Policlinico San Matteo Pavia Fondazione IRCCS

Background Prostate Cancer (PCa) is the second leading cause of cancer death in the elderly (≥75 years). There is currently little data on hypofractionated radiotherapy in older patients affected by localized PCa. We present the long-term results of hypofractionated radiotherapy in elderly patients with localized PCa from the IPOPROMISE database. Materials and Methods retrospective analysis of 719 PCa elderly (≥75 years) patients treated with daily volumetric image-guided hypofractionated radiotherapy between 2007 and 2020. For survival endpoints, we used Kaplan-Meier survival curves and univariate and multivariable Cox’s proportional hazards regression models. Results Median age at PCa diagnosis was 78.4 years (interquartile [IQR], 76.8–80.3 years), 74% of patients had a modified Charlson co-morbidity index (elderly-PCa-CCI, (e-PCCI)) of 0. Based on NCCN risk grouping, 399 patients (55.5%) were affected by unfavorable to very high-risk disease. Median follow-up was 4.2 years (IQR 2.4–6.4 years). 31/719 (4.3%) patients died from any cause. At 5 years, overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival were 95.6% (95% CI 93.4–97.1%), 99.2% (95%CI 97.9–99.7%), and 97.3% (95% CI 95.1–98.5%), respectively. In multivariate analysis, baseline PSA, and Gleason score were associated with MFS. On univariate analysis, e-PCCI ≥ 2 was associated with OS (p = 0.02). The 5-year freedom from late grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity were 95.1% (95% CI 93.0–96.5%) and 96.7% (95% CI 93.7–97.1%), respectively. Conclusions Our results represent a valuable add-on to the current literature, confirming the prominent role of radiotherapy in the cure of elderly fit patients affected by localized disease.

Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by defective NADPH oxidase function, leading to impaired microbial killing, recurrent infections and granulomatous inflammation. Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CGD, particularly effective when a fully HLA-matched donor is available. However, the place of HLA-haploidentical HSCT remains less established. This retrospective, multicenter study analyzed outcomes of 64 CGD patients (53 males, 46 with X-linked CGD) who underwent a first HSCT with HLA-haploidentical family donors either with in vitro TCRαβ/CD19 depletion or in vivo depletion using post-transplant cyclophosphamide (PTCY). The mean age at transplant was 5.8 years (0-33 years). Patients exhibited a high disease burden prior to HSCT, with 45% experiencing infections in the 6 months prior to HSCT and 67% exhibiting inflammation. Outcomes in the entire cohort showed a 3-year overall survival (OS), event-free survival (EFS) and GvHD grade III to IV-free, event-free survival (GEFS) of 75.9%, of 70.2%, and of 56.1% respectively and were not impacted by the type of depletion or age. The cumulative incidence (CI) of primary graft failure was 20.6%. The CI of grade II to IV acute GvHD was higher in the PTCY group (p=0.04) whereas the CI of GVH grade III to IV was not. These results indicate that HLA-haploidentical HSCT is a feasible transplant option for CGD patients lacking HLA-matched donors. Further refinement of transplant protocols is necessary to mitigate graft failure and acute GvHD, ultimately improving access and outcomes for this life-saving therapy.

Malabsorption is a complex and multifaceted condition characterised by the defective passage of nutrients into the blood and lymphatic streams. Several congenital or acquired disorders may cause either selective or global malabsorption in both children and adults, such as cystic fibrosis, exocrine pancreatic insufficiency (EPI), coeliac disease (CD) and other enteropathies, lactase deficiency, small intestinal bacterial overgrowth (SIBO), autoimmune atrophic gastritis, Crohn's disease, and gastric or small bowel resections. Early recognition of malabsorption is key for tailoring a proper diagnostic work‐up for identifying the cause of malabsorption. Patient's medical and pharmacological history are essential for identifying risk factors. Several examinations like endoscopy with small intestinal biopsies, non‐invasive functional tests, and radiologic imaging are useful in diagnosing malabsorption. Due to its high prevalence, CD should always be looked for in case of malabsorption with no other obvious explanations and in high‐risk individuals. Nutritional support is key in management of patients with malabsorption; different options are available, including oral supplements, enteral or parenteral nutrition. In patients with short bowel syndrome, teduglutide proved effective in reducing the need for parenteral nutrition, thus improving the quality of life of these patients. Primary care physicians have a central role in early detection of malabsorption and should be involved into multidisciplinary teams for improving the overall management of these patients. In this European consensus, involving 10 scientific societies and several experts, we have dissected all the issues around malabsorption, including the definitions and diagnostic testing (Part 1), high‐risk categories and special populations, nutritional assessment and management, and primary care perspective (Part 2).

