Molecular characterization of diffuse large B-cell lymphomas associated with hepatitis C virus infection.

Hepatitis C virus (HCV)-associated diffuse large B-cell lymphoma (DLBCL) displays peculiar clinicopathological characteristics, but its molecular landscape is not fully elucidated. In this study, we investigated the clinicopathological and molecular features of 54 patients with HCV-associated DLBCL. The median age was 71 years. An underlying marginal zone lymphoma component was detected in 14.8% of cases. FISH analysis showed rearrangements involving BCL6 in 50.9% of cases, MYC in 11.3% and BCL2 in 3.7%. Lymph2Cx-based assay was successful in 38 cases, recognizing 16 cases (42.1%) as ABC and 16 cases as GCB subtypes, while six resulted unclassified. ABC cases exhibited a higher lymphoma-related mortality (LRM). Next-generation sequencing analysis showed mutations in 158/184 evaluated genes. The most frequently mutated genes were KMT2D (42.6%), SETD1B (33.3%), RERE (29.4%), FAS and PIM1 (27.8%) and TBL1XR1 (25.9%). A mutation in the NOTCH pathway was detected in 25.9% of cases and was associated with worst LRM. Cluster analysis by LymphGen classified 29/54 cases within definite groups, including BN2 in 14 (48.2%), ST2 in seven (24.2%) and MCD and EZB in four each (13.8%). Overall, these results indicate a preferential marginal zone origin for a consistent subgroup of HCV-associated DLBCL cases and suggest potential implications for molecularly targeted therapies.

Assessment of cephalometric parameters and correlation with the severity of the obstructive sleep apnea syndrome.

BACKGROUND: In individuals diagnosed with obstructive sleep apnea syndrome (OSAS), variations in craniofacial structure have been inconsistently documented, showing differing degrees of alteration between obese and nonobese patients. In addition, sleep disturbance has also been shown to induce disequilibrium in this population of patients. This pilot observational study aimed to assess craniofacial values in obese and nonobese subpopulations of patients with OSAS and their correlation and association with the severity of OSAS. We also assessed whether OSAS patients are characterized by an impaired equilibrium in relation to and associated with the severity of OSAS. METHODS: We included all consecutive adult patients with OSAS. Through cephalometry, we assessed the upper (UPa-UPp) and lower (LPa-LPp) pharynx diameters, superior anterior facial height (Sor-ANS), anterior facial height (ANS-Me), anterior vertical dimension (Sor-Me), posterior facial height (S-Go) and craniovertebral angle (CVA). Furthermore, we analyzed postural equilibrium through a stabilometric examination. RESULTS: Forty consecutive OSAS patients (45% female with a mean age of 56 ± 8.2 years) were included. The subgroup of nonobese patients had a reduced UPa-UPp (p = 0.02). Cephalometric measurements were correlated with the severity of OSAS in nonobese patients, whereas only Sor-ANS was correlated with the severity of OSAS in the obese subpopulation. In the overall population, altered craniofacial values are associated with severe OSAS. Although there are differences in equilibrium between obese and nonobese OSAS patients, the stabilometric measurements were not correlated or associated with OSAS severity. CONCLUSION: Altered craniofacial values and compromised equilibrium in OSAS patients are linked to OSAS severity. Therefore, the management of OSAS should be tailored not only to weight management but also to craniofacial and postural rehabilitation to enhance patient outcomes.

The butterfly effect: Restoring the tricuspid coaptation after clipping the antero-septal commissure.

Edge-to-edge tricuspid transcatheter repair requires extensive echocardiographic planning before the procedure. Sometimes, anatomic features may anticipate a suboptimal result. For this reason, a tailored strategy is the key to the procedural success. We report a case of massive tricuspid regurgitation due to multiple complex mechanisms that was successfully treated by clipping the antero-septal commissure to restore functional coaptation of the valve leaflets at multiple sites.

T-Cells Subsets in Castleman Disease: Analysis of 28 Cases Including Unicentric, Multicentric and HHV8-Related Clinical Forms.

