Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in combination with FOLFOX chemotherapy as a first-line treatment for gastric cancer patients with peritoneal metastases: single-arm phase II study.

BACKGROUND: Gastric cancer (GC) remains among the most common and most lethal cancers worldwide. Peritoneum is the most common site for distant dissemination. Standard treatment for GC peritoneal metastases (PM) is a systemic therapy, but treatment outcomes remain very poor, with median overall survival ranging between 3-9 months. Thus, novel treatment methods are necessary. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is the most novel technique for intraperitoneal chemotherapy. Some preliminary data suggest PIPAC can achieve improved long-term outcomes in patients with GC PM, especially when used in combination with systemic chemotherapy. However, there is a lack of data from well-design prospective studies that would confirm the efficacy of PIPAC and systemic therapy combination for first-line treatment. METHODS: This study is an investigator-initiated single-arm, phase II trial to investigate the efficacy of PIPAC combined with systemic FOLFOX (5-fluorouracil, oxaliplatin, leucovorin) as a first-line treatment for GC PM. The study is conducted in 2 specialized GC treatment centers in Lithuania. It enrolls GC patients with histologically confirmed PM without prior treatment. The treatment protocol consists of PIPAC with cisplatin (10.5 mg/m2 body surface in 150 mL NaCl 0.9%) and doxorubicin (2.1 mg/m2 in 50 mL NaCl 0.9%) followed by 2 cycles of FOLFOX every 6-7 weeks. In total 3 PIPACs and 6 cycles of FOLFOX will be utilized. The primary outcome of the study is the objective response rate (ORR) according to RECIST v. 1.1 criteria (Eisenhauer et al., Eur J Cancer 45:228-47) in a CT scan performed 7 days after the 4th cycle of FOLFOX. Secondary outcomes include ORR after all experimental treatment, PIPAC characteristics, postoperative morbidity, histological and biochemical response, ascites volume, quality of life, overall survival, and toxicity. DISCUSSION: This study aims to assess PIPAC and FOLFOX combination efficacy for previously untreated GC patients with PM. TRIAL REGISTRATION: NCT05644249. Registered on December 9, 2022.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Gastric Cancer Peritoneal Metastases: Results from the Lithuanian PIPAC Program.

BACKGROUND: Peritoneal metastases (PM) of gastric cancer (GC) are considered a terminal condition, with reported median survival ranging from 2 to 9 months. Standard treatment typically involves systemic chemotherapy alone or combined with targeted therapy or immunotherapy, though efficacy is limited. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged as a novel technique for treating GC PM, although it remains an experimental treatment under investigation. This study aimed to summarize the outcomes of GC PM treatment with PIPAC from the Lithuanian PIPAC program. METHODS: All patients who underwent PIPAC for GC PM at Vilnius University Hospital Santaros Klinikos between 2015 and 2022 were included in this retrospective study. The safety of PIPAC was assessed by postoperative complications according to the Clavien-Dindo classification. Efficacy was evaluated based on the peritoneal carcinomatosis index (PCI), ascites dynamics throughout the treatment, and long-term outcomes. RESULTS: In total, 32 patients underwent 71 PIPAC procedures. Intraoperative and postoperative morbidity related to PIPAC occurred after three (4.2%) procedures. Following PIPAC, there was a tendency towards a decrease in median PCI from 10 (Q1 3; Q3 13) to 7 (Q1 2; Q3 12), p = 0.75, and a decrease in median ascites volume from 1300 mL (Q1 500; Q3 3600) at the first PIPAC to 700 mL (Q1 250; Q3 4750) at the last PIPAC, p = 0.56; however, these differences were not statistically significant. The median overall survival after PM diagnosis was 12.5 months (95% CI 10-17), and the median survival after the first PIPAC procedure was 5 months (95% CI 4-10). CONCLUSIONS: PIPAC is a safe and feasible treatment option for GC PM; however, well-designed prospective studies are needed to fully assess its efficacy.

Components of NOTCH Signaling for Uterine Cancer Patients' Prognosis.

