Building an Efficient Peritoneal Surface Malignancies Program Despite the Lower-Middle-Income Barriers: Ukraine Experience.

PURPOSE: Cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) programs are often limited to centers in developed countries because of extensive requirements. We aimed to analyze efficacy and challenges of CRS/HIPEC centers in lower-middle-income settings in the Ukraine example. METHODS: A multicenter descriptive study was conducted using data sets (2008-2022) from Kyiv, Lviv, and Odesa centers. Patients with appendiceal neoplasm (AN); colorectal cancer (CRC); malignant peritoneal mesothelioma (MPM); and epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) treated with CRS ± HIPEC were included. Overall survival (OS) was analyzed for N ≥ 20 cohorts using the Kaplan-Meier method. RESULTS: We included 596 patients. At Kyiv and Lviv centers, 37 and 28 patients with AN had completeness of cytoreduction (CC-0/1) rates of 84% and 71%, respectively. Thirty-day major morbidity stood at 24% and 18%, respectively. Median OS was not reached (NR) at both centers. Nineteen patients with CRC from Kyiv, 11 from Lviv, and 156 from Odesa had CC-0/1 rates of 84%, 91%, and 86%, respectively. Thirty-day major complications occurred in 16%, 18%, and 8%, respectively. Median OS in the Odesa cohort was 35 (95% CI, 32 to 38) months. Among 15 Kyiv, five Lviv, and six Odesa patients with MPM, CC-0/1 rates were 67%, 80%, and 100%, respectively, while major complications occurred in 13%, 0%, and 17%, respectively. OS was not analyzed because of small MPM cohorts. At Kyiv, Lviv, and Odesa centers, 91, 40, and 89 patients, respectively, had primary EOC. CC-0/1 rates were 79%, 100%, and 80%, and 30-day major morbidity rates were 23%, 5%, and 6%, respectively. Median OS was NR, 71 (95% CI, 32 to 110), and 67 (95% CI, 61 to 73) months, respectively. CONCLUSION: CRS/HIPEC programs in lower-middle-income environment can achieve safety and survival that meet global standards. Our discussion highlights common obstacles in such settings and proposes effective overcoming strategies.

Low infiltration of tumor-associated macrophages in high c-Myb-expressing breast tumors.

Tumor-associated macrophages (TAMs) are prominent components of tumor stroma that promotes tumorigenesis. Many soluble factors participate in the deleterious cross-talk between TAMs and transformed cells; however mechanisms how tumors orchestrate their production remain relatively unexplored. c-Myb is a transcription factor recently described as a negative regulator of a specific immune signature involved in breast cancer (BC) metastasis. Here we studied whether c-Myb expression is associated with an increased presence of TAMs in human breast tumors. Tumors with high frequency of c-Myb-positive cells have lower density of CD68-positive macrophages. The negative association is reflected by inverse correlation between MYB and CD68/CD163 markers at the mRNA levels in evaluated cohorts of BC patients from public databases, which was found also within the molecular subtypes. In addition, we identified potential MYB-regulated TAMs recruiting factors that in combination with MYB and CD163 provided a valuable clinical multigene predictor for BC relapse. We propose that identified transcription program running in tumor cells with high MYB expression and preventing macrophage accumulation may open new venues towards TAMs targeting and BC therapy.

Increased levels of the HER1 adaptor protein Rukl/CIN85 contribute to breast cancer malignancy.

The adaptor protein regulator for ubiquitous kinase/c-Cbl-interacting protein of 85kDa (Ruk/CIN85) was found to modulate HER1/EGFR signaling and processes like cell adhesion and apoptosis. Although these features imply a role in carcinogenesis, it is so far unknown how and by which molecular mechanisms Ruk/CIN85 could affect a certain tumor phenotype. By analyzing samples from breast cancer patients, we found high levels of Ruk(l)/CIN85 especially in lymph node metastases from patients with invasive breast adenocarcinomas, suggesting that Ruk(l)/CIN85 contributes to malignancy. Expression of Ruk(l)/CIN85 in weakly invasive breast adenocarcinoma cells deficient of Ruk(l)/CIN85 indeed converted them into more malignant cells. In particular, Ruk(l)/CIN85 reduced the growth rate, decreased cell adhesion, enhanced anchorage-independent growth, increased motility in both transwell migration and wound healing assays as well as affected the response to epidermal growth factor. Thereby, Ruk(l)/CIN85 led to a more rapid and prolonged epidermal growth factor-dependent activation of Src, Akt and ERK1/2 and treatment with the Src inhibitor PP2 and the PI3K inhibitor LY294002 abolished the Ruk(l)/CIN85-dependent changes in cell motility. Together, this study indicates that high levels of Ruk(l)/CIN85 contribute to the conversion of breast adenocarcinoma cells into a more malignant phenotype via modulation of the Src/Akt pathway.