Combined Anti-PD-1 and Anti-CTLA-4 Treatment in Stage IV Melanoma Patients: A Bicentric Analysis of Real-World Data and a Modern Treatment Scenario Proving Lactate Dehydrogenase's Usefulness.

BACKGROUND: This retrospective study evaluates patients with stage IV melanoma treated with nivolumab and ipilimumab combination therapy from two regional oncology centers in Romania from the year 2019 to the end of 2022. METHODS: The data were analyzed in SAS for Windows, V9.4. LDH means were stratified by the number of metastatic sites before treatment and compared using an independent sample T-test. The survival curves were estimated using the Kaplan-Meier method, and the survival distributions were compared with the log-rank test. The effects of the main clinical and pathological variables on OS and PFS were investigated with Cox regression. RESULTS: The LDH mean for patients with three or more metastases before treatment was significantly higher than that for patients with only one metastatic site. The Kaplan-Meier curve of OS in all evaluable patients enrolled in the study resulted in a median OS of 346 days (95% CI: 150) and a median PFS of 211 days (95% CI: 113-430). A total of 45.3% of the patients experienced adverse events during the nivolumab + ipilimumab treatment, with some of them having multiple organ systems involved. DISCUSSION: The OS values were lower than those reported in approved clinical trials, but the results show a marked improvement when compared to the results obtained by chemotherapy regimens previously used in these scenarios. CONCLUSION: This study provides real-world insights into the survival data and safety profiles of combination therapy with anti-PD-1 antibodies and anti-CTLA-4 antibodies.

New developments and standard of care in the management of advanced gastric cancer.

Advanced gastric adenocarcinoma is a common disease with a poor prognosis whose treatment has for decades been based on cytotoxic chemotherapy, including platinum salts in first-line, and taxane or irinotecan in second or later line. Recent years have seen the emergence of new drugs that have improved patient survival, such as trastuzumab in first-line for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel in second-line, and trifluridine-tipiracil beyond the second-line treatment. More recently, two monoclonal antibodies have demonstrated their efficacy in combination with oxaliplatin-based first-line chemotherapy, nivolumab (anti-PD1) for PD-L1 CPS ≥5 tumors, and zolbetuximab for tumors overexpressing Claudin 18.2. In addition, regorafenib has been also showed effective in phase 3 trial for heavily pretreated patients. Based on phase 2 studies, trastuzumab-deruxtecan was approved in 2022 by the EMA for HER2-positive pretreated patients. This agent is currently evaluated in phase 3 study (DESTINY-Gastric04 trial), as are several other anti-HER2 (zanidatamab, margetuximab, tucatinib), immune checkpoint inhibitors, or targeted therapies (anti-FGFR2b).

The Intertwining Roads between Psychological Distress and Gut Microbiota in Inflammatory Bowel Disease.

Inflammatory bowel disease represents one of the most life-altering gastrointestinal pathologies, with its multifactorial nature and unclear physiopathology. The most relevant clinical forms, ulcerative colitis and Crohn's disease, clinically manifest with mild to severe flares and remission periods that alter the patient's social, familial and professional integration. The chronic inflammatory activity of the intestinal wall determines severe modifications of the local environment, such as dysbiosis, enteric endocrine, nervous and immune system disruptions and intestinal wall permeability changes. These features are part of the gastrointestinal ecosystem that modulates the bottom-to-top signaling to the central nervous system, leading to a neurobiologic imbalance and clinical affective and/or behavioral symptoms. The gut-brain link is a bidirectional pathway and psychological distress can also affect the central nervous system, which will alter the top-to-bottom regulation, leading to possible functional digestive symptoms and local inflammatory responses. In the middle of this neuro-gastrointestinal system, the microbiome is a key player, as its activities offer basic functional support for both relays. The present article presents current scientific information that links the pathophysiology and clinical aspects of inflammatory bowel disease and psychiatric symptomatology through the complex mechanism of the gut-brain axis and the modulatory effects of the gut microbiota.

Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania.

Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer (p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender (p = 0.02) and the absence of lymph node invasion (p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion (p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 (p = 0.006), ulcerated histopathologic type (p = 0.04), and G2 differentiation (p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations.

Breast Sarcomas-How Different Are They from Breast Carcinomas? Clinical, Pathological, Imaging and Treatment Insights.

Breast sarcoma (BS) is a very rare and poorly studied condition. This has led to a lack of studies with a high level of evidence and to low efficacy of current clinical management protocols. Here we present our experience in treating this disease in the form of a retrospective case series study including discussion of clinical, imaging, and pathological features and treatment. We also compare the main clinical and biological features of six cases of BS (phyllodes tumors were excluded) with a cohort of 184 patients with unilateral breast carcinoma (BC) from a previous study performed at our institution. Patients with BS were diagnosed at a younger age, presented no evidence of lymph node invasion or distant metastases, had no multiple or bilateral lesions, and underwent a shorter length of hospital stay versus the breast carcinoma group. Where recommended, adjuvant chemotherapy consisted of an anthracycline-containing regimen, and adjuvant external radiotherapy was delivered in doses of 50 Gy. The comparison data obtained from our BS cases and the ones with BC revealed differences in diagnosis and treatment. A correct pathological diagnosis of breast sarcoma is essential for the right therapeutic approach. We still have more to learn about this entity, but our case series could add value to existing knowledge in a meta-analysis study.

Real Check RIO: A Real-World Analysis of Nivolumab in First Line Metastatic Melanoma Assessing Efficacy, Safety and Predictive Factors.

We performed a retrospective study on 51 metastatic melanoma patients treated with Nivolumab in first line, at the Regional Institute of Oncology (RIO) Iasi, Romania between April 2017 and December 2019. We studied the efficacy and safety of anti-PD-1 immune checkpoint inhibitor therapy on a treatment-naive population. After a median follow-up of 36 months, the median progression free survival (PFS) was 26 months (95% CI, 15-36) and the median overall survival (OS) was 31 months (95% CI, 20.1-41.8). At 12 months after the initiation of immunotherapy, the percentage of patients alive was 70%, and at 24 months 62.5%. The most common adverse events observed were dermatological (23.5%) and grade ≥3 was identified in 4 (6.8%) patients. Multivariate analysis indicated that the presence of liver metastases (HR 4.42; 95% CI: 1.88-10.4, p = 0.001) and a neutrophils/lymphocytes ratio (NLR) were associated with poor survival (HR 3.21; 95% CI: 1.04-9.87, p = 0.04). Although retrospective data on a small group of patients were analyzed, we can conclude that our results in RIO are similar to those described in clinical trials and other real-world studies. Our study highlights the potential usefulness of liver metastases and NLR as novel predictive factors in clinical decision-making.

Ischemia with Nonobstructive Coronary Artery Disease and Atrial Cardiomyopathy-Two Sides of the Same Story?

Ischemia with nonobstructive coronary artery disease (INOCA) is increasingly recognized as a significant cause of angina, myocardial remodeling, and eventually heart failure (HF). Coronary microvascular dysfunction (CMD) is a major endotype of INOCA, and it is caused by structural and functional alterations of the coronary microcirculation. At the same time, atrial cardiomyopathy (ACM) defined by structural, functional, and electrical atrial remodeling has a major clinical impact due to its manifestations: atrial fibrillation (AF), atrial thrombosis, stroke, and HF symptoms. Both these pathologies share similar risk factors and have a high comorbidity burden. CMD causing INOCA and ACM frequently coexist. Thus, questions arise whether there is a potential link between these pathologies. Does CMD promote AF or the reverse? Which are the mechanisms that ultimately lead to CMD and ACM? Are both part of a systemic disease characterized by endothelial dysfunction? Lastly, which are the therapeutic strategies that can target endothelial dysfunction and improve the prognosis of patients with CMD and ACM? This review aims to address these questions by analyzing the existing body of evidence, offering further insight into the mechanisms of CMD and ACM, and discussing potential therapeutic strategies.

