To investigate primarily the prognostic value of Ki-67, as well as other parameters, in gastrointestinal stromal tumors (GISTs). Ki-67, c-KIT, platelet-derived growth factor receptor-alpha (PDGFRα), smooth muscle actin (SMA), CD34, S100 were stained for immunohistochemistry which was performed on formalin-fixed, paraffin-embeded sections on representative block from each case. Proliferation index counted by Ki-67 antibody was calculated as a number of positive nuclear reaction over 100 cells. Immunoreactivity for c-KIT and PDGFRα was evaluated semiquantitatively (weak, intermediate, strong) and for c-KIT type of reactivity was analyzed (cytoplasmic, membrane and "dot-like" staining). Immunoreactivity for SMA, CD34 and S100 were was evaluated as positive or negative antigen expression. Pathologic parameters investigated in this study included tumor size, cell type (pure spindle, pured epitheloid mixed spindle and epitheloid), mitotic count, hemorrhage, necrosis, mucosal ulceration. Clinical data included age, gender, primary tumor location and spread of disease. χ² test and Student's t-test were used for comparisons of baseline characteristics. The Cox's proportional hazard model was used for univariable and multivariable analyses. Survival rates were calculated by Kaplan-Meier method and statistical significance was determined by the log-rank test. According to the stage of disease, there were 36 patients with localized disease, 29 patients with initially localized disease but with its recurrence in the period of follow up, and finally, 35 patients had metastatic disease from the very beginning of disease. Tumor originated most commonly in the stomach (41%), small intestine was the second most common location (36%). The mean size of primary tumors was 6.5 cm. The mean duration of follow-up was 60 mo. Multiple parameters were analyzed for their effect on overall survival, but no one reached statistical significance (P = 0.06). Analysis of time to progression/relapse in initially localized disease (univariate analysis), tumor size, mitotic count, Ki-67 and type of d-KIT distribution (cytoplasmic vs membrane/"dot-like") showed statistically significant correlation. In multivariate analysis in the group of patients with localized disease, there were only 2 parameters that have impact on relapse, Ki-67 and SMA (P < 0.0001 and P < 0.034, respectively). Furthermore, Ki-67 was analyzed in localized disease vs localized with recurrence and metastatic disease. It was shown that there is a strict difference between these 2 groups of patients (median value was 2.5 for localized disease vs 10.0 for recurrent/metastatic disease, P < 0.0001). It was also shown that the cut-off value which is still statistically significant in terms of relapse on the level of 6%. The curves for survival on that cut-off level are significantly different (P < 0.04, Cox F). Ki-67 presents a significant prognostic factor for GIST recurrence which could be of great importance in evaluating malignant potential of disease.

Nutritional issues, including malnutrition, low muscle mass, sarcopenia (i.e., low muscle mass and strength), and cachexia (i.e., weight loss characterized by a continuous decline in skeletal muscle mass, with or without fat loss), are commonly experienced by patients with cancer at all stages of disease. Cancer cachexia may be associated with poor nutritional status and can compromise a patient’s ability to tolerate antineoplastic therapy, increase the likelihood of post-surgical complications, and impact long-term outcomes including survival, quality of life, and function. One of the primary nutritional problems these patients experience is malnutrition, of which muscle depletion represents a clinically relevant feature. There have been recent calls for nutritional screening, assessment, treatment, and monitoring as a consistent component of care for all patients diagnosed with cancer. To achieve this, there is a need for a standardized approach to enable oncologists to identify patients commencing and undergoing antineoplastic therapy who are or who may be at risk of malnutrition and/or muscle depletion. This approach should not replace existing tools used in the dietitian’s role, but rather give the oncologist a simple nutritional protocol for optimization of the patient care pathway where this is needed. Given the considerable time constraints in day-to-day oncology practice, any such approach must be simple and quick to implement so that oncologists can flag individual patients for further evaluation and follow-up with appropriate members of the multidisciplinary care team. To enable the rapid and routine identification of patients with or at risk of malnutrition and/or muscle depletion, an expert panel of nutrition specialists and practicing oncologists developed the PROtocol for NuTritional risk in Oncology (PRONTO). The protocol enables the rapid identification of patients with or at risk of malnutrition and/or muscle depletion and provides guidance on next steps. The protocol is adaptable to multiple settings and countries, which makes implementation feasible by oncologists and may optimize patient outcomes. We advise the use of this protocol in countries/clinical scenarios where a specialized approach to nutrition assessment and care is not available.