Castleman disease (CD) is a rare lymphoproliferative disorder that includes various clinico-pathological subtypes. According to clinical course, CD is divided into unicentric CD (UCD) and multicentric CD (MCD). MCD is further distinguished based on the etiological driver in herpes virus-8-related MCD (that can occur in the setting of HIV); in MCD associated with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); and idiopathic MCD (iMCD). The latter can also be divided in iMCD-TAFRO (thrombocytopenia, anasarca, fever, myelofibrosis, organomegaly) and iMCD not otherwise specified. To date, CD pathogenesis is still uncertain, but CD may represent the histological and clinical result of heterogeneous pathomechanisms. Transcriptome investigations in CD lymph nodes have documented the expression and up-regulation of different cytokines; furthermore, few recent studies have shown alterations of different T-cell subsets in CD patients, suggesting a possible role of the nodal microenvironment in CD development. On this basis, our study aimed to investigate the distribution of T-cell subsets in the clinico-pathological spectrum of CD. We evaluated the CD4/CD8 ratio and the number of T-regulatory (T-reg) FOXP3+ cells in 28 CD cases. In total, 32% of cases showed a decreased CD4/CD8 ratio due to increased CD8+ T-cells, including both UCD, iMCD, and HHV8+ MCD cases. The T-reg subset analysis revealed a statistically significant (p < 0.0001) lower mean number of FOXP3+ T-reg cells in CD cases when compared with non-specific reactive lymph nodes. We did not find statistically significant differences in T-reg numbers between the different CD subtypes. These findings may suggest that alterations in T-cell subpopulations that can lead to disruption of immune system control may contribute to the numerous changes in different cellular compartments that characterize CD.

Spermatocytic Tumor: A Review.

Spermatocytic tumor (ST) is a very rare disease, accounting for approximately 1% of testicular cancers. Previously classified as spermatocytic seminoma, it is currently classified within the non-germ neoplasia in-situ-derived tumors and has different clinical-pathologic features when compared with other forms of germ cell tumors (GCTs). A web-based search of MEDLINE/PubMed library data was performed in order to identify pertinent articles. In the vast majority of cases, STs are diagnosed at stage I and carry a very good prognosis. The treatment of choice is orchiectomy alone. Nevertheless, there are two rare variants of STs having very aggressive behavior, namely anaplastic ST and ST with sarcomatous transformation, that are resistant to systemic treatments and their prognosis is very poor. We have summarized all the epidemiological, pathological and clinical features available in the literature regarding STs that have to be considered as a specific entity compared to other germ GCTs, including seminoma. With the aim of improving the knowledge of this rare disease, an international registry is required.

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

BACKGROUND: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. PATIENTS AND METHODS: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. RESULTS: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. CONCLUSIONS: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.

Effects of inhaled beclomethasone dipropionate/formoterol fumarate/glycopyrronium on diaphragmatic workload and lung function in uncontrolled asthma: a case report.

Beclomethasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) single inhaler extrafine triple therapy is effective for the treatment of uncontrolled asthma. Nevertheless, there is a lack of data about the use of diaphragmatic ultrasonography to monitor adult asthmatics while they are receiving inhaled treatment. We took into consideration a 78-year-old woman complaining of asthma, treated with inhaled corticosteroid/long-acting ß2-adrenergic agonist (ICS/LABA), characterized by an asthma control questionnaire-5 (ACQ-5) score and a lung function test suggestive of uncontrolled asthma. Moreover, a diaphragmatic ultrasound showed signs of high diaphragm workload. Because of these findings, we proposed to our patient a shift toward triple inhaled therapy with BDP/FF/G, and she underwent a second evaluation after 7 days of treatment. Improvements in the diaphragmatic ultrasound parameters, lung function test, and ACQ-5 score were found. In particular, we detected a reduction of thickening fraction (TF), and a normalization of the other diaphragmatic measures, indicative of a decrease in diaphragmatic workload. To our knowledge, this is the first literature report showing concomitant improvements of both lung function tests and diaphragmatic ultrasonography parameters, observed in an adult patient with uncontrolled asthma after short-term treatment with the single inhaler triple therapy BDP/FF/G.