Caustic ingestion (CI) in adults represents a potentially life-threatening condition. Diagnosis and management of CI in real life remain challenging. The aim of the survey is to evaluate on a national scale the multidisciplinary management of these patients. 24-item online Survey was sent to the mailing lists and social media of Italian Society of Endoscopic Surgery and New Technologies, Italian Society of Digestive Endoscopy, World Society of Emergency Surgery-Italy Chapter, and Italian Society of Surgical Endoscopy and Digestive Diseases. Overall, 240 subjects answered to the survey, corresponding to 22.1% of the total members of the scientific societies involved. 131 (54.5%) respondents evaluated fewer than ten CI patients per year. The recommendations provided by the WSES and SIED guidelines were followed by 133 (55.2%) and 83 (34.4%) participants, respectively. Emergency surgery was advocated by 180 (77.6%) of the respondents for patients with transmural necrosis or signs of perforation, using minimally invasive surgery in 47% of the cases and considering initial esophagojejunal anastomosis as safe in 33 (14.2%) of the responses. Our study is the first to provide real-life data on how the management of CI varies across Italian physicians, according to regional, institutional, and specialty-related factors. This survey highlights the need for standardized and uniform guidelines.

This study aims to evaluate the safety and efficacy of the Derivo peripher and Derivo 2 Embolization Device Flow Diverter Stents (DEDs, Acandis GmbH) in treating visceral aneurysms. This multicentric registry with core-lab evaluation involves 29 Italian Interventional Radiology and Vascular Surgery units, targeting 100 patients. Inclusion criteria include visceral artery aneurysms without signs of rupture and adherence to correct DED stent sizing and anticoagulant and antiplatelet protocols. Patients will undergo physical examination and computed tomography angiography (CTA) within 6-month and at 1-year post-procedure. A core laboratory will evaluate all pre- and post-procedure CTA and procedural angiographic images for procedural correctness (adherence to correct DED sizing, deployment accuracy, and technical issues), stent morphology during follow-up (patency and geometrical changes), and VAA morphological changes (volume variation, thrombosis grade, and number of patent branches). The primary objective is to evaluate the technical efficacy and safety of DEDs at 1-year follow-up. Efficacy will be assessed by patency of DEDs and side branches, aneurysm thrombosis (< 50%, > 50% or total volume of the aneurysm), and non-increase in aneurysm volume (percentage change relative to initial volume). Safety will be assessed by morbidity (adverse events during follow-up), mortality (any cause of death), and technical issues (adverse events during stent placement, based on CIRSE classification of complications). The DEDICATE registry will provide further information on the effectiveness of flow-diverting stents in treating visceral aneurysmal pathology. Trial Registration ClinicalTrials.gov identifier: NCT06325371.

Objective Maternal obesity and excessive weight gain during pregnancy predispose to adverse fetal outcomes and health issues for the offspring. Although maternal lipids play an important role in excess fetal fat accretion, previous studies found heterogeneous results regarding which lipid fraction is most involved in excessive fetal growth in maternal obesity and the role of cord lipids. The aim of this study was to evaluate lipid concentrations in maternal and cord blood in pregnant women with and without obesity and to correlate lipid profile with neonatal and placental biometric parameters. Methods This is a prospective case‐control study comparing 58 pregnant women with and without obesity enrolled from January 2021 to January 2022 at IRCCS Policlinico San Matteo. Lipid profiles at trimesters and in cord blood were tested. Statistical analysis was conducted with a nonparametric rank‐based approach for longitudinal data analysis. Results In both overall and time point analyses, maternal lipid concentrations were higher in participants with obesity than in subjects without obesity. Women with obesity also had higher total cholesterol and triglyceride cord blood concentrations (p < 0.001). Among participants with obesity, neonatal and placental weights were positively correlated with triglycerides and the triglycerides/HDL ratio both in maternal and in cord blood. Finally, among subjects with obesity, maternal and cord blood triglycerides and triglycerides/HDL ratio were significantly higher in large for gestational age (LGA) babies compared to non‐LGA (p < 0.05). Conclusions Compared with controls, obesity in pregnancy is associated with a significant increase in maternal and cord blood lipids, with a positive association between maternal and cord triglycerides and birthweight and placental weight. These findings suggest a further insight into maternal obesity pathophysiology leading to excessive fetal growth, dyslipidemia and insulin resistance in the offspring.