New molecular biomarkers that could have an independent prognostic value in endometrial cancer are currently under investigation. Recently, it was suggested that genetic changes in the Notch signaling pathway could be associated with the development of endometrial carcinoma. This study aimed to determine the expression of the Notch signaling pathway components in tumour and adjacent normal uterine tissue and to evaluate their importance for the survival of uterine cancer patients. The present study was performed on uterine body samples collected from 109 patients and paired adjacent noncancerous endometrial tissue samples. Kaplan-Meier curves and Cox regression were used for survival analyses. Expression alterations of NOTCH2, NOTCH3, NOTCH4, JAG2, and HES1 were evaluated as independent and significant prognostic factors for uterine cancer patients.

Targeted therapy in patients with non-small cell lung cancer previously treated with chemotherapy.

A case of successful and prolonged treatment of metastatic non-small cell lung cancer with the epidermal growth factor receptor antagonist erlotinib is presented. A never-smoker female was diagnosed with stage IV lung cancer in December 2005. A chest CT scan showed soft tissue mass 35×34 mm in size in the right lung with metastases in the lymph nodes and in the left lung. A biopsy revealed a poorly differentiated adenocarcinoma. The disease showed poor response to the first-line and second-line chemotherapy. Targeted therapy with erlotinib was started in February 2007. The most severe adverse event observed was grade 3 skin rash. The disease was stable until February 2009 when brain metastases were detected. Erlotinib was continued until May 2009 when disease progression in the lungs was confirmed. The patient died due to ongoing disease progression in December 2009. Retrospective genetic analysis of a tumor specimen was performed, and no mutations in EGFR exons 18-21 were detected. The patient had a significant clinical benefit for the period of 24 months. These results are consistent with previous reports in literature that clinical characteristics such as female gender, nonsmoker, adenocarcinoma histology, and severe cutaneous toxicity seem to predict good response to erlotinib. In the present case, erlotinib proved to be effective even in heavily pretreated, chemotherapy-resistant lung adenocarcinoma. So far, no exact predictive biomarkers of erlotinib effectiveness have been determined; and their further analyses are essential.

Outcomes of Treatment for Melanoma Brain Metastases.

BACKGROUND: Historically, melanoma with brain metastases has a poor prognosis. In this retrospective medical record review, we report basic clinicopathological parameters and the outcomes of patients with melanoma and brain metastases treated with different treatment modalities before the era of immunotherapy and modern radiotherapy technique. METHODS: Patients with metastatic melanoma were treated with surgery, radiotherapy, and/or systemic therapy from 1998 to 2017. In our study, they were identified and stratified depending on treatment methods. Overall survival was defined as the time from the date of brain metastases to the death or last follow-up (2019 June 1st). Survival curves were estimated using the Kaplan-Meier method that was employed to calculate the hazard ratio. RESULTS: Six (12%) of 50 patients are still alive as of the last follow-up. The median overall survival from the onset of brain metastases was 11 months. The longest survival time was observed in patients treated by surgery followed by radiotherapy, surgery followed by radiotherapy and systemic therapy, and also radiotherapy followed by systemic therapy. The shortest survival was observed in the best supportive care group and patients treated by systemic therapy only. CONCLUSIONS: Patients with brain metastases achieved better overall survival when treated by combined treatment modalities: surgery followed by radiotherapy (26.6 months overall survival), combining surgery, radiotherapy, and systemic therapy (18.7 months overall survival), and also radiotherapy followed by systemic therapy (13.8 months overall survival).

Changes in the expression of Notch and Wnt signalling molecules in human endometrial cancer.