Complications during Veno-Venous Extracorporeal Membrane Oxygenation in COVID-19 and Non-COVID-19 Patients with Acute Respiratory Distress Syndrome.

Background: Acute respiratory distress syndrome (ARDS) presents a significant challenge in critical care settings, characterized by compromised gas exchange, necessitating in the most severe cases interventions such as veno-venous extracorporeal membrane oxygenation (vv-ECMO) when conventional therapies fail. Critically ill ARDS patients on vv-ECMO may experience several complications. Limited data exist comparing complication rates between COVID-19 and non-COVID-19 ARDS patients undergoing vv-ECMO. This retrospective observational study aimed to assess and compare complications in these patient cohorts. Methods: We retrospectively analyzed the medical records of all patients receiving vv-ECMO for ARDS between March 2020 and March 2022. We recorded the baseline characteristics, the disease course and complication (barotrauma, bleeding, thrombosis) before and after ECMO cannulation, and clinical outcomes (mechanical ventilation and ECMO duration, intensive care unit, and hospital lengths of stay and mortalities). Data were compared between COVID-19 and non-COVID-19 patients. In addition, we compared survived and deceased patients. Results: Sixty-four patients were included. COVID-19 patients (n = 25) showed higher rates of pneumothorax (28% vs. 8%, p = 0.039) with subcutaneous emphysema (24% vs. 5%, p = 0.048) and longer non-invasive ventilation duration before vv-ECMO cannulation (2 [1; 4] vs. 0 [0; 1] days, p = <0.001), compared to non-COVID-19 patients (n = 39). However, complication rates and clinical outcomes post-vv-ECMO were similar between groups. Survival analysis revealed no significant differences in pre-vv-ECMO complications, but non-surviving patients had a trend toward higher complication rates and more pleural effusions post-vv-ECMO. Conclusions: COVID-19 patients on vv-ECMO exhibit higher pneumothorax rates with subcutaneous emphysema pre-cannulation; post-cannulation complications are comparable to non-COVID-19 patients.

Management of patients with patent foramen ovale and cryptogenic stroke: a collaborative, multidisciplinary, position paper.

OBJECTIVES: To organize a common approach on the management of patent foramen ovale (PFO) and cryptogenic stroke that may be shared by different specialists. BACKGROUND: The management of PFO related to cryptogenic stroke is controversial, despite an increase in interventional closure procedures. METHODS: A consensus statement was developed by approaching Italian national cardiological, neurological, and hematological scientific societies. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. Drafts were outlined by specific task force working groups. To obtain a widespread consensus, these drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by scientific societies. RESULTS: Definitions of transient ischemic attack and both symptomatic and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified for patients with candidate event(s) and patient foramen ovale to define the probable pathogenesis of clinical events and to describe individual PFO characteristics. Further recommendations were provided regarding medical and interventional therapy considering individual risk factors of recurrence. Finally, follow-up evaluation was appraised. CONCLUSIONS: Available data provided the basis for a shared approach to management of cryptogenic ischemic cerebral events and PFO among different Italian scientific societies. Wider international initiatives on the topic are awaited.

Management of patients with patent foramen ovale and cryptogenic stroke: a collaborative, multidisciplinary, position paper: executive summary.

OBJECTIVES: To organize a common approach on the management of patent foramen ovale (PFO) and cryptogenic stroke that may be shared by different specialists. BACKGROUND: The management of PFO related to cryptogenic stroke is controversial, despite an increase in interventional closure procedures. METHODS: A consensus statement was developed by approaching Italian national cardiological, neurological, and hematological scientific societies. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. Drafts were outlined by specific task force working groups. To obtain a widespread consensus, these drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by scientific societies. RESULTS: Definitions of transient ischemic attack and both symptomatic and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified for patients with candidate event(s) and patient foramen ovale to define the probable pathogenesis of clinical events and to describe individual PFO characteristics. Further recommendations were provided regarding medical and interventional therapy considering individual risk factors of recurrence. Finally, follow-up evaluation was appraised. CONCLUSIONS: Available data provided the basis for a shared approach to management of cryptogenic ischemic cerebral events and PFO among different Italian scientific societies. Wider international initiatives on the topic are awaited.

