The role of cancer stem cells in the modulation of anti-tumor immune responses.

Tumor lesions comprise multiple subpopulations of cells including those endowed with "stemness" properties. The latter cells are responsible of tumor initiation, metastasis formation, resistance to conventional therapies and disease recurrence. These relatively rare cells denominated cancer stem cells (CSCs) or cancer initiating cells (CICs) are defined based on self-renewing, multipotency and tumorigenicity. These cells through their immunomodulating features can evade from immunesurveillance, persisting in the form of quiescence and dormancy. They can drive the neoplastic growth and recurrence, even after long latency. Moreover, CSCs/CICs due to their ability to modulate and shape immune responses can represent the component of a tumor causing immunotherapy resistance in cancer patients. In this review a general overview of immunological properties of CSCs/CICs is provided, with a special focus on the mechanisms of modulation of T cell mediated responses. The need to further dissect the mechanisms regulating the immunological profile of CSCs/CICs and their interactions with immune cells and tumor microenvironment is discussed. An improved characterization of the immunological properties of CSCs/CICs will contribute to the rationale design of immunotherapeutic interventions which target these cells and may lead to the eradication of malignant diseases.

COVID-19 in patients with neuroendocrine neoplasms: 2-year results of the INTENSIVE study.

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

Pancytopenia And Limbic Encephalopathy Complicating Immunotherapy For Clear Cell Endometrial Cancer With Microsatellite Instability-High (MSI-H).

BACKGROUND: Clear cell carcinoma of the endometrium (CCE) has a tendency to occur in a mismatch repair protein deficient molecular background. Treatment with immunotherapy can predict a favorable response. CASE PRESENTATION: We are presenting a 53-year-old female, diagnosed with CCE 17 years ago, who was treated initially with hysterectomy and left salpingo-oophorectomy, who relapsed a few months later, and was then treated with left pelvic mass excision and sigmoidectomy. Recently, the disease recurred as a retroperitoneal lymphadenopathy, which was resected but then relapsed locally, spread to the lungs, and progressed further after three lines of chemotherapy. On pathological review of the tumor, it was found to harbor loss of nuclear expression of MLH-1 and PMS-2. Based on a strong predictor of response to immunotherapy, pembrolizumab was tried. However, within a few days of the single dose of pembrolizumab, immune thrombocytopenia followed by pancytopenia, recurrent seizures, visual hallucination, and cerebellar signs consistent with limbic encephalitis developed, which were not responding to steroid and intravenous immunoglobulin. CONCLUSION: We are presenting a case of a CCE with deficient mismatch repair that developed two autoimmune side effects, pancytopenia and limbic encephalitis, within a few days of a single injection of pembrolizumab.

Atypical manifestations of multiple myeloma: radiological appearance.

Diagnostic procedures performed on patients with multiple myeloma typically reveal lytic bone lesions, osteopenia or osteoporosis, bone marrow infiltration by plasma cells as well as overproduction of immunoglobulin or light chains in the serum or urine. Skeletal manifestations are extremely variable and the unusual forms have been described extensively. Extramedullary plasma-cell tumours (plasmocytoma) are found in about 5% of newly diagnosed patients with multiple myelomas. In this paper we present eight patients with atypical forms of multiple myeloma.

Characterization of regulatory sequences in alternative promoters of hypermethylated genes associated with tumor resistance to cisplatin.

The development of cisplatin resistance in human cancers is controlled by multiple genes and leads to therapeutic failure. Hypermethylation of specific gene promoters is a key event in clinical resistance to cisplatin. Although the usage of multiple promoters is frequent in the transcription of human genes, the role of alternative promoters and their regulatory sequences have not yet been investigated in cisplatin resistance genes. In a new approach, we hypothesized that human cancers exploit the specific transcription factor-binding sites (TFBS) and CpG islands (CGIs) located in the alternative promoters of certain genes to acquire platinum drug resistance. To provide a useful resource of regulatory elements associated with cisplatin resistance, we investigated the TFBS and CGIs in 48 alternative promoters of 14 hypermethylated cisplatin resistance genes previously reported. CGIs prone to methylation were identified in 28 alternative promoters of 11 hypermethylated genes. The majority of alternative promoters harboring CGIs (93%) were clustered in one phylogenetic subclass, whereas the ones lacking CGIs were distributed in two unrelated subclasses. Regulatory sequences, initiator and TATA-532 prevailed over TATA-8 and were found in all the promoters. B recognition element (BRE) sequences were present only in alternative promoters harboring CGIs, but CCAAT and TAACC were found in both types of alternative promoters, whereas downstream promoter element sequences were significantly less frequent. Therefore, it was hypothesized that BRE and CGI sequences co-localized in alternative promoters of cisplatin resistance genes may be used to design molecular markers for drug resistance. A more extensive knowledge of alternative promoters and their regulatory elements in clinical resistance to cisplatin is likely to usher novel avenues for sensitizing human cancers to treatment.

