Immunologic signatures of response and resistance to nivolumab with ipilimumab in advanced metastatic cancer.

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8-35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1-43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8-51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.

Small Bowel Perforation Due to Renal Carcinoma Metastasis: A Comprehensive Case Study and Literature Review.

This case report presents a unique instance of small bowel perforation caused by solitary metastasis from renal cell carcinoma (RCC), a rare and complex clinical scenario. The patient, a 59-year-old male with a history of RCC treated with nephrectomy four years prior, presented with acute abdomen symptoms. Emergency diagnostic procedures identified a significant lesion in the small intestine. Surgical intervention revealed a perforated jejunal segment due to metastatic RCC. Postoperatively, the patient developed complications, including pneumonia and multi-organ failure, leading to death 10 days after surgery. Histopathological analysis confirmed the metastatic nature of the lesion. This case underscores the unpredictable nature of RCC metastasis and highlights the need for vigilance in post-nephrectomy patients. The rarity of small bowel involvement by RCC metastasis, particularly presenting as perforation, makes this case a significant contribution to medical literature, emphasizing the challenges in the diagnosis and management of such atypical presentations.

Exploring Perforated Jejunal GIST: A Rare Case Report and Review of Molecular and Clinical Literature.

This case report details a rare instance of a perforated jejunal gastrointestinal stromal tumor (GIST) in a 76-year-old female patient. The patient presented with acute abdominal pain and distension without any changes in bowel habits or episodes of nausea and vomiting. Initial diagnostics, including abdominal plain radiography and ultrasonography, were inconclusive; however, a computed tomography (CT) scan revealed pneumoperitoneum and an irregular fluid collection suggestive of small intestine perforations. Surgical intervention uncovered a 35 mm jejunal GIST with a 10 mm perforation. Histopathological examination confirmed a mixed cell type GIST with high malignancy potential, further substantiated by immunohistochemistry markers CD117, DOG1, and vimentin. Molecular analysis illuminated the role of key oncogenes, primarily KIT and PDGFRA mutations, emphasizing the importance of molecular diagnostics in GIST management. Despite the severity of the presentation, the patient's postoperative recovery was favorable, highlighting the effectiveness of prompt surgical and multidisciplinary approaches in managing complex GIST cases.

Burnout syndrome among medical nurse-technicians in intensive care units in cardiovascular surgery.

Background: Healthcare workers in intensive care units work under specifically hard conditions compared to healthcare workers who work under regular clinical conditions. In this sense, the research aims at assessing the level of burnout symptomatology among nurse technicians working in intensive care units for cardiovascular surgery and to compare those burnout levels with those recorded for medical technicians working under regular clinical conditions. Method: The research was designed as a cross-sectional study. The sample consisted of nurse technicians working in intensive care units specializing in cardiovascular surgery (70 participants) and nurse technicians working under regular clinical conditions (70 participants) at the Institute for Cardiovascular Diseases "Dedinje," Belgrade, Serbia. To evaluate the manifestation of burnout syndrome at work, the analysis uses the Serbian version of the Maslach Burnout Inventory-Human Services Survey (MBI-HSS). Results: To examine the variances in the average sub-scores for burnout within two groups of medical technicians, the study used Two Independent Samples T-test. The statistically noteworthy differentiation was ascertained for emotional exhaustion and personal accomplishment, but this does not hold true for depersonalization. However, the mean score values across the different burnout levels (low, moderate, high) are similar in two cohorts of respondents (p > 0.05). Conclusion: This study will serve as an impetus for a policy reform focused on ameliorating working conditions and improving healthcare workers' satisfaction and overall healthcare quality.

Metastatic Breast Cancer Presenting as Acute Appendicitis: A Rare Case Study and Review of Current Knowledge.