Colorectal adenosquamous carcinoma: genomic profiling of a rare histotype of colorectal cancer.

Colorectal adenosquamous carcinoma (ASC) is exceedingly rare, comprising less than 0.1% of all colorectal malignancies, and is characterized by an aggressive disease course, with a higher metastatic rate and worse outcome than conventional colorectal adenocarcinoma. A comprehensive molecular profile of this group of neoplasms is still lacking. A total of 22 cases of colorectal ASCs (with 22 primary lesions and 7 metastases matched with 4 primaries) were subject to NGS targeting 67 cancer-related genes (VariantPlex solid tumor; Archer). Mismatch repair (MMR), p53, and V600EBRAF status were also investigated by immunohistochemistry. In 28 of 29 (96.6%) ASC samples, at least one single-nucleotide variant (SNV) or copy number variation (CNV) was detected. Among the 22 primary tumors, the most frequently mutated genes were TP53 (59.1%), APC (40.9%), KRAS (27.3%), BRAF (13.6%), and GNAS (9.1%). Only 1/22 (4.5%) primary ASC was MMR-deficient (MMRd) and harbored a BRAF mutation. Limited differences in SNVs were observed between primary and metastatic diseases. This study sheds light on the molecular landscape of colorectal ASCs. According to our data, the genomic profile of colorectal ASC is similar to that of conventional colorectal carcinoma, with significant druggable genetic alterations. Further studies are required to understand the more aggressive clinical behavior of this neoplasm.

Severe and mild-moderate SARS-CoV-2 vaccinated patients show different frequencies of IFNγ-releasing cells: An exploratory study.

BACKGROUND: Despite an apparent effective vaccination, some patients are admitted to the hospital after SARS-CoV-2 infection. The role of adaptive immunity in COVID-19 is growing; nonetheless, differences in the spike-specific immune responses between patients requiring or not hospitalization for SARS-CoV-2 infection remains to be evaluated. In this study, we aim to evaluate the spike-specific immune response in patients with mild-moderate or severeSARS-CoV-2 infection, after breakthrough infection following two doses of BNT162b2 mRNA vaccine. METHODS: We included three cohorts of 15 cases which received the two BNT162b2 vaccine doses in previous 4 to 7 months: 1) patients with severe COVID-19; 2) patients with mild-moderate COVID-19 and 3) vaccinated individuals with a negative SARS-CoV-2 molecular pharyngeal swab (healthy subjects). Anti-S1 and anti-S2 specific SARS-CoV-2 IgM and IgG titers were measured through a chemiluminescence immunoassay technology. In addition, the frequencies of IFNγ-releasing cells were measured by ELISpot. RESULTS: The spike-specific IFNγ-releasing cells were significantly lower in severe patients (8 [0; 26] s.f.c.×106), as compared to mild-moderate patients (135 [64; 159] s.f.c.×106; p<0.001) and healthy subjects (103 [50; 188] s.f.c.×106; p<0.001). The anti-Spike protein IgG levels were similar among the three cohorts of cases (p = 0.098). All cases had an IgM titer below the analytic sensitivity of the test. The Receiver Operating Curve analysis indicated the rate of spike-specific IFNγ-releasing cells can discriminate correctly severe COVID-19 and mild-moderate patients (AUC: 0.9289; 95%CI: 0.8376-1.000; p< 0.0001), with a diagnostic specificity of 100% for s.f.c. > 81.2 x 106. CONCLUSIONS: 2-doses vaccinated patients requiring hospitalization for severe COVID-19 show a cellular-mediated immune response lower than mild-moderate or healthy subjects, despite similar antibody titers.