Can Extended Chemotherapy Improve Glioblastoma Outcomes? A Retrospective Analysis of Survival in Real-World Patients.

Standard treatment for glioblastoma multiforme (GBM) is surgery followed by radiotherapy plus concurrent chemotherapy with daily temozolomide (TMZ), and six subsequent TMZ 5/28-day cycles. Research has focused on identifying more effective alternatives to the current protocol, including extension of the number of adjuvant TMZ cycles. We performed a retrospective analysis of all GBM patients treated in our hospital (160 patients, 2011−2020). Median follow-up was 16.0 months. Analysis of prognostic factors was performed with a particular focus on the benefit of extending TMZ chemotherapy. Improved survival correlated with younger age, female gender, good performance status, absence of cognitive dysfunctions, no steroid use, and total tumor resection. Median progression-free survival (PFS) was 12 months and median overall survival (OS) was 20.0 months for the entire cohort. Median OS by adjuvant TMZ was 10.0 months if no adjuvant chemotherapy given (group 0), 15.0 months for patients that did not complete six TMZ cycles (group A), 24.0 months for those that did (group B), and 29.0 months for patients having received more than six cycles (group C) (p < 0.0001). At the three-year mark, 15.9% patients were alive in group A, 24.4% in group B and 38.1% in group C. Carefully selected GBM patients may derive benefit from extending the standard adjuvant chemotherapy beyond six TMZ cycles, but more data is required.

Hair EDX Analysis-A Promising Tool for Micronutrient Status Evaluation of Patients with IBD?

Micronutrient deficiencies can arise in various conditions, including inflammatory bowel diseases (IBD), and diagnosing these deficiencies can be challenging in the absence of specific clinical signs. The aim of this study was to evaluate the status of various trace elements hair concentration in IBD patients compared to a healthy control group and to identify potential correlations between the micronutrient status and relevant parameters related to disease activity. The concentrations of iron, magnesium, calcium, zinc, copper, manganese, selenium and sulfur in the hair of 37 IBD patients with prior diagnosed IBD (12 Crohn's disease and 25 ulcerative colitis) and 31 healthy controls were evaluated by Energy Dispersive X-Ray spectroscopy (EDX). Significant differences in hair concentration profile of studied trace elements were identified for IBD patients compared to healthy controls. A significantly decreased hair concentration of iron, magnesium, calcium and selenium and a significantly increased sulfur hair concentration were observed in IBD patients at the time of evaluation. A decreased hair calcium concentration (r = -0.772, p = 0.003) and an increased sulfur concentration (r = 0.585, p = 0.046) were significantly correlated with disease activity. Conclusion: Hair mineral and trace elements evaluation may contribute to a proper evaluation of their status in IBD patients and improving the management of nutritional status of IBD patients.

The relationship between chronic lung diseases and lung cancer - a narrative review.

Lung cancer and chronic lung diseases are currently two of the main causes of death in the world. Both conditions have common etiological factors and multiple research directions in the last decades demonstrated the presence of some common relevant biological mechanisms which can explain why patients with chronic respiratory diseases are at higher risk of developing lung cancer. In this review, we discuss the role of chronic pulmonary diseases, such as chronic obstructive pulmonary disease, tuberculosis, sarcoidosis, asthma, pneumoconioses, idiopathic pulmonary fibrosis and their impact on lung cancer development. We also summarize the possible mechanisms involved in this relationship and how these chronic diseases influence the prognosis of patients with lung cancer. Our aim was to inform the clinicians in this respect for a careful follow-up of this category of patients and for the application of a personalized treatment approach.

Persistent Left Superior Vena Cava with Absent Right Superior Vena Cava and Discrete Subaortic Stenosis Diagnosed in a Patient with Sick Sinus Syndrome: A Case Report and Brief Review of the Literature.

