Prognostic significance of DNA ploidy, S-phase fraction, and tissue levels of aspartic, cysteine, and serine proteases in operable gastric carcinoma

A consecutive series of 63 untreated patients undergoing surgical resection for stage I-IV gastric adenocarcinomas (GCs) has been prospectively studied. Our purpose was to analyze the predictive relevance of DNA ploidy, S-phase fraction (SPF), and tissue levels of lysosomal proteinases cathepsin D (CD), cathepsin B (CB), cathepsin L (CL), and urokinase-type plasminogen activator (uPA) and that of the intracellular cysteine proteinase inhibitor stefin A on clinical outcome. All of the patients taking part in this study were followed up for a median of 73 months. DNA aneuploidy was present in 71% of the cases (45/63), whereas 9% of these (4/45) showed multiclonality. Both DNA ploidy and SPF were associated with tumor-node-metastasis (TNM) stage and node status, whereas only DNA ploidy was related to depth of invasion. CB, CL, uPA, but not CD, levels were significantly higher in GC as compared to paired normal mucosa, whereas stefin A levels were lower in tumor tissues. CB levels were significantly associated with TNM stage, nodal status, histological grade, and DNA ploidy. At univariate analysis, only node involvement, advanced TNM stage, DNA aneuploidy, and high SPF proved to be significantly related to quicker relapse and to shorter overall survival, whereas depth of invasion was related only to survival. With multivariate analysis, only high SPF (>15.2%) was related to risk of relapse (RR = 8.50), whereas high SPF and DNA aneuploidy were independently related to risk of death (RR = 1.88 and 2.09, respectively). Our preliminary prospective study has identified SPF and DNA ploidy as important biological indicators for predicting the outcome of patients with GC

Duodenal Signet Ring Cell Carcinoma in a Celiac Patient

Celiac disease results from damage to the small intestinal mucosa due to an inappropriate immune response to a cereal protein. Long-standing or ‘refractory’ celiac disease is associated with an increased risk of autoimmunity and malignancy. We produced a brief literature review starting from a case of duodenal cancer in a celiac patient. The patient with an history of celiac disease since six months presented with acute manifestation of gastric outlet syndrome. A duodenal stricture was diagnosed at upper gastrointestinal endoscopy and confirmed by abdominal computed tomography. He was successfully treated by segmental duodenal resection. In the resected specimens, the diagnosis was duodenal signet cell adenocarcinoma. 6-month follow-up is uneventful. Primary carcinoma of the duodenum is rare (duodenal adenocarcinoma accounts for less than 0.5% of all gastrointestinal cancers and 30–45% of small intestinal cancers). Some patients with duodenal carcinoma are potentially curable by surgery, but conflicting opinions exist on the factors influencing the survival rate and on surgical treatment as the gold standard. Nevertheless, the goal in surgical treatment is to achieve clear margins. At present, surgical resection (pancreaticoduodenectomy or pancreas-sparing duodenal segmental resection) is the only available option for cure of this disease

Genetic Ablation of the MET Oncogene Defines a Crucial Role of the HGF/MET Axis in Cell-Autonomous Functions Driving Tumor Dissemination

Cancer cell dissemination is sustained by cell-autonomous and non-cell-autonomous functions. To disentangle the role of HGF (Hepatocyte Growth Factor) and MET ligand/receptor axis in this complex process, we genetically knocked out the MET gene in cancer cells in which MET is not the oncogenic driver. In this way, we evaluated the contribution of the HGF/MET axis to cancer cell dissemination independently of its direct activities in cells of the tumor microenvironment. The lack of MET expression in MET−/− cells has been proved by molecular characterization. From a functional point of view, HGF stimulation of MET−/− cancer cells was ineffective in eliciting intracellular signaling and in sustaining biological functions predictive of malignancy in vitro (i.e., anchorage-independent growth, invasion, and survival in the absence of matrix adhesion). Cancer cell dissemination was assessed in vivo, evaluating: (i) the ability of MET−/− lung carcinoma cells to colonize the lungs following intravenous injection and (ii) the spontaneous dissemination to distant organs of MET−/− pancreatic carcinoma cells upon orthotopic injection. In both experimental models, MET ablation affects the time of onset, the number, and the size of metastatic lesions. These results define a crucial contribution of the HGF/MET axis to cell-autonomous functions driving the metastatic process