Mismatch repair deficiency as prognostic factor for stage III small bowel adenocarcinoma: A multicentric international study.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare cancer with an aggressive behavior. No study has specifically addressed the putative prognostic role of mismatch repair status in stage III SBAs. AIMS: We aimed to investigate whether mismatch repair deficiency is associated with cancer-specific survival in a Western cohort of patients with stage III SBAs. METHODS: In this retrospective multicentric international cohort study, we enrolled 70 patients who underwent surgically resection for stage III SBAs and we analyzed the frequency of mismatch repair deficiency, tested by immunohistochemistry for mismatch repair proteins and by polymerase chain reaction for microsatellite instability, and its association with cancer-specific survival and other clinic-pathologic factors. RESULTS: We found sixteen (23%) patients with mismatch repair deficient adenocarcinoma, without discordance between immunohistochemical and polymerase chain reaction for microsatellite instability analyses. Mismatch repair deficiency proved to be associated with a better outcome both at univariable analysis (hazard ratio: 0.28, 95% confidence interval: 0.08-0.91, p: 0.035) and in bivariable models adjusted for patient age or gender, tumor site, pT4 stage, tumor budding, and perineural invasion. CONCLUSION: This study highlights the importance of testing mismatch repair status to improve prognostic stratification in stage III SBAs.

Clinical and Histopathological Features of an Italian Monocentric Series of Primary Small Bowel T-Cell Lymphomas.

The gastrointestinal (GI) tract is the most common extranodal site of occurrence of non-Hodgkin lymphomas. Most GI lymphomas are of B-cell lineage, while T-cell lymphomas are less frequent. The aim of our retrospective study was to depict the clinical-pathological profile of a series of patients affected by intestinal T-cell lymphomas (ITCL) and possibly define hallmarks of these neoplasms. A total of 28 patients were included: 17 enteropathy-associated T-cell lymphomas (EATL), 5 monomorphic epitheliotropic T-cell lymphomas (MEITL), 3 indolent T-cell lymphoproliferative disorders of the gastrointestinal tract (ITCLDGT), and 3 intestinal T-cell lymphomas not otherwise specified (ITCL-NOS). Celiac disease (CD) was diagnosed in around 70% of cases. Diagnosis of EATL showed a significant correlation with CD30 expression, whereas MEITL with angiotropism and CD56 positivity. ITCLDGT cases showed plasma cells infiltration. Peripheral lymphocytosis, the absence of a previous diagnosis of CD, an advanced Lugano clinical stage, and the histological subtype ITCL-NOS were significantly associated with worse survival at multivariate analysis. Our findings about the epidemiological, clinical, and histopathological features of ITCL were in line with the current knowledge. Reliable prognostic tools for these neoplasms are still lacking but according to our results lymphocytosis, diagnosis of CD, Lugano clinical stage, and histological subtype should be considered for patient stratification.

Use of Impella device in cardiogenic shock and its clinical outcomes: A systematic review and meta-analysis.

Introduction: Cardiogenic shock (CS) is a life-threatening condition and mechanical circulatory support (MCS) might exert a relevant impact on its clinical course. Among MCS devices, Impella is very promising. Yet, its usefulness is still debated. We performed a meta-analysis of all studies evaluating the clinical impact of Impella in CS. Methods: All studies including patients with CS and treated with Impella were included. The primary endpoint was short-term mortality. Secondary endpoints were vascular access complications and major bleeding. Data synthesis was obtained using random-effects metanalysis. Results: Thirty-three studies and 5204 patients were included. Short-term mortality was 47%. Meta-regression analysis showed that patients age (p = 0.01), higher support level (p = 0.004) and pre-PCI insertion (p < 0.001) were significant moderators for the primary endpoint. Vascular access complications were registered in 6.4% of cases, whereas age (p = 0.05) and diabetes (p = 0.007) were significant predictors. Major bleeding occurred in 16.4% of patients. Meta-analysis of the subgroup of studies comparing Impella to IABP showed no significant difference in short-term mortality (RR = 1.08, p = 0.45), while rates of vascular access complications (p < 0.001) or major bleeding (p < 0.001) were significantly higher with Impella. Subgroup and metaregression analyses showed that these results were influenced by lower adoption rates of higher degree of MCS support (p = 0.003), and by higher vascular complications rates (p = 0.014). Conclusions: Our results suggest that the choice of adequate device size, careful patients selection and optimal timing of MCS initiation are key to clinical success with Impella in CS. Large prospective studies are mandatory to confirm these results deriving from retrospective studies.

