Locally Advanced Gastric Cancer Management: A Cost-Effectiveness Analysis.

Across the nation, patients with locally advanced gastric cancer (LAGC) are managed with modalities including upfront surgery (US) and perioperative chemotherapy (PCT). Preoperative therapies have demonstrated survival benefits over US and thus long-term outcomes are expected to vary between the options. However, as these 2 modalities continue to be regularly employed, we sought to perform a decision analysis comparing the costs and quality-of-life associated with the treatment of patients with LAGC to identify the most cost-effective option. We designed a decision tree model to investigate the survival and costs associated with the most commonly utilized management modalities for LAGC in the United States: US and PCT. The tree described costs and treatment strategies over a 6-month time horizon. Costs were derived from 2022 Medicare reimbursement rates using the third-party payer perspective for physicians and hospitals. Effectiveness was represented using quality-adjusted life-years (QALYs). One-way, two-way, and probabilistic sensitivity analyses were utilized to test the robustness of our findings. PCT was the most cost-effective treatment modality for patients with LAGC over US with a cost of $40,792.16 yielding 3.11 QALYs. US has a cost of $55,575.57 while yielding 3.15 QALYs; the incremental cost-effectiveness ratio (ICER) was $369,585.25. One-way and two-way sensitivity analyses favored PCT in all variations of variables across their standard deviations. Across 100,000 Monte Carlo simulations, 100% of trials favored PCT. In our model simulating patients with LAGC, the most cost-effective treatment strategy was PCT. While US demonstrated improved QALYs over PCT, the associated cost was too great to justify its use.

NFĸB Targeting in Bone Marrow Mesenchymal Stem Cell-Mediated Support of Age-Linked Hematological Malignancies.

Mesenchymal stem cells (MSCs) can become dysfunctional in patients with hematological disorders. An unanswered question is whether age-linked disruption of the bone marrow (BM) microenvironment is secondary to hematological dysfunction or vice versa. We therefore studied MSC function in patients with different hematological disorders and found decreased MHC-II except from one sample with acute myeloid leukemia (AML). The patients' MSCs were able to exert veto properties except for AML MSCs. While the expression of MHC-II appeared to be irrelevant to the immune licensing of MSCs, AML MSCs lost their ability to differentiate upon contact and rather, continued to proliferate, forming foci-like structures. We performed a retrospective study that indicated a significant increase in MSCs, based on phenotype, for patients with BM fibrosis. This suggests a role for MSCs in patients transitioning to leukemia. NFĸB was important to MSC function and was shown to be a potential target to sensitize leukemic CD34+/CD38- cells to azacitidine. This correlated with their lack of allogeneic stimulation. This study identified NFĸB as a potential target for combination therapy to treat leukemia stem cells and showed that understanding MSC biology and immune response could be key in determining how the aging BM might support leukemia. More importantly, we show how MSCs might be involved in transitioning the high risk patient with hematological disorder to AML.

Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive tumor with limited treatment options and poor prognosis. We applied the in vivo phage display technology to isolate peptides homing to the immunosuppressive cellular microenvironment of TNBC as a strategy for non-malignant target discovery. We identified a cyclic peptide (CSSTRESAC) that specifically binds to a vitamin D receptor, protein disulfide-isomerase A3 (PDIA3) expressed on the cell surface of tumor-associated macrophages (TAM), and targets breast cancer in syngeneic TNBC, non-TNBC xenograft, and transgenic mouse models. Systemic administration of CSSTRESAC to TNBC-bearing mice shifted the cytokine profile toward an antitumor immune response and delayed tumor growth. Moreover, CSSTRESAC enabled ligand-directed theranostic delivery to tumors and a mathematical model confirmed our experimental findings. Finally, in silico analysis showed PDIA3-expressing TAM in TNBC patients. This work uncovers a functional interplay between a cell surface vitamin D receptor in TAM and antitumor immune response that could be therapeutically exploited.

Coexistence of Two Different Thyroid Malignancies: A Collision Phenomenon.

