Palliative Gastrointestinal Surgery in Patients With Advanced Peritoneal Carcinomatosis: Clinical Experience and Development of a Predictive Model for Surgical Outcomes

BackgroundPalliative gastrointestinal (GI) surgery potentially relieves distressing symptoms arising from intestinal obstruction (IO) in patients with advanced peritoneal carcinomatosis (PC). As surgery is associated with significant morbidity risks in advanced cancer patients, it is important for surgeons to select patients who can benefit the most from this approach. Hence, we aim to determine predictors of morbidity and mortality after palliative surgery in patients with PC. In addition, we evaluate the utility of the UC Davis Cancer Care nomogram (UCDCCn) and develop a simplified model to predict short-term surgical mortality in these patients.MethodsA retrospective review of patients with IO secondary to PC undergoing palliative GI surgery was performed. Logistic regression was used to determine independent predictors of 30-day morbidity and mortality after surgery. UCDCCn was evaluated using the area under the curve (AUC) for discriminatory power and the Hosmer-Lemeshow test for calibration. Our simplified model was developed using logistic regression and evaluated using cross-validation.ResultsA total of 254 palliative GI surgeries were performed over a 10-year duration. The 30-day morbidity and mortality were 43% (n = 110) and 21% (n = 53), respectively. Preoperative albumin, age, and emergency nature of surgery were significant independent predictors for 30-day morbidity. A simplified model using preoperative Eastern Cooperative Oncology Group (ECOG) status and albumin (AUC = 0.71) achieved better predictive power than UCDCCn (AUC = 0.66) for 30-day mortality.ConclusionGood ECOG status and high preoperative albumin levels were independently associated with good short-term outcomes after palliative GI surgery. Our simplified model may be used to conveniently and efficiently select patients who stand to benefit the most from surgery.

Blood Transfusion Has An Adverse Impact On The Prognosis of Patients Receiving Chemotherapy For Advanced Colorectal Cancer: Experience From a Single Institution With a Patient Blood Management Program

Purpose: Perioperative blood transfusion in early stage cancer patients had a negative effect on the prognosis of patients, but the prognostic impact of transfusion in advanced cancer patients remains unclear. To minimize transfusion, a institutional patient blood management (PBM) program was launched, and we evaluated the new program has changed practice and impacted on prognosis of advanced cancer patients. Methods: We investigated the medical records of colorectal cancer patients who received chemotherapy from 2015 to 2020. The amount and frequency of transfusion, iron replacement and laboratory findings, and overall survival were compared before and after implementation of PBM. Results: The rate of transfusion in colorectal cancer patients was significantly decreased from 23.5/100 person-quarter in 2015 to 1.2/100 person-quarter in 2020, but iron supplementation therapy was frequently used and the proportion of patients who received transfusion under haemoglobin 7 g/dL significantly increased from 15.9% in 2015 to 55.3% in 2020. Multivariate analysis revealed that transfusion was a significant risk factor affecting the overall survival of patients (HR 2.70, 95% CI: 1.93–3.78, p<0.001). Kaplan–Meier analysis revealed that overall survival was significantly longer in non-transfused patients than in transfused patients (11.0 versus 22.4 months; HR 0.69, 95% CI: 0.56–0.86, p<0.001). Conclusions: This study shows that minimized transfusion through an institutional PBM can positively affect the prognosis of patients who are receiving chemotherapy for advanced colorectal cancer.

HDAC Inhibition to Prime Immune Checkpoint Inhibitors

Immunotherapy has made a breakthrough in medical oncology with the approval of several immune checkpoint inhibitors in clinical routine, improving overall survival of advanced cancer patients with refractory disease. However only a minority of patients experience a durable response with these agents, which has led to the development of combination strategies and novel immunotherapy drugs to further counteract tumor immune escape. Epigenetic regulations can be altered in oncogenesis, favoring tumor progression. The development of epidrugs has allowed targeting successfully these altered epigenetic patterns in lymphoma and leukemia patients. It has been recently shown that epigenetic alterations can also play a key role in tumor immune escape. Epidrugs, like HDAC inhibitors, can prime the anti-tumor immune response, therefore constituting interesting partners to develop combination strategies with immunotherapy agents. In this review, we will discuss epigenetic regulations involved in oncogenesis and immune escape and describe the clinical development of combining HDAC inhibitors with immunotherapies.

Risk Factors for Opioid-induced Constipation in Cancer Patients: a Single-institution, Retrospective Analysis

Purpose: To identify risk factors for opioid-induced constipation (OIC).Methods: This study retrospectively analysed 175 advanced cancer patients who were receiving pain treatment with opioids and were newly prescribed laxatives for OIC at Seirei Hamamatsu General Hospital between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from medical charts. The effect of laxatives was evaluated 3 days after administration. The effect of laxatives was evaluated based on whether the OIC was improved. The OIC was defined based on Rome IV diagnostic criteria. Multivariate ordered logistic regression analysis was performed to identify risk factors for OIC. Optimal cut-off thresholds were determined using receiver operating characteristic analysis. Values of P < 0.05 (two-tailed) were considered significant. Results: Significant factors identified included body mass index (BMI) (odds ratio [OR] = 0.141, 95% confidence interval [CI] = 0.027–0.733; P = 0.020), chemotherapy with taxane within 1 month of evaluation of laxative effect (OR = 0.255, 95%CI = 0.068–0.958; P = 0.043), use of naldemedine (OR = 2.791, 95%CI = 1.220–6.385; P = 0.015) and addition or switching due to insufficient prior laxatives (OR = 0.339, 95%CI = 0.143–0.800; P = 0.014).Conclusion: High BMI, chemotherapy including a taxane within 1 month of evaluation of laxative effect, no use of naldemedine and addition or switching due to insufficient prior laxatives were identified as risk factors for OIC in advanced cancer patients with cancer pain.

Differential Expression of PD-L1 during Cell Cycle Progression of Head and Neck Squamous Cell Carcinoma

The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.

Walker-256 Tumour-Induced Cachexia Altered Liver Metabolomic Profile and Function in Weanling and Adult Rats

Cancer cachexia occurs in up to 85% of advanced cancer patients, affecting different tissues and organs, mainly the liver, which plays a central role in body metabolism control. However, liver responses to cancer cachexia progression are still poorly understood. Considering the possible different challenges provided by the rodent’s phase of life and the cachexia progression, we evaluated the liver metabolic alterations affected by Walker-256 tumour growth in weanling and young-adult rats. For this, we applied a metabolomics approach associated with protein and gene expression analyses. Higher amino acid levels and impaired glucose metabolism were important features in tumour-bearing animals’ liver tissue. The weanling hosts had more pronounced cachexia, with higher carcass spoliation, liver lipid metabolism and impaired CII and CIV mitochondrial complexes. The liver alterations in young adult tumour-bearing rats were related to energy status and nucleotide metabolites, such as uridine, NAD+, xanthosine, hypoxanthine and inosine. In conclusion, the Walker-256 tumour-induced cachexia impaired liver metabolism, being more severe in the weanling hosts. Further studies are needed to correlate these changes in the preclinical model, which can be correlated to the clinical features of cancer cachexia, allowing for a translational potential involving the liver function and its responses to potential treatments.