Bivalirudin vs. Enoxaparin in Intubated COVID-19 Patients: A Pilot Multicenter Randomized Controlled Trial.

(1) Background: In COVID-19 patients, the occurrence of thromboembolic complications contributes to disease progression and mortality. In patients at increased risk for thrombotic complications, therapeutic enoxaparin should be considered. However, critically ill COVID-19 patients could develop resistance to enoxaparin. Bivalirudin, a thrombin inhibitor, may be an alternative. This pilot multicenter randomized controlled trial aims to ascertain if bivalirudin may reduce the time spent under invasive mechanical ventilation, as compared to enoxaparin. (2) Methods: Intubated COVID-19 patients at risk for thrombo-embolic complications were randomized to receive therapeutic doses of enoxaparin or bivalirudin. We ascertained the time spent under invasive mechanical ventilation during the first 28 days from Intensive Care Unit (ICU) admission. A standardized weaning protocol was implemented in all centers. In addition, we assessed the occurrence of thromboembolic complications, the number of patients requiring percutaneous tracheostomy, the gas exchange, the reintubation rate, the ICU length of stay, the ICU and 28-days mortalities. (3) Results: We enrolled 58 consecutive patients. Bivalirudin did not reduce the time spent under invasive mechanical ventilation as compared to enoxaparin (12 [8; 13] vs. 13 [10; 15] days, respectively; p = 0.078). Thrombotic (p = 0.056) and embolic (p = 0.423) complications, need for tracheostomy (p = 0.423) or reintubation (p = 0.999), the ICU length of stay (p = 0.076) and mortality (p = 0.777) were also similar between treatments. Patients randomized to bivalirudin showed a higher oxygenation at day 7 and 15 after randomization, when compared to enoxaparin group. (4) Conclusions: In intubated COVID-19 patients at increased risk for thromboembolic complications, bivalirudin did not reduce the time spent under invasive mechanical ventilation, nor improved any other clinical outcomes.

Characteristics of unvaccinated and vaccinated critically ill COVID-19 patients in calabria region (Italy): A retrospective study.

Introduction: After the rapid surge of a novel coronavirus (SARS-CoV-2) in 2020 anti-SARS-CoV-2 vaccines have been developed to prevent the development of critical forms of COVID-19 leading to Intensive Care Unit (ICU) admission. The possibility of ICU admission after the first-cycle vaccination has been already reported; however, no data have been published regarding vaccinated patients with a "booster" dose. This retrospective study describes the characteristics of critically ill patients after the implementation of the regional "booster" dose vaccination program in a southern region of Italy. Materials and methods: We screened all medical records of critically ill COVID-19 patients in the period between January to April 2022. We collected the demographic characteristics, the presence of comorbidities, the vaccination status, the clinical course (arterial blood gases and type of respiratory support) and outcomes (rate of tracheostomy, ICU length of stay and mortality). Results: A total of 272 patients were admitted to ICUs during the study period. 161 patients were unvaccinated, whereas 111 were vaccinated with the complete first-cycle or "booster" dose. The type of respiratory support was similar between groups. Vaccinated patients were characterized by a better oxygenation throughout the whole ICU length of stay. Fourteen unvaccinated and 3 vaccinated patients required tracheostomy (p = 0.045). ICU length of stay was 12.2 (± 7.3) days in unvaccinated patients and 10.4 (± 6.7) days in vaccinated patients (p = 0.036). ICU mortalities were 38.5 and 24.3% in unvaccinated and vaccinated patients, respectively (p = 0.014). Conclusion: Vaccinated patients have better clinical course and outcomes as compared to the unvaccinated population.

Poorly Cohesive Carcinoma of the Nonampullary Small Intestine: A Distinct Histologic Subtype With Prognostic Significance.