The term "collision tumor" is described as the coexistence of two or more histologically distinct neoplastic morphologies separated by normal tissue in the same organ. Simultaneous papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) of the same thyroid lobe is a very rare pathology. Herein, we report a case of PTC and FTC of the same thyroid lobe. A 79-year-old man was evaluated at our hospital for the presence of left hip pain of two-month duration after sustaining a physical trauma to the left side of his body three days prior to admission. X-ray imaging of the left femur revealed a large lytic bony lesion at the proximal end of left femur. Biopsy of the bone lesion was suggestive of FTC. Computed tomography (CT) of the neck revealed an enlarged thyroid with a cystic lesion in the left lobe of the thyroid gland. Total thyroidectomy was performed. Histopathology revealed two separate primary malignancies of PTC and FTC. Genetic studies for RAS gene mutation were negative. He was initiated on suppressive doses of levothyroxine following thyroidectomy. Three months after surgery, thyrotropin alfa stimulated 204.5 mCi I-131 was administered. At seven months of follow-up, the thyroglobulin level was in the lower end of the normal range and anti-thyroglobulin antibody (anti Tg) remained negative (< 1.0 IU/mL). He was doing well and reported no symptoms. For each type of well-differentiated thyroid cancers, several genes have been identified. However, thus far, no specific gene mutation responsible for the pathogenesis of the different tumor types has been described. Management of thyroid collision tumor is usually complex due to the presence of different pathology in the tumor tissues and given the fact that literature on this condition is limited. Typically, the treatment needs to be individualized. Our report brings up a concept that the occurrence is a rare phenomenon of simultaneous mutation of different genes that could give rise to different thyroidal neoplasms.

OSSMAR: An Observational Study to Describe the Use of Sunitinib in Real-Life Practice for the Treatment of Metastatic Renal Cell Carcinoma.

PURPOSE: Sunitinib offers improved efficacy for patients with metastatic renal cell carcinoma (mRCC). To provide better disease management in the Middle East, we studied its use in mRCC in real-life practice in this region. MATERIAL AND METHODS: Patients diagnosed with mRCC and started on sunitinib between 2006 and 2016 from 10 centers in Africa and the Middle East region were studied in this regional, multicenter, observational, retrospective trial to obtain routine clinical practice data on the usage patterns and outcomes of sunitinib in mRCC in real-life practice. RESULTS: A total of 289 patients were enrolled. Median age at diagnosis was 58.7 years. The patient characteristics were as follows: 73.6% of patients were males; 85.8% had clear-cell renal cell carcinoma (RCC); 97.5% had unilateral RCC; 66.3% had metastatic disease at initial diagnosis; 56.3% received previous treatment for RCC, among which 98.7% had undergone surgery; and 15.2% and 31.4% were classified in the favorable and poor-risk groups (expanded Memorial Sloan Kettering Cancer Center criteria), respectively. On treatment initiation, the mean total sunitinib dose was 48.1 mg, and 87.6% of patients were started on a sunitinib dose of 50 mg. The mean duration of sunitinib treatment was 9.6 months. Overall response rate was 20.8%, with a median duration of 8.2 months. Median time to progression was 5.7 months. Median follow-up time was 7.8 months. By months 12 and 24, 34.3% and 11.4% of patients, respectively, were still alive. Seventy-six patients (60.9%) experienced 314 adverse events. Twenty-three patients (8.0%) experienced 28 serious adverse events. Overall, 83 patients (28.7%) discontinued their sunitinib treatment. CONCLUSION: The results are indicative of the general treatment outcomes of patients with mRCC in the Middle East using sunitinib in routine clinical practice. Reported adverse events are similar to those described in the literature but at lower frequencies.

Increased Levels of Circulating and Tumor-Infiltrating Granulocytic Myeloid Cells in Colorectal Cancer Patients.