BACKGROUND: Endometrial cancer is the  sixth most frequent type of cancer among women worldwide. Type  I adenocarcinomas account for 80-85% of endometrial cancer cases and sometimes require more aggressive treatment than the remaining part of this group. Therefore, molecular markers to stratify adenocarcinomas are needed. MATERIALS AND METHODS: In this study, we analysed Notch and Wnt signalling in human endometrial cancer cases to evaluate these pathway elements as potential biomarkers for type  I endometrial cancer. Endometrial samples were obtained from 47 women undergoing surgery for stage I-IV endometrial cancer in the National Cancer Institute (Vilnius, Lithuania) in 2015-2016. The expression at the mRNA level of signalling molecules genes (NOTCH1, NOTCH2, NOTCH3, NOTCH4, JAG1, JAG2, DLL1, HES1, AXIN2 and CTNNB1) was analysed by the quantitative real-time polymerase chain reaction. Relative expression of NOTCH1, NOTCH4, HES1 and ß-catenin proteins in endometrioid adenocarcinoma was evaluated by the Western blot method. RESULTS: The  expression level of Notch receptors, ligands, and the target gene, as well as CTNNB1 and AXIN2, was reduced in stage I endometrioid adenocarcinoma if compared to the adjacent non-tumour tissue. The expression of all receptors, ligands, and target molecules was reduced in adenocarcinomas of later stages. The statistically significant correlations between transcript amounts of Notch receptors and ligands were found. There was a statistically significant difference in the  gene expression of Notch signalling pathway components between different tumour differentiation grade samples. A positive correlation between mRNA and protein the expression level of NOTCH1, NOTCH4, HES1 was determined in stage I samples. CONCLUSIONS: Analysis of 47 human endometrial cancer samples revealeda reduction in the transcript levels of Notch and Wnt signalling molecule compared to the adjacent non-tumour tissue. These results suggest tumour suppressor function of Notch and Wnt signalling in human endometrial cancer. More detailed research on these signalling pathways should reveal their importance as potential biomarkers.

NOTCH signalinio kelio ir ginekologiniu piktybiniu naviku sasaja.

THE ASSOCIATION BETWEEN THE NOTCH SIGNALING PATHWAY AND GYNAECOLOGICAL MALIGNANCIES: Background. The body's cell behaviour is controlled by various signalling pathways, one of which is NOTCH. It has been found that a partial loss of the NOTCH function or abnormal strengthening of NOTCH signalling are related to various human diseases and developmental disorders. Materials and methods. PubMed was the main source of information for this paper. Results. The paper overviews the association between oncologic diseases and the participants of the NOTCH signalling pathway. In cancerogenesis, the NOTCH signalling pathway can act as a tumour suppressor or an oncogene. The mechanisms of such an effect are yet unknown. The NOTCH signalling pathway is an object of active research because its modulation by pharmacological and genetic approaches could be helpful in discovering new treatment methods of tumours. In this review more attention is paid to gynaecological malignancies, especially to uterine cancer. Conclusions. The findings of recently published studies show that the NOTCH signalling pathway is definitely important for the development of uterine cancer, therefore its components can be potential prognostic biomarkers and molecular therapeutic targets. However, further studies in this field are needed in order to clarify the role of the components of the NOTCH signalling pathway and their interaction with participants of other signalling pathways, which can be important in the development and progression of uterine cancer as well. Keywords: NOTCH signalling pathway, cancer, gynaecological malignancies.

Down-regulated expression of Notch signaling molecules in human endometrial cancer.

Notch signaling pathway is a highly conserved developmental pathway, which plays an important role in the regulation of cellular proliferation, differentiation and apoptosis. Deregulation of Notch pathway has been connected with the carcinogenesis in a variety of cancers. In this study, we investigated the expression of Notch receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4), ligands (JAG1, JAG2 and DLL1) and target gene HES1. Fifty paired samples of endometrial cancer and adjacent nontumor endometrial tissue from endometrial cancer patients were analyzed by quantitative PCR. The mRNA levels of all investigated molecules were lower in endometrial cancer compared to adjacent nontumor tissue. The expression of NOTCH1, NOTCH4 and DLL1 in IB stage adenocarcinoma was significantly lower (P < 0.05) than the expression in IA stage adenocarcinoma. Significant correlations were found between mRNA expression levels of Notch target gene HES1 and several Notch signaling molecules: NOTCH1, NOTCH3, DLL1 (P < 0.001) and NOTCH2, JAG2 (P < 0.05). This supports the notion that Notch pathway can function as tumor suppressor in human endometrial cancer.