Impact of immunotherapy with pseudomonas serotip xv etanolic extract (Cantastim) on local recurrence and survival at 3 and 5 years in operated rectal cancer

Although most recurrences (approximately 80%) occur in the first three years after a curative resection, a recurrence of CRC can occur even ten years after the initial curative resection (dormant spread of cancer cells). Immunotherapy is an emerging therapy with high potential. The immune system plays a major role in the development of CRC. This has led to innovative new therapies, such as cancer vaccines and T-cell stimulation therapies. Cantastim belongs to the class of nonspecific immunostimulators or immunomodulators, most of which are of bacterial origin and are used as mono- or polymicrobial suspensions. Cantastim is an ethanolic extract obtained from a pathogenic strain of Pseudomonas aeruginosa serotype XV. The beneficial effect of immunotherapy with Cantastim was more pronounced for the local developmental stages (I and II) than for the later stages

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p &lt; 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Updates of Risk Factors for Anastomotic Leakage after Colorectal Surgery

Anastomotic leakage is a potentially severe complication occurring after colorectal surgery and can lead to increased morbidity and mortality, permanent stoma formation, and cancer recurrence. Multiple risk factors for anastomotic leak have been identified, and these can allow for better prevention and an earlier diagnosis of this significant complication. There are nonmodifiable factors such as male gender, comorbidities and distance of tumor from anal verge, and modifiable risk factors, including smoking and alcohol consumption, obesity, preoperative radiotherapy and preoperative use of steroids or non-steroidal anti-inflammatory drugs. Perioperative blood transfusion was shown to be an important risk factor for anastomotic failure. Recent studies on the laparoscopic approach in colorectal surgery found no statistical difference in anastomotic leakage rate compared with open surgery. A diverting stoma at the time of primary surgery does not appear to reduce the leak rate but may reduce its clinical consequences and the need for additional surgery if anastomotic leakage does occur. It is still debatable if preoperative bowel preparation should be used, especially for left colon and rectal resections, but studies have shown similar incidence of postoperative leak rate

Abdominal Compartment Syndrome in Acute Pancreatitis: A Narrative Review

Abdominal compartment syndrome (ACS) represents a severe complication of acute pancreatitis (AP), resulting from an acute and sustained increase in abdominal pressure &gt;20 mmHg, in association with new organ dysfunction. The harmful effect of high intra-abdominal pressure on regional and global perfusion results in significant multiple organ failure and is associated with increased morbidity and mortality. There are several deleterious consequences of elevated intra-abdominal pressure on end-organ function, including respiratory, cardiovascular, gastrointestinal, neurologic, and renal effects. It is estimated that about 15% of patients with severe AP develop intra-abdominal hypertension or ACS, with a mortality rate around 50%. The treatment of abdominal compartment syndrome in acute pancreatitis begins with medical intervention and percutaneous drainage, where possible. Abdominal compartment syndrome unresponsive to conservatory treatment requires immediate surgical decompression, along with vacuum-assisted closure therapy techniques, followed by early abdominal fascia closure

Risk Factors for Severe Postoperative Complications after Oncologic Right Colectomy: Unicenter Analysis

Background and Objectives: This study aimed to investigate the potential risk factors for severe postoperative complications after oncologic right colectomy. Materials and Methods: All consecutive patients with right colon cancer who underwent right colectomy in our department between 2016 and 2021 were retrospectively included in this study. The Clavien–Dindo grading system was used to evaluate postoperative complications. Univariate and multivariate logistic regression analyses were used to investigate risk factors for postoperative severe complications. Results: Of the 144 patients, there were 69 males and 75 females, with a median age of 69 (IQR 60–78). Postoperative morbidity and mortality rates were 41.7% (60 patients) and 11.1% (16 patients), respectively. The anastomotic leak rate was 5.3% (7 patients). Severe postoperative complications (Clavien–Dindo grades III–V) were present in 20 patients (13.9%). Univariate analysis showed the following as risk factors for postoperative severe complications: Charlson score, lack of mechanical bowel preparation, level of preoperative proteins, blood transfusions, and degree of urgency (elective/emergency right colectomy). In the logistic binary regression, the Charlson score (OR = 1.931, 95% CI = 1.077–3.463, p = 0.025) and preoperative protein level (OR = 0.049, 95% CI = 0.006–0.433, p = 0.007) were found to be independent risk factors for postoperative severe complications. Conclusions: Severe complications after oncologic right colectomy are associated with a low preoperative protein level and a higher Charlson comorbidity index

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis.

Contains fulltext : 51133.pdf (publisher's version ) (Closed access)Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P &lt; 1 × 10(-12)) and X-linked CLDN2 (P &lt; 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07)

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P &lt; 1 × 10(-12)) and X-linked CLDN2 (P &lt; 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07)

Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer.

Contains fulltext : 50765.pdf (publisher's version ) (Closed access)Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine pancreatic insufficiency. These experimental data are in accordance with a recent report describing an association between KRT8 variations and chronic pancreatitis. This prompted us to investigate KRT8 polymorphisms in patients with pancreatic disorders. The KRT8 Y54H and G62C polymorphisms were assessed in a cohort of patients with acute and chronic pancreatitis of various aetiologies or pancreatic cancer originating from Austria (n=16), the Czech Republic (n=90), Germany (n=1698), Great Britain (n=36), India (n=60), Italy (n=143), the Netherlands (n=128), Romania (n=3), Spain (n=133), and Switzerland (n=129). We also studied 4,234 control subjects from these countries and 1,492 control subjects originating from Benin, Cameroon, Ethiopia, Ecuador, and Turkey. Polymorphisms were analysed by melting curve analysis with fluorescence resonance energy transfer probes. The frequency of G62C did not differ between patients with acute or chronic pancreatitis, pancreatic adenocarcinoma and control individuals. The frequency of G62C varied in European populations from 0.4 to 3.8%, showing a northwest to southeast decline. The Y54H alteration was not detected in any of the 2,436 patients. Only 3/4,580 (0.07%) European, Turkish and Indian control subjects were heterozygous for Y54H in contrast to 34/951 (3.6%) control subjects of African descent. Our data suggest that the KRT8 alterations, Y54H and G62C, do not predispose patients to the development of pancreatitis or pancreatic cancer