Poorly cohesive carcinomas (PCCs) are neoplasms characterized by a dyshesive cell invasion pattern featuring single-cell or cord-like stromal infiltration. Although they have been extensively studied in the stomach and other digestive system organs, limited data regarding nonampullary small bowel poorly cohesive carcinomas (SB-PCCs) are hitherto available. The aims of our study were to analyze the clinicopathologic and immunophenotypical features of SB-PCCs (PCC pattern accounting for >50% of the neoplasm) and to compare them with small bowel adenocarcinomas (SBAs), not otherwise specified (SBAs-NOS) and with cancers with a histologically distinct PCC component accounting for 10% to 50% of the neoplasm (mixed-poorly-cohesive-glandular-SBAs). Fifteen SB-PCCs were identified and compared with 95 SBAs-NOS and 27 mixed-poorly-cohesive-glandular-SBAs. Most SB-PCCs (67%) were composed of <10% of signet-ring cells, and all but 1 SB-PCCs exhibited loss of membranous expression of E-cadherin. Compared with SBAs-NOS, SB-PCCs showed a significantly younger patient age at diagnosis, and a stronger association with Crohn disease, and both SB-PCCs and mixed-poorly-cohesive-glandular-SBAs featured a higher rate of lymphovascular and perineural invasion and a lower percentage of mismatch repair-deficient cases. Importantly, the cancer-specific survival of SB-PCC (hazard ratio: 3.81; 95% confidence interval: 1.90-7.64; P<0.001) and mixed-poorly-cohesive-glandular-SBA (4.12; 2.20-7.71; P<0.001) patients was significantly worse compared with SBAs-NOS cases. This study provides objective evidence to the World Health Organization (WHO) 2019 introduction of SB-PCC as a distinctive subtype of nonampullary SBA, by virtue of its unique clinical and histologic features, and suggests that both SB-PCCs and mixed-poorly-cohesive-glandular-SBAs should be separated from SBAs-NOS.

Long Survival and Prolonged Remission after Surgery and Chemotherapy in a Metastatic Mismatch Repair Deficient Pancreatic Neuroendocrine Carcinoma with MLH1/PMS2 Immunodeficiency and Minimal Microsatellite Shift.

Pancreatic neuroendocrine carcinomas (NECs) are rare and very aggressive neoplasms with dismal prognosis, especially when metastatic or with negative prognostic factors, such as vascular invasion. To the best of our knowledge, no case of pancreatic NEC with mismatch repair deficiency has been reported to date. We describe a 62-year-old patient who underwent pancreaticoduodenectomy for a NEC located in the pancreatic head, with peripancreatic lymph node metastases. Tumor necrosis was prominent and the Ki67 proliferative index was 60%. One year after the diagnosis, the patient experienced recurrence with a left supraclavicular lymph node metastasis, which was surgically removed, followed by standard cisplatin-etoposide chemotherapy. Neoplastic cells showed combined loss of expression of MLH1 and PMS2 in both primary tumor and lymph node metastasis. Microsatellite instability (MSI) test using a mononucleotide repeats pentaplex PCR (BAT-25, BAT-26, NR-21, NR-22, and NR-24) revealed minimal mononucleotide shifts showing deletion of less than 3 bp at NR-21, BAT-26, NR-24, and NR-22 loci. MLH1 methylation analysis revealed absence of the gene promoter methylation. BRAF and KRAS mutations were not detected. In gut, NECs' mismatch repair deficiency phenotype has been reported in about 10% of cases, and it represents an independent factor of more favorable outcome. Likewise, our patient is currently alive with a follow-up of more than 12 years after pancreaticoduodenectomy, by itself an unexpected finding for such an aggressive neoplasm.

Small Bowel Adenocarcinomas Featuring Special AT-Rich Sequence-Binding Protein 2 (SATB2) Expression and a Colorectal Cancer-Like Immunophenotype: A Potential Diagnostic Pitfall.

Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn's disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7-/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7-/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7-/CK20- or CK7-/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20- or CK7+/CK20+ cancers (p = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7-/CK20- cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.