Unusual presentation of luminal breast carcinoma metastatic to the brain and coma: a case report of dramatic response to abemaciclib and literature review

Patients with luminal breast cancer (BC) may develop central nervous system metastases in 20%–40% of cases. Radiation or surgical therapy represents the cornerstone of treating central nervous system metastases. Meanwhile, the best practice for metastatic luminal BC involves using cyclin-dependent kinase 4/6 inhibitors combined with endocrine therapy. To our knowledge, this is the first case to report a dramatic response of breast metastases to abemaciclib plus endocrine therapy without radiation therapy, particularly in a patient who presented with seizures and sudden coma. She received brain surgery to control a large bleeding metastasis. Abemaciclib was crushed and diluted in water for administration via the nasogastric tube, while an upfront fulvestrant was given since aromatase inhibitors cannot be diluted. Beyond the radiological response, the clinical improvement was notable, with complete symptom recovery to the point where she is again working. Our paper supports the activity of abemaciclib in brain metastases from luminal BC and includes a review of the medical literature. Further investigation is warranted in this clinical setting

Food Beliefs and the Risk of Orthorexia in Patients with Inflammatory Bowel Disease

: Patients with inflammatory bowel disease (IBD) believe that diet plays a significant role in the pathogenesis of their disease and the exacerbation of their symptoms. They often adopt restrictive diets that can lead to malnutrition, anxiety, and stress. Recent studies have found a correlation between IBD and eating disorders, such as anorexia nervosa and ARFID (Avoidant Restrictive Food Intake Disorder). None of these studies report an association with orthorexia nervosa, which is an obsession with healthy and natural foods. The aim of this study was to assess the risk of orthorexia nervosa in patients with IBD. A total of 158 consecutive subjects were recruited, including 113 patients with IBD and 45 controls. The standardized Donini questionnaire ORTO-15 was administered to assess the risk of orthorexia, and clinical and demographic data were collected. The results showed that patients with IBD had a risk of developing orthorexia nervosa of 77%. This was significantly higher than the 47% observed in the control group. In the patients with IBD, the risk of orthorexia was associated with a lower BMI, at least in patients older than 30 years, and it was also associated with marital status in patients younger than 30. In conclusion, many patients with IBD are at increased risk of developing orthorexia nervosa, which may have a negative impact on their psychological wellbeing and social sphere, expose them to a high risk of nutritional deficiencies, and affect their overall quality of life. Further high-quality studies are needed to assess the clinical impact of orthorexia and its correlation with clinical features and classified eating disorders

Gastrinomas and non-functioning pancreatic endocrine tumors in multiple endocrine neoplasia syndrome type-1 (MEN-1)

Purpose: Illustrate imaging findings of gastrinomas and non-functioning pancreatic endocrine tumors (NF-PNET) in a patient with multiple endocrine neoplasia type-1 (MEN-1) syndrome with a radiologic-pathologic correlation for both along with the results of a 13 yrs observational study. Methods: A 48 yrs old male patient with MEN-1 and a Zollinger-Ellison syndrome was submitted to a duodeno-cephalopancreatectomy (DCP) extended to the pancreatic body to remove several gastrinomas shown by an endoscopic-ultrasonography as well as a large (> 2 cm) hypo-vascular pancreatic nodule shown by a contrast-enhanced multi-detector CT (CE-MDCT). Further conventional (CT/MR) and functional imaging (68Ga-PET-DOTA-TOC) studies were performed over the next 13 years. Results: Up to 14 gastrin-positive NET-G1 (pT2,N1) as well as a single PNET-G2 (pT2,N0) were found at histo-pathology which also showed a NET-G1 in the uncinate process where CE-MDCT documented a 9 mm hyper-vascular nodule. A 7 mm pancreatic nodule with identical contrast-enhancement pattern was also shown at the level of the pancreatic tail which was left to preserve endocrine function. At this level, follow-up studies documented the occurence of a small (< 1 cm) hypo-vascular nodule which was metastatic at presentation and rapidly progressed under somastatin-analogs therapy whereas the hyper-vascular nodule remained stable over 13 years. Both the pancreatic lesion as well as the hepatic metastasis showed pathologic uptake of the radiotracer with a SUVmax of 6.3 and 29.5, respectively, allowing the patient to be scheduled for a Peptide Receptor Radionuclide Therapy performed with 29.6 GBq of 177Lu-Oxotreotide. Conclusions: Contrast-enhancement patterns are correlated with both the histological grade as well as the biological behaviour of PNETS