Increased levels of myeloid cells, especially myeloid-derived suppressor cells (MDSCs), have been reported to correlate with bad prognosis and reduced survival in cancer patients. However, limited data are available on their conclusive phenotypes and their correlation with clinical settings. The aim of this study was to investigate levels and phenotype of myeloid cells in peripheral blood and tumor microenvironment (TME) of colorectal cancer (CRC) patients, compared to blood from healthy donors (HDs) and paired, adjacent non-tumor colon tissue. Flow cytometric analysis was performed to examine the expression of different myeloid markers in fresh peripheral blood samples from CRC patients and HDs, and tissue-infiltrating immune cells from CRC patients. We found significantly higher levels of cells expressing myeloid markers and lacking the expression of major histocompatibility complex class II molecule HLA-DR in blood and tumor of CRC patients. Further analysis revealed that these cells were granulocytic and expressed Arginase 1 indicative of their suppressive phenotype. These expanded cells could be neutrophils or granulocytic MDSCs, and we refer to them as granulocytic myeloid cells (GMCs) due to the phenotypical and functional overlap between these cell subsets. Interestingly, the expansion of peripheral GMCs correlated with higher stage and histological grade of cancer, thereby suggesting their role in cancer progression. Furthermore, an increase in CD33+CD11b+HLA-DR-CD14-CD15- immature myeloid cells was also observed in CRC tumor tissue. Our work shows that GMCs are expanded in circulation and TME of CRC patients, which provides further insights for developing immunotherapeutic approaches targeting these cell subsets to enhance antitumor immune and clinical responses.

Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer.

Despite major advances in early detection and prognosis, chemotherapy resistance is a major hurdle in the battle against breast cancer. Identifying predictive markers and understanding the mechanisms are key steps to overcoming chemoresistance. Methylation-controlled J protein (MCJ, also known as DNAJC15) is a negative regulator of mitochondrial respiration and has been associated with chemotherapeutic drug sensitivity in cancer cell lines. Here we show, in a retrospective study of a large cohort of breast cancer patients, that low MCJ expression in breast tumors predicts high risk of relapse in patients treated with chemotherapy; however, MCJ expression does not correlate with response to endocrine therapy. In a prospective study in breast cancer patients undergoing neoadjuvant therapy, low MCJ expression also correlates with poor clinical response to chemotherapy and decreased disease-free survival. Using MCJ-deficient mice, we demonstrate that lack of MCJ is sufficient to induce mammary tumor chemoresistance in vivo. Thus, loss of expression of this endogenous mitochondrial modulator in breast cancer promotes the development of chemoresistance.

Patterns of epidermal growth factor receptor mutation in non-small-cell lung cancers in the Gulf region.

The aim of the present study was to determine the prevalence of epidermal growth factor receptor mutations (EGFRmut) in the Gulf region (GR) and its correlation with demographic and clinical characteristics. A multisite retrospective study was conducted, including institutions from Saudi Arabia, the United Arab Emirates and Qatar. All consecutive patients with non-small-cell lung cancer tested for EGFRmut were eligible. Data collected included demographic information, disease characteristics and EGFR test results. Data on 230 patients were obtained. The median age of the patients was 61 years (range, 26-87 years); 169 patients (69.83%) were male and 204 (88.7%) were Arab. The histological subtype was adenocarcinoma in 191 (83.4%) and squamous cell carcinoma in 21 cases (9.17%). Overall, EGFRmut were detected in 66 patients (28.7%), with a prevalence of 32.46% in adenocarcinoma. No squamous cell carcinomas were found to harbor EGFRmut. The univariate and multivariate analyses revealed that female gender, non-smoking status and adenocarcinoma subtype were significant predictors for EGFRmut. There was no difference between Arabs and non-Arabs. In conclusion, to the best of our knowledge, this is the first multisite study to report the prevalence of EGFRmut in the GR population, which was found to be higher compared with that in Western, but lower compared with that in Far Eastern populations. Studies evaluating the efficacy of targeted therapy in this population are underway.

Impact of Oncotype†DX testing on adjuvant treatment decisions in patients with early breast cancer: a single-center study in the United Arab Emirates.