This manuscript discusses a rare case of acute appendicitis caused by metastasis from invasive breast carcinoma of no special type in a 70-year-old female previously diagnosed with breast cancer. It delves into the diagnostic challenges and management complexities of such unusual clinical presentations. The paper includes an analysis of 19 documented cases, enriching the understanding of metastatic patterns and treatment strategies in breast cancer. It underlines the importance of considering a history of malignancy when diagnosing acute abdominal conditions and emphasizes a comprehensive approach in interpreting diagnostic imaging in patients with past oncological issues to effectively manage metastatic breast cancer exhibiting atypical manifestations.

The Enigma of Mammaglobin: Redefining the Biomarker Paradigm in Breast Carcinoma.

The continuous evolution of cancer biology has led to the discovery of mammaglobin, a potential novel biomarker for breast carcinoma. This review aims to unravel the enigmatic aspects of mammaglobin and elucidate its potential role in redefining the paradigm of breast carcinoma biomarkers. We will thoroughly examine its expression in tumoral and peritumoral tissues and its circulating levels in the blood, thereby providing insights into its possible function in cancer progression and metastasis. Furthermore, the potential application of mammaglobin as a non-invasive diagnostic tool and a target for personalized treatment strategies will be discussed. Given the increasing incidence of breast carcinoma worldwide, the exploration of novel biomarkers such as mammaglobin is crucial in advancing our diagnostic capabilities and treatment modalities, ultimately contributing to improved patient outcomes.

Appendiceal Signet Ring Cell Carcinoma: An Atypical Cause of Acute Appendicitis-A Case Study and Review of Current Knowledge.

Appendiceal signet ring cell carcinoma (ASRCC) is a rare and aggressive form of appendiceal cancer, often presenting with nonspecific symptoms that overlap with acute appendicitis. Early diagnosis and appropriate management are crucial for improving patient outcomes in these rare malignancies. This case report and literature review aims to raise awareness among clinicians about ASRCC of the appendix as a cause of acute appendicitis and highlight the importance of considering this diagnosis in patients with atypical presentations or unexpected histopathological findings. We present a 65-year-old female patient with ASRCC who underwent successful surgical treatment and remains disease-free at the one-year follow-up. It also highlights the necessity of early detection and appropriate treatment in order to improve patient outcomes. In addition, a comprehensive literature review is provided, discussing the clinical presentation, histopathological characteristics, potential pathogenesis, treatment options, and prognosis of ASRCC.

Secondary Breast Malignancy from Renal Cell Carcinoma: Challenges in Diagnosis and Treatment-Case Report.

Renal cell carcinoma represents about 2% of all malignant tumours in adults. Metastases of the primary tumour in the breast make up to about 0.5-2% of the cases. Renal cell carcinoma metastases in the breast are extremely rare and have been sporadically recorded in the literature. In this paper, we present the case of a patient with breast metastasis of renal cell carcinoma 11 years after primary treatment. Case presentation: An 82-year-old female who had right nephrectomy due to renal cancer in 2010 felt a lump in her right breast in August 2021, whereby a clinical examination revealed a tumour at the junction of the upper quadrants of her right breast, about 2 cm, movable toward the base, vaguely limited, and with a rough surface. The axillae were without palpable lymph nodes. Mammography showed a circular and relatively clearly contoured lesion in the right breast. Ultrasound showed an oval lobulated lesion of 19 × 18 mm at the upper quadrants, with strong vascularisation and without posterior acoustic phenomena. A core needle biopsy was performed, and the histopathological findings and obtained immunophenotype indicated a metastatic clear cell carcinoma of renal origin. A metastasectomy was performed. Histopathologically, the tumour was without desmoplastic stroma, comprising predominantly solid-type alveolar arrangements of large moderately polymorphic cells, bright and abundant cytoplasm, and round vesicular cores with focally prominent nuclei. Immunohistochemically, tumour cells were diffusely positive for CD10, EMA, and vimentin, and negative for CK7, TTF-1, renal cell antigen, and E-cadherin. With a normal postoperative course, the patient was discharged on the third postoperative day. After 17 months, there were no new signs of the underlying disease spreading at regular follow-ups. Conclusion: Metastatic involvement of the breast is relatively rare and should be suspected in patients with a prior history of other cancers. Core needle biopsy and pathohistological analysis are required for the diagnosis of breast tumours.