Synthetic recovery of impulse propagation in myocardial infarction via silicon carbide semiconductive nanowires

: Myocardial infarction causes 7.3 million deaths worldwide, mostly for fibrillation that electrically originates from the damaged areas of the left ventricle. Conventional cardiac bypass graft and percutaneous coronary interventions allow reperfusion of the downstream tissue but do not counteract the bioelectrical alteration originated from the infarct area. Genetic, cellular, and tissue engineering therapies are promising avenues but require days/months for permitting proper functional tissue regeneration. Here we engineered biocompatible silicon carbide semiconductive nanowires that synthetically couple, via membrane nanobridge formations, isolated beating cardiomyocytes over distance, restoring physiological cell-cell conductance, thereby permitting the synchronization of bioelectrical activity in otherwise uncoupled cells. Local in-situ multiple injections of nanowires in the left ventricular infarcted regions allow rapid reinstatement of impulse propagation across damaged areas and recover electrogram parameters and conduction velocity. Here we propose this nanomedical intervention as a strategy for reducing ventricular arrhythmia after acute myocardial infarction

Heightened IDO1 levels predict Bacillus Calmette-Guèrin failure in high-risk non-muscle-invasive bladder cancer patients

: Recent studies have indicated a potential link between immune-related gene expression and Bacillus Calmette-Guèrin (BCG) treatment response in non-muscle-invasive bladder cancer (NMIBC) patients, however, prognostic gene signatures have not significantly improved risk stratification beyond clinical characteristics. To identify predictive biomarkers in T1 high-risk (HR) bladder cancer (BC) patients responding to BCG treatment, a gene signature was derived from a discovery cohort of 73 BCG-naïve patients, both responders and non-responders, using the publicly available dataset GSE1542618. Among the identified genes, Indoleamine 2,3-dioxygenase (IDO1), an immunosuppressive enzyme, emerged as a crucial determinant of treatment outcomes. The association between IDO1 expression and worse prognosis was subsequently validated in a cohort of 75 BC patients using formalin-fixed paraffin-embedded (FFPE) BC specimens collected prior BCG treatment. This research revealed significant insights into the mechanisms underlying unsatisfactory responses to BCG treatment in HR patients, posing IDO1 as a promising prognostic biomarker and therapeutic target for NMIBC

Multicentric Retrospective Analysis of Oncocytic Adrenocortical Carcinoma: Insights into Clinical and Management Strategies

Oncocytic adrenocortical carcinoma (OAC) is a rare variant of conventional adrenocortical carcinoma (ACC), characterized by oncocytic tumor cells comprising more than 90% of the tumor. Due to its rarity, there is a lack of reliable data on the clinicopathological features and outcomes of OAC. The aim of this study was to assess the clinical presentation, treatment modalities, and outcomes of patients with OAC, comparing these results with a cohort of patients with conventional ACC. Data from 9 referral centers in Italy on 44 patients with OAC were retrospectively analyzed and compared with data from 145 patients with conventional ACC. Patients with OAC had a smaller median tumor size, more favorable resection margin status, and lower incidences of venous invasion and persistent/recurrent disease during follow-up. Additionally, patients with OAC exhibited longer times to progression (TTP) and overall survival (OS) compared to patients with conventional ACC. Multivariable analyses identified Ki67 and tumor size as features independently associated with disease progression during post-surgical follow-up, while Ki67 and distant metastases at diagnosis were independently associated with OS in OAC patients. After complete tumor removal, the risk of recurrent disease was higher in patients with either Ki67 ≥ 20% or ENSAT stage III/IV. OAC appears to have a more indolent clinical course and better prognosis than conventional ACC. Similar to conventional ACC, Ki67 remains a significant prognostic marker for OAC and, along with ENSAT stage, serves as a reliable biomarker for identifying patients who may benefit from adjuvant mitotane therapy