The SARS-CoV2 pandemic has posed unprecedented challenges between temporary or permanent discontinuation of immunosuppressive treatment to protect patients, or disease control prioritization by not interrupting treatment. Maintenance treatment with anti-CD20 monoclonal antibodies (MoAbs) improves progression-free survival (PFS) in follicular lymphoma (FL), but also impairs anti-SARS-CoV2 immune response. This challenge has been addressed in Italy by temporary, definitive or no discontinuation of anti-CD20 treatment. We report the outcome of 539 FL patients receiving anti-CD20 MoAbs (rituximab in 431, obinutuzumab in 108), which were temporarily discontinued in 150 patients (group A), definitively discontinued in 166 (group B), or uninterrupted in 223 (group C). In the overall cohort, the 3-year progression-free survival (3y PFS) and 3-year overall survival (3y OS) rates were 80% and 88%. PFS and OS were significantly better in group A compared to group B and C (p = 0.01). Induction chemoimmunotherapy significantly influenced OS: the 3y OS was 91% vs 85% in CHOP vs bendamustine treated patients (p = 0.04), while the 3y OS was 90% vs 77% in rituximab vs obinutuzumab treated patients (p = 0.002). SARS-Cov2 infection was the main cause of death (67% of cases). Vaccination with multiple doses demonstrated to be clinically helpful, with impact on OS.

As the treatment paradigm for Waldenström macroglobulinemia (WM) continues to evolve, the debate surrounding the prioritization of depth of response versus disease control as therapeutic goals gains significant relevance. However, the impact of depth of response from fixed‐duration therapy on overall survival (OS) was unclear. This multicenter study evaluated the prognostic impact of depth of response using a landmark survival analysis. A total of 440 patients with WM treated with frontline fixed‐duration regimens were included. Attaining a major response (MaR) was associated with superior outcomes, including significantly longer OS. The estimated 5‐year PFS rates for patients with MaR at 6 months versus not were 50% versus 32%, respectively, p < 0.001, and the estimated 5‐year OS rates for patients with MaR at 6 months versus not were 89% versus 70%, respectively, p < 0.001. In a multivariable analysis, MaR at 6 months was independently associated with superior PFS (HR 0.66, p = 0.007) and OS (HR 0.28, p < 0.001). Similar results were seen when considering deeper responses (CR + VGPR vs. PR). Depth of response at 6 months is an important prognostic marker in WM and an independent predictor of PFS and OS. These results support its utilization as a suitable endpoint in clinical studies in WM.

Quadricuspid aortic valve (QAV) is a rare congenital anomaly of the aortic valve, with an incidence of 0.05-0.1%, often associated with aortic regurgitation. The condition typically presents between the ages of 46 and 50, with a slight male predominance. While diagnosis is generally made via transthoracic echocardiography (TTE), this method can occasionally fail to identify QAV, necessitating the use of transoesophageal echocardiography and cardiac computed tomography for more accurate assessment of valve morphology. We present the case of a 57-year-old male who experienced chest pain for three months. Although TTE revealed severe aortic regurgitation, it did not detect the QAV. The anomaly was ultimately identified through advanced imaging techniques prior to surgery, which confirmed the presence of this rare aortic valve morphology.

BACKGROUND The benefits and safety of mechanical thrombectomy (MT) in patients with prestroke disability, classified as modified Rankin Scale (mRS) score of 3 to 4, and anterior circulation stroke remain uncertain. This study aims to evaluate these factors using data from the Italian Registry of Endovascular Treatment in Acute Stroke. METHODS We analyzed data collected between 2015 and 2021, comparing functional outcomes (mRS), symptomatic intracerebral hemorrhage, and recanalization rates (Thrombolysis in Cerebral Infarction) at 90 days post-MT in patients with prestroke mRS score of 3 to 4 versus 0 to 2. A good outcome was defined as no change in the mRS score from baseline. Subgroup analysis was stratified by age. RESULTS A total of 11.411 (96%) patients with prestroke mRS score of 0 to 2 and 477 (4%) patients with prestroke mRS score of 3 to 4 were included. Compared with patients with a baseline mRS score 0 to 2, those with mRS score 3 to 4 were older (82 versus 75 years; P <0.001) and predominantly female (71.7% versus 53%; P <0.001). The maintenance of the same mRS score after MT was observed in 100 (23.3%) patients with prestroke mRS score 3 to 4, compared with 2332 (22.1%) patients with mRS score 0 to 2 ( P =0.556). Mortality was significantly higher in the mRS score 3 to 4 group (n=159 [37.1%] versus n=1939 [18.4%]; P <0.001). Successful recanalization (Thrombolysis in Cerebral Infarction score ≥2b) was lower in the mRS score 3 to 4 group (n=333 [71.6%] versus n=8706 [77.7%]; P =0.002), while no significant differences in symptomatic intracerebral hemorrhage were found. The benefit of MT was maintained in patients aged 80 to 85 and over 85 years with prestroke mRS score 3 to 4, although mortality remained higher. CONCLUSIONS Our data suggest that prestroke disability does not imply less chance of returning to prestroke conditions after MT, even in octogenarians, despite higher mortality and lower recanalization rate. More data are warranted to better understand the benefit of MT in this subgroup of patients.