Resource Use and Costs Related to Hematological Complications of Chemotherapy: Cost of Illness Study Based on Data from Balkan Country with Recent History of Socioeconomic Transition.

Background: The administration of chemotherapy positively correlates with diverse adverse drug reactions, including the significant impact of hematological hazards such as anemia, leukopenia-neutropenia, thrombocytopenia, and pancytopenia. This pilot pharmacoeconomic study aimed to estimate the total direct costs of treating hematological toxicity induced by chemotherapy and its main determinants. Methods: The study was conducted as a retrospective cost of illness study using the "from bottom to the top" approach from the perspective of the Republic Health Insurance Fund. This study included 88 patients treated due to developing at least one episode of one of the types of hematological complications of cytostatics in 2018 at the Oncology Clinic of the University Clinical Center Kragujevac, Kragujevac, the Republic of Serbia. Results: Among cancer patients who developed haematological toxicity, treating pancytopenia was most demanding in a pharmacoeconomic manner compared to neutropenia and thrombocytopenia, with an estimated value of direct costs of 264,14, 178,19 and 157,76 euros per patient per year respectively. Regarding total direct costs, the main determinants were the costs of drugs, their parenteral administration, and costs due to hospitalization. Conclusion: Due to the rising cancer incidence and obligatory hospital treatment of hematological toxicity induced by chemotherapy, the identification of the pharmacoeconomic aspects of the treatment of these complications is needed. Future research should focus on the development of new modalities of treatment regarding patient characteristics anticipating high costs.

Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial.

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

Lifestyle, Physical Activity, Eating and Hygiene Habits: A Comparative Analysis Before and During the COVID-19 Pandemic in Student Population.

Background: Changing daily habits such as diet, hygiene and physical activity may be some of the consequences of the COVID-19 pandemic. The aim of the study was to analyze the effect of this pandemic on lifestyle, physical activity, eating and hygiene habits among students. Methods: This cross-sectional study involved 171 students from the Faculty of Medical Sciences, University of Kragujevac, Serbia. Data were statistically analyzed using Wilcoxon Signed-Rank test, Marginal homogeneity test and Chi-square test. The differences were considered statistically significant when p ≤ 0.05. Results: In this study, it was observed that the most common physical activity before the pandemic was walking, while during the pandemic was home exercising. Compared to the period before the pandemic, there was no difference in the time spent engaging in daily physical activity (p = 0.334). However, there was a significant increase in sitting time during the pandemic (p = 0.005). Difference was noticed in the use of breakfast, the number of meals, and the type of fat in the diet before and during the pandemic (p = 0.000). During the pandemic, there was an increase in the use of fruits (p = 0.000), vegetables, and nuts (p = 0.001), while the use of fast food and alcohol have decreased. During the COVID-19 pandemic, a significant increase in the use of dietary supplements was observed (40.2%), (p = 0.008). Conclusions: Given that the COVID-19 pandemic is ongoing, certain changes in lifestyle observed in this study should be confirmed in more extensive population studies.

Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity.

Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.

