BRCA in Gastrointestinal Cancers: Current Treatments and Future Perspectives

: A strong association between pancreatic cancer and BRCA1 and BRCA2 mutations is documented. Based on promising results of breast and ovarian cancers, several clinical trials with poly (ADP-ribose) polymerase inhibitors (PARPi) are ongoing for gastrointestinal (GI) malignancies, especially for pancreatic cancer. Indeed, the POLO trial results provide promising and awaited changes for the pancreatic cancer therapeutic landscape. Contrariwise, for other gastrointestinal tumors, the rationale is currently only alleged. The role of BRCA mutation in gastrointestinal cancers is the subject of this review. In particular, we aim to provide the latest updates about novel therapeutic strategies that, exploiting DNA repair defects, promise to shape the future therapeutic scenario of GI cancers

Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients

Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. The impact of the physicians experience on the management of these AEs and the relative implications on clinical outcomes are unknown. We verified if the AEs management changed over time and if these modifications impacted on treatment duration and overall survival (OS)

ADHD Follow-Up in Adulthood among Subjects Treated for the Disorder in a Child and Adolescent Mental Health Service from 1995 to 2015

Background and Objectives: ADHD is a neurodevelopmental disorder characterized by inattention and hyperactivity/impulsivity and can persist in adulthood. The aim of this study is to deepen knowledge about adult ADHD follow-up. Materials and Methods: This observational study consists of one retrospective part aimed at collecting records of children and adolescents treated for ADHD in the Children and Adolescent Mental Health Service (CAMHS) from 1995 to 2015 and, successively, at identifying their adult follow-up in Adult Mental Health Service (AMHS); the second part consists of ADHD scale administration, Diagnostic Interview for ADHD in Adults (DIVA 2-0) and Adult Self Rating Scale (ASRSv1.1), for the subjects currently being treated at AMHS who agreed to participate in the study. Results: We observed that among the 55 patients treated at CAMHS between 1995 and 2015 for ADHD and subsequently at the AMHS, none presented a diagnosis of ADHD; instead, they were treated for Intellectual Dysfunction (33%), Borderline Personality Disorder (15%) and Anxiety Disorders (9%), and two individuals were also diagnosed with comorbid substance/alcohol abuse (4%). Of the 55 patients, only 25 (45%) were treated at AMHS during the study period. Though we asked for their informed consent to administer the questionnaires, we were able to test only seven patients. The ASRS-V1.1 score showed that 43% of patients reported symptoms of ADHD persistence in adulthood. For DIVA 2.0, 57% of individuals reported scores indicating the persistence of the ADHD inattention component, and 43% the persistence of both ADHD dimensions. Conclusions: ADHD cannot be considered a disorder confined to childhood/adolescence but instead is a chronic and complex condition that can persist into adulthood. The very small size of our final sample may account for both the high ADHD dropout rate over the long follow-up period and the difficult transition from child to adult health care in ADHD treatment. Our investigation suggests the need for specific training in the diagnosis and treatment of adult ADHD and the implementation of transition protocols between minor and adult services to improve long-term treatments

Involuntary Hospitalizations in an Italian Acute Psychiatric Ward: A 6-Year Retrospective Analysis

Purpose: We evaluated the differences between demographic (age, sex, nationality, employment, housing, schooling, support administrator), clinical (hospitalization reason, aggressive behaviour, length of hospitalization, psychiatric diagnosis and comorbidities, psychiatric medications, discharge destination, “revolving door” hospitalizations) and environmental (pre-and pandemic period) variables in voluntary (VHs) and involuntary hospitalizations (IHs) in an acute psychiatric ward during a 6-year period. Patients and Methods: We retrospectively collected the selected variables concerning the hospitalizations of subjects over 18 years of age in the Service for Psychiatric Diagnosis and Care of Mental Health and Drug Abuse Department in Modena from 01/01/2017 to 31/12/2022. Results: We observed a progressive and sharp reduction in the number of VHs (n = 1800; 61.41%) during the pandemic and a stability of IHs (n = 1131; 38.59%), which in 2022 became prevalent. We highlighted the following differences between VHs and IHs: an increase in hospitalization length in IHs (14.25 mean days ± 15.89 SD) in comparison with VHs (8.78 mean days ± 13.88 SD), which increased more during the pandemic; an increase in aggressive behavior in IHs, especially during the pandemic (Pearson Chi2 = 90.80; p = 0.000); a prevalence of schizophrenia and bipolar disorders (Pearson Chi2 = 283.63; p = 0.000) and more frequent maladaptive social conditions among subjects in IHs. Conclusion: During the 6-year observation period, we underscored a trend of increasingly reduced recourse to VHs, whereas IHs increased even in the pandemic. Our results suggest that IHs in Psychiatry represented an extreme measure for treating the most severe psychopathological situations such as schizophrenia and bipolar disorders, characterized by aggressive behaviour and precarious social conditions, which needed longer stay than VHs, especially during the pandemic

TRAIL receptors are expressed in both malignant and stromal cells in pancreatic ductal adenocarcinoma