This multicenter retrospective study included patients undergoing EUS-guided GI anastomoses from 2016 to 2023. Indications for EUS-guided anastomosis were GOO, ALS or patients with altered anatomy needing endoscopic interventions. The primary outcome was technical success, while secondary outcomes included clinical success, safety, lumen-apposing metal stent (LAMS) patency, and the need for reinterventions. A total of 216 patients (mean age 64.5 [±13.94] years; 49.1% males) were included. In total, 149 cases (69%) were GOO, 44 (20.4%) cases were bilioenteric anastomotic strictures or lithiasis in altered anatomy, 14 cases (6.5%) were ALS, and 9 patients (4.2%) were for ERCP in altered anatomy after EUS-GG. Overall, EUS-GE was performed in 181 patients (83.8%), EUS-JJ in 44 cases (20.4%), and EUS-GG in 10 (4.6%). Technical success was 94.91%, and clinical success was 93.66%. The adverse event (AE) rate was 11.1%. The reintervention rate was 7.69%. The median follow-up was 85 days. In conclusions, EUS-guided GI anastomoses are technically feasible and safe in both malignant and benign diseases.

Hemophilic arthropathy (HA) is a complication of hemophilia, which is a genetic disorder characterized by a deficiency in blood clotting factors. HA is characterized by joint damage with inflammatory responses, pain, and movement limitations due to recurrent bleeding in the joints. The inflammatory reactions contribute to the activation of coagulation factors, which can exacerbate bleeding and further damage the affected joints. Therefore, the interaction between inflammation and coagulation plays a crucial role in the progression and complications of HA. Management strategies often focus both on inflammation and coagulation to alleviate symptoms and preserve joint function. Temperature can influence the inflammatory response and coagulation. The aim of this work was to understand how temperature management can positively or negatively influence the HA. We have carried out a narrative review of the available literature. This review explores the impacts of temperature on biological processes, and it discusses the possible clinical implications for the HA treatment. Our research shows that cold exposure has anti-inflammatory and analgesic effects, while heat is linked to pro-inflammatory cytokine release. Both hot and cold treatments are ill-advised for hemophilia patients. Heat stimulates neo-angiogenesis, and cold hampers coagulation, posing risks for increased bleeding in individuals with hemophilia.

Both immunoglobulin light-chain (LC) amyloidosis (AL) and multiple myeloma (MM) share the overproduction of a clonal LC. However, while LCs in MM remain soluble in circulation, AL LCs misfold into toxic-soluble species and amyloid fibrils that accumulate in organs, leading to distinct clinical manifestations. The significant sequence variability of LCs has hindered the understanding of the mechanisms driving LC aggregation. Nevertheless, emerging biochemical properties, including dimer stability, conformational dynamics, and proteolysis susceptibility, distinguish AL LCs from those in MM under native conditions. This study aimed to identify a ² conformational fingerprint distinguishing AL from MM LCs. Using small-angle X-ray scattering (SAXS) under native conditions, we analyzed four AL and two MM LCs. We observed that AL LCs exhibited a slightly larger radius of gyration and greater deviations from X-ray crystallography-determined or predicted structures, reflecting enhanced conformational dynamics. SAXS data, integrated with molecular dynamics simulations, revealed a conformational ensemble where LCs adopt multiple states, with variable and constant domains either bent or straight. AL LCs displayed a distinct, low-populated, straight conformation (termed H state), which maximized solvent accessibility at the interface between constant and variable domains. Hydrogen-deuterium exchange mass spectrometry experimentally validated this H state. These findings reconcile diverse experimental observations and provide a precise structural target for future drug design efforts.

