Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants.

BACKGROUND: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. METHODS: Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. RESULTS: Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment. CONCLUSION: Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.

Intestinal transplantation: current status and future directions.

Three decades after the first intestinal transplant was performed in humans, this life-saving procedure has come of age and now offers hope of long-term survival in a small group of patients with life-threatening complications of intestinal failure and parenteral nutrition. Success rates have greatly improved, largely through advances in immunosuppression protocols, improved surgical technique and postoperative care, and accumulated experience. Management of the intestinal transplant recipient entails careful surveillance, prevention, and treatment of rejection and infection, as well as optimization of feeding and nutrition. With this approach, survival and quality of life are demonstrably improved, such that intestinal transplantation is now an established and accepted procedure for this very select group of highly-complex patients.

Norfloxacin and trimethoprim-sulfamethoxazole therapy have similar efficacy in prevention of spontaneous bacterial peritonitis.

BACKGROUND AND AIM: Although norfloxacin (N) is widely accepted as the drug of choice for spontaneous bacterial peritonitis (SBP) prophylaxis, there is data to suggest that trimethoprim-sulfamethoxazole (TS) may be similarly effective. However, no studies have compared the efficacy and safety of N and TS in SBP prophylaxis. The aim of this retrospective analysis was to compare outcomes in patients who received either N or TS for the prevention of SBP. METHODS: Records of all cirrhotic patients prescribed either N or TS for SBP prevention between April 2001 and May 2004 were reviewed. Data collected included age, sex, Child-Pugh score, ascitic protein concentration, etiology of liver disease, infections (SBP, bacteremia, and extraperitoneal infections), side-effects, and survival. RESULTS: Sixty-nine patients (18 female, 51 male), mean age 53.9 +/- 10.6 years, were prescribed N (n = 37) or TS (n = 32). The Child-Pugh score, model for end-stage liver disease score, and the prevalence of a low ascitic protein (<15 g/L) were similar between the groups (12.0 vs 12.4, 19.7 vs 18.2, and 78% vs 84%, respectively, P > 0.05). Fourteen (38%) infections occurred in the N group and 16 (50%) in the TS group (P > 0.05). Eight patients (21.6%) in the N group and nine (28%) in the TS group developed SBP (P > 0.05). The rates of liver transplantation (10 vs 13), adverse events (two in each group) and death (13 vs 14) were similar in the two treatment groups. CONCLUSIONS: Our findings suggest N and TS have similar efficacy in preventing SBP. This has significant implications for both the cost of SBP prophylaxis and the prevalence of fluoroquinolone resistance in patients with cirrhosis.

Current pharmacotherapy in the management of cirrhosis: focus on the hyperdynamic circulation.

Many major complications of hepatic cirrhosis relate to the development of a characteristic hyperdynamic circulatory state in these patients, irrespective of the underlying disease aetiology. Vasodilatation of the systemic and splanchnic circulations leads to a reduced total systemic vascular resistance, increased cardiac output and intense activation of neurohumoral vasoconstrictor systems including the sympathetic nervous system, renin-angiotensin system and vasopressin. Vasoconstriction of the renal and hepatic circulations contributes to the development of renal failure and portal hypertension, respectively. Current treatments that focus on amelioration of these circulatory derangements offer much promise, however, they are often limited by side effects in these patients.

Biliary stenting versus surgical bypass for palliation of periampullary malignancy.

BACKGROUND: Patients with periampullary cancers may not be suitable for curative resection due to locally advanced disease, metastases, or poor health. Biliary stenting and surgical bypass are utilized for symptom control, but the true benefit of one technique over the other is not clear. METHODS: A retrospective analysis of case records was undertaken of patients with periampullary (pancreatic head/uncinate process, distal bile duct, and ampulla of Vater and surrounding duodenum) malignancy treated between June 2004 and June 2010 in a tertiary center by palliative biliary stenting or palliative surgical bypass. RESULTS: Of the 69 patients included in the analysis, combined biliary and gastric bypass was performed on 28, while 41 underwent biliary stent (metallic, n = 39) insertion. Patients undergoing stenting were significantly older and less likely to be offered chemotherapy than those from the surgical bypass group. Overall, there were significantly more complications in the stent insertion group (85 %) than the surgical bypass group (36 %) (p = 0.003). The stent group required significantly more subsequent procedures than the surgical bypass group. Metal stent obstruction occurred in 16 of 39 (41 %) patients, with a median stent patency of 224 days. The overall median survival of patients in this study was 7 months with no significant difference between the groups (p = 0.992). The presence of metastases at presentation was the only independent factor associated with decreased survival. CONCLUSION: There was no survival difference between stenting vs. surgical bypass for palliation of periampullary cancer. There was, however, a high rate of stent occlusion and need for repeat procedures in patients treated by metal stenting, suggesting that stenting may be best suited to patients predicted as having the shortest survival.

Vasoconstrictor responses are normal but prostanoid-mediated vasodilatation is enhanced in human cirrhotic mesenteric arteries.

BACKGROUND AND AIMS: The mechanisms responsible for mesenteric vasodilatation in cirrhosis have not been fully elucidated. The aim of the present study was to examine whether there is altered intrinsic vascular reactivity of human mesenteric vessels in cirrhosis, which might contribute to vasodilatation in vivo. METHODS: Ten mesenteric arteries from six cirrhosis patients undergoing liver transplantation were compared with 11 arteries from six control patients. Vasoconstrictor responses to potassium, norepinephrine and methoxamine were determined. Endothelium-dependent vasodilatation responses to acetylcholine and substance P were determined both before and after inhibition of nitric oxide (NO) and prostanoid synthesis. RESULTS: Cirrhotic vessels responded normally to potassium depolarization and did not differ to control vessels with respect to sensitivity and maximal response to norepinephrine. In cirrhotic vessels, inhibition of NO synthesis had significantly less effect on substance P-induced vasorelaxation than in controls (% Relaxation: cirrhosis 70.3 +/- 9.6; control 34.9 +/- 9.5; P = 0.03). However, after inhibition of both NO and prostanoid synthesis, vasodilatory responses were eliminated in both groups. CONCLUSIONS: The findings of the present study indicate that intrinsic hyporesponsiveness to vasoconstrictors does not play a pathogenetic role in the mesenteric vasodilatation in human cirrhosis. Furthermore, vasodilator prostanoids might make a significant contribution in mediating enhanced endothelium-dependent vasorelaxation in the mesenteric circulation.

Predictors of improvement in renal function after calcineurin inhibitor withdrawal for post-liver transplant renal dysfunction.

BACKGROUND: Renal dysfunction after liver transplantation is a major management problem. Predictors of improvement in renal dysfunction after calcineurin inhibitor therapy (CNI) withdrawal and replacement with either mycophenolate mofetil (MMF) or azathioprine (AZA) have not previously been examined. METHODS: Retrospective analysis of 33 post-transplant patients with creatinine clearance (CrCl) below 50 mL/min who were changed from CNI to either MMF or AZA. Following CNI withdrawal patients were divided into two groups: those with improved CrCl after switching and those without, to identify the variables associated with improved renal function. RESULTS: Variables associated with improved CrCl were: absence of hypertension or diabetes, shorter time between transplantation and switch, deterioration in CrCl in months prior to switch and treatment with MMF (compared with AZA). CONCLUSIONS: Our findings suggest CNI withdrawal should be targeted to a subgroup of patients whose renal function is most likely to improve.