CFTR IVS8 Poly-T Variation Affects Severity of Acute Pancreatitis in Women.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) is important for normal pancreatic function. Its coding gene is polymorphic, and the variations have been associated with the increased risk for acute pancreatitis. However, their impact on the disease severity is still unknown. Therefore, the aim of our study was to determine the functional importance of common cystic fibrosis transmembrane conductance regulator variations IVS8-poly T, R117H, and M470V for the severity of acute pancreatitis. METHOD: The study involved 98 acute pancreatitis patients. The severity of the disease was determined based on the Atlanta Classification system. IVS8-poly T, R117H, and M470V genotyping was performed using PCR-RFLP method. RESULTS: IVS8-5T, IVS8-7T, IVS8-9T, and M470V alleles were found at the frequencies of 5.7, 75.5, 18.9, and 55.7%, respectively, while R117H was not observed. Among women, the severe form of the disease was more frequent in carriers of at least one IVS8 9T allele (RR for 9T/9T + 9T/non-9T vs. non-9T/non-9T: 2.115; 95% CI: 1.241-3.605). This association was not detected in men and was not affected by M470V. In addition, co-morbidities increased the severity of acute pancreatitis (p = 0.022). CONCLUSION: Our study reveals that IVS8 poly-T variation affects severity of acute pancreatitis in women and that existent co-morbidities worsen the clinical course of the disease.

Minimally Invasive Middle Fossa Keyhole Craniectomy for Repair of Superior Semicircular Canal Dehiscence.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) presents with varying degrees of auditory and vestibular dysfunction. The condition is confirmed on high-resolution computed tomography (CT) imaging, and symptoms are often improved by surgical repair. Although a classic middle fossa craniotomy has been used with good results, recent advances in technique have allowed for modification of the traditional approach into a smaller skin incision and a minimally invasive middle fossa keyhole craniectomy roughly 1.7 cm in diameter. OBJECTIVE: To delineate this novel approach and describe the technique for accurate localization of the dehiscence using preoperative measurements and intraoperative image guidance, thereby minimizing the need for a larger skin incision and craniotomy. METHODS: Patients were independently diagnosed with SSCD by the senior authors. Once relevant imaging was acquired, the novel keyhole technique was performed. Patients' vestibular and auditory symptoms before and after the procedure were assessed. Outcomes from a series of patients treated with this keyhole approach were tabulated and reported. RESULTS: Twelve cases from 11 patients were included in this series. Auditory symptoms had high rates of resolution with pulsatile tinnitus, internal amplification of sounds, and autophony being resolved in a majority of cases. Only 2 cases reported hearing decline. Sound/pressure induced vertigo and disequilibrium also demonstrated high rates of resolution. No complications were reported. CONCLUSION: The minimally invasive middle fossa keyhole craniectomy is a novel approach for the repair of SSCD. This approach may contribute to resolved auditory and vestibular symptoms with low morbidity and quick recovery.

Incidental Meningiomas: Management in the Neuroimaging Era.

The number of patient imaging studies has increased because of precautious physicians ordering scans when a vague symptom is presented; subsequently, the number of incidental meningiomas detected has increased as well. These brain tumors do not present with related symptoms and are usually small. MRI and computed tomographic scans most frequently capture incidental meningiomas. Incidental meningiomas are managed with observation, radiation, and surgical resection. Ultimately, a conservative approach is recommended, such as observing an incidental meningioma and then only radiating if the tumor displays growth, whereas a surgical approach is to be used only when proven necessary.

Clinical Characteristics of Posterior and Lateral Semicircular Canal Dehiscence.

The objective of this study was to evaluate the characteristic symptoms of and treatments for lateral semicircular canal dehiscence (LSCD) and posterior semicircular canal dehiscence (PSCD) and its proposed mechanism. A dehiscence acquired in any of the semicircular canals may evoke various auditory symptoms (autophony and inner ear conductive hearing loss) or vestibular symptoms (vertigo, the Tullio phenomenon, and Hennebert sign) by creating a "third mobile window" in the bone that enables aberrant communication between the inner ear and nearby structures. A PubMed search was performed using the keywords lateral, posterior, and semicircular canal dehiscence to identify all relevant cases. Our data suggest that PSCD, although clinically rare, is most likely associated with a high-riding jugular bulb and fibrous dysplasia. Patients may experience auditory manifestations that range from mild conductive to extensive sensorineural hearing loss. LSCD is usually associated with chronic otitis media with cholesteatoma.

PD-1 blockade induces responses by inhibiting adaptive immune resistance.

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.