AIM: To evaluate the distribution of the Oncotype DX Recurrence Score (a validated prognostic/predictive tool in early-stage estrogen-receptor positive [ER+] breast cancer) and its impact on adjuvant treatment decisions in the United Arab Emirates. METHODS: A retrospective analysis of a single-center cohort. RESULTS: The analysis included 47 node-negative ER+ breast cancer patients with low-to-intermediate risk according to the St. Gallen criteria. The mean (SD) Recurrence Score result was 17.7 (8.0); 25 (53.2%), 19 (40.4%) and 3 (6.4%) patients had low, intermediate and high Recurrence Score results, respectively. Recurrence Score risk categories were concordant with risk groups according to the St. Gallen criteria in 23 patients (48.9%). Before testing, 24 patients (51.1%) were recommended endocrine therapy alone and 23 patients (48.9%) were recommended chemoendocrine therapy. After testing, 13 patients (27.7%; 95% confidence interval 16.3-42.4%) had a treatment change (from pretesting recommendation to posttesting actual treatment), and chemotherapy use decreased overall (from 48.9 to 25.5%; P = 0.0023, McNemar's test), and particularly in the low Recurrence Score category (from 56.0 to 8.0%; P = 0.0005, McNemar's test). After testing, the proportions of patients with chemoendocrine therapy recommendations differed significantly across the Recurrence Score categories (8.0, 36.8 and 100% in the low, intermediate and high Recurrence Score categories, respectively; P = 0.0012, Fisher's exact test). With an average follow-up of 31.2 months (range: 17-51), no locoregional/systemic relapses were observed. CONCLUSION: This first decision impact study in a Middle Eastern country showed the significant effect of Oncotype DX testing on clinical practice, further demonstrating the consistent impact of such testing worldwide.

High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study.

BACKGROUND: The aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment. METHODS: A comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4-5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins. RESULTS: A total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd41, Tp53-Alu, and Mfd28 was evident. A significant association between mismatch repair/loss of heterozygosity and incidence of secondary tumors was also established. CONCLUSION: Our results suggest that microsatellite instability, loss of heterozygosity, and deficiency in mismatch repair may serve as early prognostic factors for potential chemotherapy-related side effects in breast cancer patients.

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

Published data from the Middle East and North Africa (MENA) region indicate suboptimal quality of cancer care, while the World Health Organization predicts an increase in cancer cases in developing countries. Major advances in breast cancer management mandate the development of guidelines to improve the quality and efficacy of oncology practice in the MENA region. A Breast Cancer Regional Guidelines Committee was organized and activated, comprising experts from various regional cancer institutions. The multidisciplinary team included 12 medical oncologists, 3 radiation oncologists, 2 radiologists, 2 surgeons, and 1 pathologist. The committee members agreed on adapting the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Breast Cancer for use in the MENA region to achieve common practice standards for treating patients. The members suggested several modifications to the guidelines, especially those related to risk factor profiles. United States-based NCCN experts reviewed these recommendations before final approval. The MENA-NCCN Breast Cancer Guidelines modification process was the first initiative in the development of common practice guidelines in the region. This project may serve as a foundation for the development of evidence-based practice standards, and improve collaborative projects and initiatives.

Thromboembolic events as an emerging adverse effect during high-dose intravenous immunoglobulin therapy in elderly patients: a case report and discussion of the relevant literature.

A case of an 82-year-old man who suffered an acute ST-elevation myocardial infarction while receiving treatment with intravenous immunoglobulin (IVIg) for thrombocytopenia is discussed. A total of 29 other cases of thromboembolism related to IVIg therapy have been reported, and the incidence seems to be especially high in elderly patients with cerebrovascular risk factors and also in patients with paraproteinemias. Possible mechanisms to account for this complication may include some of the following: platelet activation, increased blood viscosity, contamination of IVIg with activated coagulation factors, induced arterial vasospasm, production of vasoconstrictive cytokines, and vasculitis. Ten patients out of the 29 reported patients died from this serious complication. In our patient, spontaneous reperfusion occurred without any treatment and he had an uneventful outcome.

Splenic rupture from metastatic granulosa cell tumor 29 years after curative resection: case report and review of the literature.

Granulosa cell tumors account for 2 to 3 per cent of all ovarian neoplasms. This case report describes a patient with splenic rupture from a bulky metastatic deposit 29 years after her initial surgery. A review of the literature regarding the patterns and timing of recurrence is also discussed.