: This study assesses the expression of all TNF-related apoptosis-inducing ligand (TRAIL) receptors in pancreatic ductal adenocarcinoma (PDAC) tumor tissue. We aimed to include TRAIL receptor expression as an inclusion parameter in a future clinical study using a TRAIL-based therapy approach for PDAC patients. Considering the emerging influence of PDAC desmoplastic stroma on the efficacy of anti-PDAC therapies, this analysis was extended to tumor stromal cells. Additionally, we performed PDAC stroma characterization. Our retrospective cohort study (N=50) included patients with histologically confirmed PDAC who underwent surgery. The expression of TRAIL receptors (DR4, DR5, DcR1, DcR2, and OPG) in tumor and stromal cells was evaluated by immunohistochemistry (IHC). The amount of tumor stroma was assessed by anti-vimentin IHC and Mallory's trichrome staining. The prognostic impact was determined by the univariate Cox proportional hazards regression model. An extensive expression of functional receptors DR4 and DR5 and a variable expression of decoy receptors were detected in PDAC tumor and stromal cells. Functional receptors were detected also in metastatic tumor and stromal cells. A poor prognosis was associated with low or absent expression of decoy receptors in tumor cells of primary PDAC. After assessing that almost 80% of tumor mass was composed of stroma, we correlated a cellular-dense stroma in primary PDAC with reduced relapse-free survival. We demonstrated that TRAIL functional receptors are widely expressed in PDAC, representing a promising target for TRAIL-based therapies. Further, we demonstrated that a low expression of DcR1 and the absence of OPG in tumor cells, as well as a cellular-dense tumor stroma, could negatively impact the prognosis of PDAC patients

Axillary Ectopic Carcinoma of the Breast. Report of Two Cases with Different Clinical Presentation and Review of the Literature.

Aims: Primary ectopic breast cancer (PEBC) is a rare and often misdiagnosed condition. Through the discussion of two clinical cases, we want to focus on clinical presentation, outcomes and treatment of PEBC, to lead clinicians to awareness and optimal management. Methods: We present the case of a 47-year-old patient, with a 30 mm axillary mass, that was diagnosed as a PEBC (infiltrating lobular carcinoma, triple negative). The patient underwent systemic staging: diffuse metastatic bone lesions and leptomeningeal metastasis were found. The second patient is a 73-year-old woman with personal history of right breast tumor. She came to our attention for a 9 mm left axillary mass, suspicious for a metastatic lymph node. A fine-needle cytology revealed the absence of lymphoid cells but the presence of atypical epithelial cells, as in a primary breast carcinoma. She was treated with local excision and sentinel node biopsy. Results: The first patient presented with metastatic disease at the time of diagnosis and she deceased after three months from the diagnosis, despite systemic chemotherapy. The diagnosis was performed at an early stage in the second patient. She underwent surgery, complementary endocrine therapy and radiotherapy. She has no evident disease after two years from surgery. Conclusion: Primary ectopic breast cancer is a rare clinical entity, often misdiagnosed or diagnosed with a long delay. The treatment of PEBC is analogous to that of orthotopic breast cancer, but we strongly recommend to approach the patient with a multidisciplinary team to provide the best staging workout and therapie

Utility of neutrophil-to-lymphocyte ratio to identify long-term survivors among HCC patients treated with sorafenib

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Autologous anti-GD2 CAR T cells efficiently target primary human glioblastoma

Glioblastoma (GBM) remains a deadly tumor. Treatment with chemo-radiotherapy and corticosteroids is known to impair the functionality of lymphocytes, potentially compromising the development of autologous CAR T cell therapies. We here generated pre-clinical investigations of autologous anti-GD2 CAR T cells tested against 2D and 3D models of GBM primary cells. We detected a robust antitumor effect, highlighting the feasibility of developing an autologous anti-GD2 CAR T cell-based therapy for GBM patients

ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited ecacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73\u20138.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73\u20138.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44\u20130.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30\u20130.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib

Could Inflammatory Indices and Metabolic Syndrome Predict the Risk of Cancer Development? Analysis from the Bagnacavallo Population Study

Background: Despite the robust data available on inflammatory indices (neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)) and clinical outcome in oncological patients, their utility as a predictor of cancer incidence in the general population has not been reported in literature. Methods: The Bagnacavallo study was performed between October 2005 and March 2009. All citizens of Bagnacavallo (Ravenna, Emilia-Romagna, Italy) aged 30-60 years as of January 2005 were eligible and were invited by written letter to participate to the study. All participants underwent a detailed clinical history and physical examination following the model of the Dionysos Study. All blood values included in the analysis were obtained the day of physical examination. Cancer incidence data were obtained from the population-based Romagna Cancer Registry, which operates according to standard methods. The aim of this analysis was to examine the association between metabolic syndrome and baseline SII, NLR, and PLR levels, and the diagnosis of an invasive cancer in the Bagnacavallo study cohort. Results: At univariate analysis, metabolic syndrome was not associated with an increase of cancer incidence (HR 1.30; p = 0.155). High glucose (HR 1.49; p = 0.0.16), NLR HR 1.54, p = 0.002), PLR (HR 1.58, p = 0.001), and SII (HR 1.47, p = 0.006) were associated with an increase of cancer incidence. After adjusting for clinical covariates (smoking, physical activity, education, age, and gender) SII, PLR, and NLR remained independent prognostic factors for the prediction of cancer incidence. Conclusions: Inflammatory indices are promising, easy to perform, and inexpensive tools for identifying patients with higher risk of cancer in cancer-free population