Background: Indocyanine green (ICG) fluorescence has seen extensive application across medical and surgical fields, praised for its real-time navigation capabilities and low toxicity. Initially employed to assess liver function, ICG fluorescence is now integral to liver surgery, aiding in tumor detection, liver segmentation, and the visualization of bile leaks. This study reviews current protocols and ICG fluorescence applications in liver surgery, with a focus on optimizing timing and dosage based on clinical indications. Methods: Following PRISMA guidelines, we systematically reviewed the literature up to 27 January 2024, using PubMed and Medline to identify studies on ICG fluorescence used in liver surgery. A systematic review was performed to evaluate dosage and timing protocols for ICG administration. Results: Of 1093 initial articles, 140 studies, covering a total of 3739 patients, were included. The studies primarily addressed tumor detection (40%), liver segmentation (34.6%), and both (21.4%). The most common ICG fluorescence dose for tumor detection was 0.5 mg/kg, with administration occurring from days to weeks pre-surgery. Various near-infrared (NIR) camera systems were utilized, with the PINPOINT system most frequently cited. Tumor detection rates averaged 87.4%, with a 10.5% false-positive rate. Additional applications include the detection of bile leaks, lymph nodes, and vascular and biliary structures. Conclusions: ICG fluorescence imaging has emerged as a valuable tool in liver surgery, enhancing real-time navigation and improving clinical outcomes. Standardizing protocols could further enhance ICG fluorescence efficacy and reliability, benefitting patient care in hepatic surgeries.

PARP inhibitors are a class of agents that have shown significant preclinical activity in models defective in homologous recombination (HR). The identification of synthetic lethality between HR defects and PARP inhibition led to several clinical trials in tumors with known HR defects (initially mutations in BRCA1/2 genes and subsequently in other genes involved in HR). These studies demonstrated significant responses in breast and ovarian cancers, which are known to have a significant proportion of patients with HR defects. Since the approval of the first PARP inhibitor (PARPi), olaparib, several other inhibitors have been developed, expanding the armamentarium available to clinicians in this setting. The positive results obtained in breast and ovarian cancer have expanded the use of PARPi in other solid tumors with HR defects, including prostate and pancreatic cancer in which these defects have been identified. The clinical trials have demonstrated responses to PARPi which are now also available for the subset of patients with prostate and pancreatic cancer with HR defects. This review summarizes the results obtained in solid tumors with PARPi and their potential use when combined with other agents, including immune checkpoint inhibitors that are likely to further increase the survival of these patients which still needs a dramatic improvement.

Introduction The impact of an immune checkpoint inhibitor (ICI)–based systemic treatment strategy with or without local radical treatment (LRT) on outcomes for patients with NSCLC and synchronous oligometastatic disease (sOMD) is unknown. Methods Multicenter retrospective study including adequately staged patients, with sOMD NSCLC (maximum five metastases in three organs [European Organization for Research and Treatment of Cancer definition]) between January 1, 2015 and December 31, 2022, treated with a first-line ICI-based versus chemotherapy-only regimen. Primary end points were progression-free survival and overall survival (OS) for an ICI-based versus chemotherapy-only strategy. Subgroup analyses were performed for patients who were deemed candidates for LRT in the multidisciplinary meeting and those proceeding to LRT. Results A total of 416 patients were included, treated with chemotherapy-ICI (n = 138) or chemotherapy-only (n = 278), 319 out of 416 were deemed candidates by multidisciplinary meetings for LRT, whereas 192 (60%) proceeded to LRT. The median OS was significantly longer in the chemotherapy-ICI compared with the chemotherapy-only group (33.6 versus 15.9 mo, hazard ratio [HR] = 0.5, 95% confidence interval [CI]: 0.4–0.7, p < 0.001), in the subgroups who were candidate for LRT (36.1 versus 17.2 mo, HR = 0.5, 95% CI: 0.4–0.7, p < 0.001) and those proceeding to LRT (not reached versus 23.1 mo, HR = 0.4, 95% CI: 0.2–0.7, p < 0.001). In multivariate analysis, an ICI-based strategy was associated with improved survival in the total group (HR = 0.6, 95% CI: 0.4–0.9, p < 0.001), in those with intention of LRT (HR = 0.6, 95% CI: 0.4–0.9, p = 0.02) and those who proceeded to LRT (HR = 0.3, 95% CI: 0.1–0.6, p = 0.002). Conclusions An ICI-based systemic treatment strategy (±LRT) is associated with improved survival compared with chemotherapy-only (±LRT) for patients with sOMD NSCLC. Prospective randomized trial data are necessary to identify patients most likely to benefit from adding LRT.