A persistent left superior vena cava (PLSVC) is the most frequent anomaly of the venous drainage system. While both a right and left superior vena cava (SVC) are usually present, a unique, left-sided SVC, also known as an isolated PLSVC, accounts for only 10-20% of cases. It is frequently associated with arrhythmias and other congenital cardiac anomalies. Though it is usually an asymptomatic condition, it may pose significant problems whenever central venous access is needed. We report a case of an isolated PLSVC that was diagnosed incidentally during pacemaker implantation for sinus node dysfunction. The venous anomaly was associated with subvalvular aortic stenosis determined by a subaortic membrane; this particular association of congenital cardiovascular anomalies is a rare finding, with only a few cases reported in the literature. We aim to highlight the clinical and practical implications of this condition, as well as to discuss the embryonic development and diagnostic methods of this congenital defect.

The Coexistence of RAS and BRAF Mutations in Metastatic Colorectal Cancer: A Case Report and Systematic Literature Review.

BACKGROUND AND AIMS: The coexistence of RAS and BRAF mutations is extremely rare, occurring in approximately 0.05% of patients with metastatic colorectal cancer (mCRC). Starting from a case presentation, this review aims to examine the prevalence, clinical, histopathological and molecular features of tumors with concomitant mutations. METHODS: Case report and systematic review. We performed a systematic literature search in PubMed and EMBASE using the following MeSH terms: "coexistence" OR "concomitant" AND "RAS" AND "BRAF" AND "colorectal cancer" from the inception of the databases onwards. RESULTS: We present the case of a 53-year-old man diagnosed with metastatic rectal adenocarcinoma with both a KRAS and a BRAF mutation. The review included eleven papers reporting on a total of 30 mCRC cases with concomitant RAS and BRAF mutations. The male/female ratio was 11/5. The average age was 58.5 years. The tumor was located in nine cases on the right colon and in two cases in the left colon. 43.3% of subjects had liver metastases, and 6.6% had lung metastases. Next-generation sequencing (NGS) was used in 36.6% of cases and polymerase chain reaction (PCR) in 16.6% of cases. KRAS mutations were present in 83.3% of patients and NRAS mutations in 16.6% of patients. Survival could be assessed in 10 patients and the median was 21.1 months (about 30% lower than the survival in the general mCRC population). CONCLUSION: The results of this systematic review suggest the need to design a cohort study (either prospective or retrospective) to better characterize the patients with concomitant RAS and BRAF mutations and to establish the optimal treatment for this rare situation.

A very rare presentation of lung cancer: Metastases to the distal phalanx of index-case report.

RATIONALE: Acrometastases of the hand are an unusual sign of lung cancer onset and may often be mistaken for other benign disorders, thus delaying diagnosis and treatment. PATIENT CONCERNS: A 58-year-old man presented at the Rheumatology Clinic with a lump in the distal phalanx of the right index finger associated with intense pain, swelling, rib pain, and hemoptysis. DIAGNOSES: Given the clinical manifestations, an x-ray of the right hand was performed, and it revealed an osteolytic lesion in the distal phalanx of the right index finger. The subsequent CT of the thorax and abdomen showed a lung tumor, osteolytic lesions in the ribs, sternum, and the thoracic spine. INTERVENTIONS: Amputation of the phalanx was decided on account of intense pain refractory to NSAIDs and opioids. Pathology assessment established the diagnosis of bone metastases secondary to lung adenocarcinoma. The patient underwent 6 cycles of first-line palliative chemotherapy with cisplatin and gemcitabine with partial response according to the RECIST 1.1. criteria. EGFR and ALK testing were not available at the time. A year later, the patient presented with progressive disease, which lead to 6 more cycles of chemotherapy with docetaxel. The disease progressed during chemotherapy and the patient was switched to erlotinib. OUTCOMES: After 7 months of anti-EGFR treatment, the patient passed away due to disease progression, thus having an overall survival of 25 months. LESSONS: On rare occasions, acrometastases of the hand may be the first manifestation of a lung cancer and, as such, they must be taken into consideration in the differential diagnosis of rheumatologic disorders. They are a poor prognosis marker, but some cases like this one can have a better survival than reported in the literature, most likely due to that particular cancer's biology.

KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer - practical implications for the clinician.

Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.