Clinical presentation, management and outcomes of gastrointestinal stromal tumors.

INTRODUCTION: The present study investigated the incidence, management and outcome of Gastrointestinal Stromal Tumors (GIST) in Qatar. METHODS: A retrospective review of all GIST patients admitted between 1995 and 2012 was conducted. Patients' demographics, clinical presentation, tumor characteristics, radiological, pathological and immunohistochemical findings, surgical procedures, recurrence and mortality were recorded. RESULTS: A total of 48 GIST patients were identified. Stomach (56%) and small intestine (27%) were the most common sites of tumor. The majority of cases (n = 27) had tumor size >5 cm, 31 cases had primary and 15 cases had locally advanced tumor. Patients were stratified as high, intermediate, and low risk (43.8%, 18.8% and 37.5%, respectively). Almost all the cases were surgically managed and 94% were completely resectable. Robotic partial resection was performed in 4 cases and 5 cases underwent laparoscopic resection. Chemotherapy was initiated in half of patients. During follow up (average 37.5 months), 33 patients showed complete recovery, 7 had recurrent or metastatic disease and 2 died due to liver metastasis. CONCLUSION: The incidence of GIST in Qatar is apparently low. Surgical resection is the preferred choice of treatment; however, robotic and laparoscopic resections are feasible and safe approaches in some cases.

Status of hepatocellular carcinoma in Gulf region.

Hepatocellular carcinoma (HCC) has a unique geographic distribution that is likely to be determined by specific etiologic factors. There is a distinctive difference in sex and age related occurrence of disease. In the Gulf region, there are contradicting data on the prevalence and death rates due to HCC. In this review we highlight some aspects of HCC specific to the Gulf region. A retrospective analysis of 150 patient's data is presented, including demographic, epidemiological, aetiological disease status assessment with child Pugh criteria, modes of treatment and treatment related outcome. Hepatitis C virus (HCV) infection was the most common (45%) documented etiology, similar to Western European countries, followed by hepatitis B virus (HBV) infection in 27% of cases, alcoholic liver disease only in six patients (4%). Child-Pugh assessment was A in 33%, B in 37% and C in 30% of observed patients. Surgery (liver resection or transplantation) was performed in 12% and local ablation in 5% of cases. The others were treated by chemo-embolization in 17% and by systemic therapy with sorafenib in 13% of patients. Nearly half of the patients (53%) were in advanced stages and received palliative treatment. To improve the outcome of treatment in HCC patients in the Gulf region, an effective and strategic screening program must be implemented for early diagnosis and treatment to improve the outcome of this mostly fatal disease.

Modification and implementation of NCCN guidelines on colon cancer in the Middle East and North Africa region.

Colorectal cancer is less common in the Middle East and South Asia than in western countries, with the rectum the most common primary site, unlike in the United States. A project was planned to address various local issues regarding the management of common cancers, including colorectal cancer, and to adapt the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to the Middle East and North Africa (MENA) region. A survey of oncologists in this geographic area showed that the management practices and issues regarding colorectal cancer are similar to those presented in the NCCN Colorectal Cancer Guidelines. However, 2 major differences exist: most oncologists in the MENA region prefer chest radiograph over CT in pretreatment workup, and almost 50% of them prefer to use cetuximab in the first-line treatment of patients with the wild-type KRAS gene. The committee, comprising 9 oncologists from different countries, proposed 4 modifications to the 2009 version of the NCCN Colorectal Cancer Guidelines for use in the MENA region, relating to 1) short-course preoperative radiotherapy, 2) dose of capecitabine, 3) stereotactic radiotherapy for liver metastasis, and 4) qualification of surgeons performing colorectal surgery. The modification of NCCN Colorectal Cancer Guidelines for use in the MENA region represents a step toward creating a uniform practice in the region based on evidence and local experience.

Malignant peritoneal mesothelioma. Is there a new treatment?

The authors report a novel, alternative approach to treat malignant peritoneal mesothelioma (MPeM) targeting, vascular endothelial growth factor (VEGF) using anti-VEGF (bevacizumab) chemotherapy combination.