Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain‐1 interacts with cellular proteins inducing pro‐oncogenic pathways. Thus, we explore genetic variations in NS5A domain‐1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype‐1b infected DAA‐naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC‐group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell‐cycle regulation (p53, p85‐PIK3, and β‐ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV‐mediated oncogenesis. The role of these NS5A domain‐1 mutations in triggering pro‐oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

Background & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

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 < 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)

The myths surrounding mild stimulation in vitro fertilization (IVF)

Abstract So-called mild controlled ovarian hyperstimulation (mCOH) has in recent years increased in popularity, claiming to be safer and more patient-friendly, while also improving in vitro fertilization (IVF) outcomes. We here challenge the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) definition of mild stimulation, and especially address four fundamental issues, where our review found conventional COH (cCOH) advantageous over mCOH. They are: prevalence of severe ovarian hyperstimulation syndrome (OHSS), oocyte/embryo quality, pregnancy/live birth rates, and cost. We conclude that an objective review of the literature does not support the routine utilization of mCOH in assisted reproduction

Is the oocyte quality affected by endometriosis? A review of the literature

Abstract Endometriosis is an estrogen-dependent chronic inflammatory condition that affects women in their reproductive period causing infertility and pelvic pain. The disease, especially at the ovarian site has been shown to have a detrimental impact on ovarian physiology. Indeed, sonographic and histologic data tend to support the idea that ovarian follicles of endometriosis patients are decreased in number and more atretic. Moreover, the local intrafollicular environment of patients affected is characterized by alterations of the granulosa cell compartment including reduced P450 aromatase expression and increased intracellular reactive oxygen species generation. However, no comprehensive evaluation of the literature addressing the effect of endometriosis on oocyte quality from both a clinical and a biological perspective has so far been conducted. Based on this systematic review of the literature, oocytes retrieved from women affected by endometriosis are more likely to fail in vitro maturation and to show altered morphology and lower cytoplasmic mitochondrial content compared to women with other causes of infertility. Results from meta-analyses addressing IVF outcomes in women affected would indicate that a reduction in the number of mature oocytes retrieved is associated with endometriosis while a reduction in fertilization rates is more likely to be associated with minimal/mild rather than with moderate/severe disease. However, evidence in this field is still far to be conclusive, especially with regards to the effects of different stages of the disease and to the impact of patients’ previous medical/surgical treatment(s)

Response to Controlled Ovarian Stimulation Is Not Impaired in Young Patients with a Sarcoma: Results from a Monocentric Case–Control Study

Sarcomas are relatively common in the young and their treatment can impair fertility. Fertility preservation can be achieved via the cryopreservation of gametes after controlled ovarian stimulation before cancer treatment. A reduced response to hormonal stimulation in patients suffering from certain types of malignancy is reported. The purpose of this study was to assess the performance of oocyte cryopreservation in patients with sarcoma by comparing their outcomes with those of a population without cancer. Patients were matched by age with control women undergoing hormonal stimulation for isolated male factor infertility. The population included 84 women with a sarcoma and 355 controls. In the final analysis, 37 patients with sarcoma were matched in a 1:3 ratio with 109 healthy controls. Patients with sarcoma were generally younger and were stimulated with lower FSH doses. They did not perform worse than controls during stimulation, with an average retrieval of 10.6 oocytes vs. 8.1 in the controls. Linear regression on the number of retrieved mature oocytes confirmed that patients with sarcoma performed comparably to controls. In conclusion, patients with sarcoma can expect retrieval outcomes comparable to those of patients without cancer

Clinical application of a nomogram based on age, serum FSH and AMH to select the FSH starting dose in IVF/ICSI cycles: a retrospective two-centres study

Objective To externally validate a nomogram based on ovarian reserve markers as a tool to optimize the FSH starting dose in IVF/ICSI cycles. Study design A two-centres retrospective study including 398 infertile women undergoing their first IVF/ICSI cycle (June 2013âJune 2014). IVF data were retrieved from two independent IVF centres in Italy (San Raffaele Hospital, Centre 1; Verona Hospital, Centre 2). A central lab for the routine measurement of AMH and FSH was used for both centres. All women were treated based on physical and hormonal characteristics according to locally adopted protocols. The nomogram was then retrospectively applied to the patients comparing the calculated starting dose to the one actually given. Results In Centre 1, 64/131 women (48.8%) had an ovarian response below the target. While 45 of these patients were treated with a maximal FSH starting dose (â¥225 IU), n = 19/131 (14.5%) were treated with a submaximal dose. The vast majority of them (n = 17/19) would have received a higher FSH starting dose by using the nomogram. Seventeen patients (n = 17/131) had hyper response and about half of them would have been treated with a reduced FSH starting dose according to the nomogram. In Centre 2, 142/267 patients (53.2%) had an ovarian response below the target. While 136 of these were treated with a maximal FSH starting dose (â¥225 IU), n = 6/267 were treated with a submaximal dose. The majority of them (n = 5/6) would have received a higher FSH starting dose. Thirty-two (n = 32/267) patients had hyper response and more than half of them would have been treated with a reduced FSH dose. Conclusion In both Centres, applying the nomogram would have resulted in more appropriate FSH starting doses compared to the the ones actually given based on clinicians choices. The use of an objective algorithm based on patient's age, serum FSH and AMH levels may thus be an effective advice on the selection of the tailored FSH starting dose. Hence, the use of this easily available nomogram could increase the proportion of patients achieving the optimal ovarian response

Recombinant LH administration in subsequent cycle after "unexpected" poor response to recombinant FSH monotherapy

Abstract Poor ovarian response (POR) is most frequently linked to the condition known as diminished ovarian reserve, but it can also occur in the absence of pathological ovarian reserve tests ("unexpected" POR). Because possible explanations include theca cells function deficiency, our aim was to evaluate the effect of r-LH administration in "unexpected" poor responders. A retrospective, single-centre, cohort study was conducted on 65 patients with AMH >0.5 ng/ml and/or AFC >5 with POR in their first cycle. Patients underwent a second IVF cycle with same protocol (long- or antagonist) and same starting dose of r-FSH used in the first cycle, plus daily addiction of 150 IU of r-LH from day 1. Compared to the first cycle, r-LH addition in the second cycle determined an increase in number of oocytes retrieved (p < 0.001), number of metaphase II oocytes (p < 0.05), E2 levels at hCG triggering (p < 0.001) and number of embryos transferred (p = 0.002). A 15% clinical pregnancy rate was also observed in the second cycle. Our results suggest that patients with non-pathological ovarian reserve tests and previous "unexpected" POR seem to benefit from r-LH addition in subsequent cycles without the need to increase the r-FSH starting dose, possibly due to an underlying occult theca cells deficiency