Background/Objectives: The mitochondrial unfolded protein response (UPRmt) is one of the mitochondrial quality control mechanisms that is responsible for reparation and removal of damaged proteins in mitochondria. Methods: Here we investigated the role of the UPRmt in the myocardium of humans with and without heart failure and in the cell culture model. Results: The analysis of myocardial samples by ELISA from patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), as well as healthy donors, revealed a significantly reduced expression of the UPRmt proteins HSP10, CLPP, LONP1, OMA1, and SPG7 in patients with DCM and ICM. Furthermore, patients with DCM and ICM exhibited elevated levels of myocardial reactive oxygen species (ROS, tested by 4-hydroxynonenal) compared to controls, and a positive correlation between ROS production and mt-HSP70, OMA1, and SPG7 protein expression. The correlation analysis indicated a negative correlation between cardiomyocyte hypertrophy and the expression of several UPRmt genes. The inhibition of four tested UPRmt effector proteins exacerbated the injury of cultured cells under oxidative stress. The patients with ICM, DCM, or both, who showed lower myocardial expression of HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L, underwent heart transplantation or implantation of a left ventricular assist device earlier in life compared to those with the higher protein expression. Conclusions: In conclusion, our findings indicate that the reduced expression of several UPRmt effector proteins is associated with accelerated heart failure in patients, which, together with other results, indicates that impaired UPRmt may contribute to the pathogenesis of heart failure in humans.

Cancer cachexia is a syndrome characterized by weight and muscle loss and functional impairment, strongly influencing survival in cancer patients. In this study, we aimed to establish the role of saliva cytokine measurement in cancer cachexia investigation and define two potential independent salivary biomarkers of the condition. Methods: serum and saliva specimens were obtained from 78 patients. Forty-six patients were non-cachectic, and 32 patients were cachectic (per SCRINIO group criteria), all with metastatic solid tumors. Commercial ELISA kits were used to determine the salivary and serum concentrations of interleukin 13 (IL-13) and transforming growth factor beta (TGF-β) in two patient groups and healthy controls. Laboratory values were obtained from the hospital information system, and weight and height were measured at the time of sampling. Results: A statistically significant difference was observed between the groups in saliva IL-13 concentrations but no difference in serum concentrations. Statistically significant differences were also observed between the groups in saliva and serum concentrations of TGF-β. Logistic regression analysis has identified salivary IL-13 and TGF-β as independent factors for cancer cachexia. Conclusions: We demonstrated saliva as a valuable specimen for cachexia investigation and established IL-13 and TGF-β as potential cancer cachexia biomarkers. Further research is needed to evaluate these findings.

Fibroblast growth factor receptor 2 (FGFR2) inhibitors such as pemigatinib are targeted therapies for cholangiocarcinoma with FGFR2 alterations. While generally well tolerated, they are associated with unique adverse events. Calciphylaxis, a potentially fatal vascular calcification disorder, is a rare complication. We present a 43-year-old woman with metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 fusion who developed calciphylaxis after seven months of pemigatinib therapy. Despite drug discontinuation, antibiotics, and multidisciplinary supportive care, she deteriorated rapidly and died from sepsis and advanced disease. Histopathological analysis confirmed dermal and vascular calcifications consistent with calciphylaxis. This case highlights the importance of early recognition of cutaneous lesions in patients on FGFR inhibitors. Prompt cessation of therapy, management of metabolic derangements, and consideration of sodium thiosulfate may be lifesaving.