were found in the alimentary tract of the tawny owls. Centrorhynchus aluconis was the most prevalent helminth found and had the highest intensity. It appears that C. aluconis is widely distributed in the tawny owls of Great Britain. Porrocaecum spirale (Nematoda) was the second most prevalent species of helminth. This species and C. aluconis are believed to be dependent on shrews (Sorex araneus and Sorex minutus) for their transmission to owls.

The occurrence of Centrorhynchus (Acanthocephala) in shrews (Sorex araneus and Sorex minutus) in the United Kingdom.

Encysted acanthocephalans belonging to the genus Centrorhynchus were found in the body cavities of Sorex araneus (common shrew) and Sorex minutus (pygmy shrew) from Boxworth, Cambridgeshire, U.K. Fifty percent of the male S. araneus and 67% of the male S. minutus examined were found to be infected, with the mean intensity (+/-SD) being 54.3 +/- 91.3 and 14.7 +/- 18.4, respectively. The species of Centrorhynchus in the shrews may be Centrorhynchus aluconis, which is distributed widely in tawny owls, Strix aluco, in the United Kingdom. Shrews appear to serve as paratenic hosts for C. aluconis.

The use of living donors. Glomerular filtration rate during the first year after donor nephrectomy.

The functional increase in the remaining kidney after donor nephrectomy has two distinct components in man. There is a rapid initial increase in function within the first 24 hours, due to the circulatory adjustments in the kidney, but the mechanisms have not been elucidated. Thereafter, there is a further functional increase during the first year which in addition to the haemodynamic changes, also includes an increase in tubular function. The increased work-load on the kidney handling the increased volume of filtrate presented to the tubules may induce the increase in tubular function, but hormonal factors have been shown to contribute to the long-term increase in tubular function after contralateral nephrectomy.

Factors influencing the prognosis in diabetic patients accepted for renal transplantation.

Out of 27 patients with advanced diabetic nephropathy accepted for renal transplantation. 11 had cardiac symptoms and 10 others had advanced neuropathy. The former group had a poor outcome with 100% mortality within one year, seven patients dying before transplantation. Neuropathy also indicated a poor prognosis. Early transplantation, before the stage of terminal uraemia, was at no advantage in this material.

Pancreatic neuroendocrine tumor: A multivariate analysis of factors influencing survival.

BACKGROUND: The outcomes of pancreatic neuroendocrine tumors are extremely diverse, and determining the best strategy, optimal timing of therapy and the therapeutic results depend on understanding prognostic factors. We determined the clinical, radiological and histological factors associated with survival and tumor recurrence for patients with pancreatic neuroendocrine tumor. METHODS: From January 1, 1991 to December 31, 2011, 127 patients with pancreatic neuroendocrine tumor underwent pancreatectomy. The variables including clinical characteristics, surgical data and pathological findings were examined by univariate and multivariate analyses. RESULTS: There were 103 patients with non-functional tumors (81%). Sixty-four patients (50%) underwent left pancreatectomy, 51 (42%) patients underwent pancreatico-duodenectomy, 12 (9%) patients underwent enucleation and 2 patients (1%) underwent central pancreatectomy. Forty-eight patients (38%) had synchronous liver metastases. Six patients (5%) required portal vein resection, and 19 (15%) patients required enlarged "en-bloc" resection of adjacent organs. The overall morbidity and mortality rates were 48% and 2.3%, respectively. The 1-, 3- and 5-year overall survival rates were 94%, 84%, and 74%, respectively. In multivariate analyses, synchronous liver metastases (p = 0.02) and portal vein resection (p < 0.01) were independent prognostic factors of survival. CONCLUSIONS: Synchronous liver metastases and portal vein resection were found to be independent factors influencing survival.

Two-stage hepatectomy: who will not jump over the second hurdle?

BACKGROUND: Two-stage hepatectomy uses compensatory liver regeneration after a first noncurative hepatectomy to enable a second curative resection in patients with bilobar colorectal liver metastasis (CLM). OBJECTIVE: To determine the predictive factors of failure of two-stage hepatectomy. METHOD: Between 2000 and 2010, 48 patients with irresectable CLM were eligible for two-stage hepatectomy. The planned strategy was a) cleaning of the left hepatic lobe (first hepatectomy), b) right portal vein embolisation and c) right hepatectomy (second hepatectomy). Six patients had occult CLM (n = 5) or extra-hepatic disease (n = 1), which was discovered during the first hepatectomy. Thus, 42 patients completed the first hepatectomy and underwent portal vein embolisation in order to receive the second hepatectomy. Eight patients did not undergo a second hepatectomy due to disease progression. RESULTS: Upon univariate analysis, two factors were identified that precluded patients from having the second hepatectomy: the combined resection of a primary tumour during the first hepatectomy (p = 0.01) and administration of chemotherapy between the two hepatectomies (p = 0.03). An independent association with impairment to perform the two-stage strategy was demonstrated by multivariate analysis for only the combined resection of the primary colorectal cancer during the first hepatectomy (p = 0.04). CONCLUSION: Due to the small number of patients and the absence of equivalent conclusions in other studies, we cannot recommend performance of an isolated colorectal resection prior to chemotherapy. However, resection of an asymptomatic primary tumour before chemotherapy should not be considered as an outdated procedure.