Xianming Tan

Photodynamic priming overcomes platinum resistance from short‐term exposure to select perfluoroalkyl substances in endometrial cancer cell lines

AbstractFirst‐line treatment for advanced‐stage or recurrent endometrial cancer consists of platinum‐ and taxane‐based chemotherapy, to which many patients will develop resistance. Determining the factors that contribute to platinum resistance and developing alternate treatment options for patients with advanced‐stage gynecologic malignancies is critical to improving survival outcomes. Recently, we published the first study evaluating the contribution of perfluoroalkyl substances (PFAS) exposure to platinum resistance in endometrial cancer cell lines and found that select PFAS induce carboplatin resistance, potentially by dysregulating mitochondrial function. The present study expands upon those findings by examining the efficacy of photodynamic priming (PDP) in combination with carboplatin to overcome PFAS‐induced platinum resistance. Due to the suspected role of mitochondrial dysfunction in platinum resistance, two clinically approved photosensitizers that, in part, localize to mitochondrial membranes or are synthesized in mitochondria were evaluated: benzoporphyrin derivative (BPD) and aminolevulinic acid‐induced protoporphyrin IX (ALA‐PpIX), respectively. Combination of ALA‐PpIX‐mediated PDP + carboplatin resulted in a greater reduction in survival fraction than the same combination with BPD. While PDP with both photosensitizers reduced mitochondrial membrane potential, the reduction was greater with BPD‐PDP than ALA‐PpIX‐PDP. These findings demonstrate that BPD‐PDP and ALA‐PpIX‐PDP in combination with carboplatin can be used to overcome PFAS‐induced platinum resistance in endometrial cancer cells.

Demographic and clinical factors associated with variations in opioid administration using conscious sedation during HDR brachytherapy for cervical cancer

PURPOSE/OBJECTIVES To examine patient characteristics that predispose to higher opioid administration during tandem and ovoid (T&O) high-dose rate (HDR) brachytherapy. METHODS A single-institution retrospective review was performed on patients who underwent brachytherapy for cervical cancer. Patients were included if they received at least one fraction of HDR T&O brachytherapy with analgesia administration recorded in the Medication Administration Record. Fentanyl dose was dichotomized as "low" (mean <125 μg per fraction), or "high" (mean ≥ 125 μg per fraction). Descriptive statistics and multiple logistic regression analysis were performed comparing mean opioid dose per fraction with demographic and clinical information. RESULTS From July 2014 through May 2020, 113 patients underwent 531 T&O HDR brachytherapy fractions with oral benzodiazepine and intravenous opioid fentanyl for conscious sedation. The median opioid dose per fraction was 100 μg fentanyl (range 0-250 μg). Using multiple logistic regression analysis, younger age (OR 1.071, p = 0.002) and higher BMI (OR 1.091, p = 0.019) were associated with increased opioid administration during brachytherapy. Black women received less opioid during brachytherapy when compared to White women (OR 0.296, p = 0.047). FIGO stage, ECOG score, smoking status, prior narcotic use, prior illicit drug use, parity, prior cervical procedure, Smit sleeve placement, and distance to treatment center were not associated with high opioid dose. CONCLUSION Cervical cancer patients who are younger or have higher BMI receive more narcotic analgesia during HDR brachytherapy whereas Black women received less narcotic analgesia, irrespective of age and BMI. This underscores the immediate need to address how pain is assessed and managed during brachytherapy.

Overcoming the effects of fluid shear stress in ovarian cancer cell lines: Doxorubicin alone or photodynamic priming to target platinum resistance

AbstractResistance to platinum‐based chemotherapies remains a significant challenge in advanced‐stage high‐grade serous ovarian carcinoma, and patients with malignant ascites face the poorest outcomes. It is, therefore, important to understand the effects of ascites, including the associated fluid shear stress (FSS), on phenotypic changes and therapy response, specifically FSS‐induced chemotherapy resistance and the underlying mechanisms in ovarian cancer. This study investigated the effects of FSS on response to cisplatin, a platinum‐based chemotherapy, and doxorubicin, an anthracycline, both of which are commonly used to manage advanced‐stage ovarian cancer. Consistent with prior research, OVCAR‐3 and Caov‐3 cells cultivated under FSS demonstrated significant resistance to cisplatin. Examination of the role of mitochondria revealed an increase in mitochondrial DNA copy number and intracellular ATP content in cultures grown under FSS, suggesting that changes in mitochondria number and metabolic activity may contribute to platinum resistance. Interestingly, no resistance to doxorubicin was observed under FSS, the first such observation of a lack of resistance under these conditions. Finally, this study demonstrated the potential of photodynamic priming using benzoporphyrin derivative, a clinically approved photosensitizer that localizes in part to mitochondria and endoplasmic reticula, to enhance the efficacy of cisplatin, but not doxorubicin, thereby overcoming FSS‐induced platinum resistance.