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Accurate prediction neoadjuvant chemotherapy (NACT) response in ovarian cancer (OC) is essential for personalized medicine. We aimed to develop and validate a deep learning (DL) model based on pretreatment contrast-enhanced CT (CECT) images for predicting NACT responses and classifying high-grade serous ovarian cancer (HGSOC) to identify patients who may benefit from NACT. This multicenter study, which contained both retrospective and prospective studies, included consecutive OC patients (n = 757) from three hospitals. Using WHO RECIST 1.1 for the reference standard, a total of 587 women with 1761 images were included in the training and validation sets, 67 women with 201 images were included in the prospective sets, and 103 women with 309 images were included in the external sets. A multitask DL model based on the multiperiod CT image was developed to predict NACT response and HGSOC. Logistic regression analysis showed that peritoneal invasion, retinal invasion, and inguinal lymph node metastasis were independent predictors. The DL achieved promising segmentation performances with DICE mean = 0.83 (range: 0.78-0.87). For predicting NACT response, the DL model combined with clinical risk factors obtained area under the receiver operating characteristic curve (AUCs) of 0.87 (0.83-0.89), 0.88 (0.86-0.91), 0.86 (0.82-0.89), and 0.79 (0.75-0.82) in the training, validation, prospective, and external sets, respectively. The AUCs were 0.91 (0.87-0.94), 0.89 (0.86-0.91), 0.80 (0.76-0.84), and 0.80 (0.75-0.85) in four sets in HGSOC classification. The multitask DL model developed using multiperiod CT images exhibited a promising performance for predicting NACT response and HGSOC with OC, which could provide valuable information for individualized treatment. [ABSTRACT FROM AUTHOR]

To predict the overall pathologic response to neoadjuvant chemotherapy (NACT) of patients with locally advanced cervical cancer (LACC) creating a prediction model based on clinical-pathological factors and biomarkers (p53, Bcl1 and Bcl2) and to evaluate the prognostic outcomes of NACT. This is a retrospective study of 88 consecutive patients with LACC who underwent NACT followed by nerve sparing surgery with retroperitoneal lymphadenectomy at National Cancer Institute of Milan, between January 2000 and June 2013. Clinical pathologic data were retrieved from the institutional database. Biomarkers (p53, Bcl1 and Bcl2) were evaluated before and after NACT in the specimen. To investigate their role as predictors of response, we tried several statistical machine learning algorithms. Responders to NACT showed a 5-years survival between 100%(CR) and 85.7%(PR). Clinical factors were the most important predictor of response. Age, BMI and grade represented the most important predictors of response at random forest analysis. Tree-based boosting revealed that after adjusting for other prognostic factors, age, grade, BMI and tumor size were independent predictors of response to NACT, while p53 was moderately related to response to NACT. Area under the curve (crude estimate): 0.871. Whereas Bcl1 and Bcl2, were not predictors for response to NACT. The final logistic regression reported that grade was the only significant predictor of response to NACT. Combined model that included clinical pathologic variables plus p53 cannot predict response to NACT. Despite this, NACT remain a safe treatment in chemosensitive patients avoiding collateral sequelae related to chemo-radiotherapy. [ABSTRACT FROM AUTHOR]

Study Objective: Compare survival of patients with advanced epithelial ovarian cancer (EOC) undergoing interval debulking surgery (IDS) with either robot-assisted (R-IDS) or open (O-IDS) approach. Second, we assessed the impact of adjuvant and neoadjuvant chemotherapy (NACT) cycles as independent variables associated with survival in this patient population.Design: Retrospective cohort study.Setting: Single tertiary care center.Patients: Total of 93 patients diagnosed with advanced EOC who underwent NACT before primary debulking surgery after consultation with a gynecologic oncologist.Interventions: All patients underwent IDS after completion of NACT with either R-IDS or O-IDS between 2011 and 2018 at a single tertiary care center. Exclusion criteria included receiving fewer than 3 or more than 6 cycles of NACT or having concurrent diagnoses of other malignancies during the treatment period.Measurements and Main Results: A total of 93 patients were identified (n = 43 R-IDS; n = 50 O-IDS). Median age (63.0 vs 66.2 years) did not differ between the 2 groups (p = .1). Of the total patients, 91% were optimally cytoreduced (57% R0 and 34% R1), and R0 rate was not influenced by surgical modality (52% O-IDS vs 63% R-IDS, p = .4). Progression-free survival (PFS) and overall survival (OS) did not differ between patients undergoing O-IDS and those undergoing R-IDS (PFS 15.4 vs 16.7 months, p = .7; OS 38.2 vs 35.6 months, p = .7). Cytoreduction to R0 improved both PFS and OS independent of surgical approach. Subgroup analysis showed that, specifically in patients undergoing R-IDS, receiving >6 total cycles of chemotherapy was independently associated with both decreased PFS (hazard ratio 3.85; 95% confidence interval, 1.52-9.73) and OS (hazard ratio 3.97; 95% confidence interval, 1.08-14.59). When analyzed separately, neither NACT nor adjuvant cycle numbers had any effect on survival.Conclusion: In this retrospective study of patients with advanced EOC undergoing IDS after NACT, the use of robot-assisted surgery did not affect debulking success or oncologic survival indices. Receiving >6 total cycles of chemotherapy before IDS was associated with a decrease in both PFS and OS in patients undergoing R-IDS in this cohort and warrants further investigation. [ABSTRACT FROM AUTHOR]

Dual blockade with trastuzumab and pertuzumab combined with neoadjuvant chemotherapy (NACT) has been increasingly used for HER2-positive tumours >2 cm and/or with positive axillary lymph nodes in order to evaluate pathologic response and obtain better surgical management. SB3 is a registered biosimilar trastuzumab approved following a phase III trial demonstrating similar efficacy in the neoadjuvant setting as trastuzumab. However, the study was done without pertuzumab. The database of the Danish Breast Cancer Group was used to extract data on all patients who started NACT with SB3 and pertuzumab between September 1, 2018 and August 31, 2019. The primary endpoint was pathological complete response (pCR) rate. In total 215 patients received NACT and dual blockade. The median age was 55 (24–81). NACT used was cyclophosphamide and epirubicin followed by weekly paclitaxel (62% on six cycles, 35% on eight cycles) or other chemotherapy followed by weekly paclitaxel (3%). Overall, 56% of patients achieved pCR. 60 of 88 node-positive patients pre-NACT achieved ypN0(i-) after neoadjuvant treatment. pCR rate was significantly associated with estrogen receptor status and malignancy grade. An association with CEP17/HER2-ratio was assessed. Real world data on dual blockade with SB3 and pertuzumab in combination with NACT in a nationwide population-based study show a pCR rate comparable to that seen in previous clinical studies. • Real world data on 215 patients with HER2-positive early breast cancer. • SB3 (biosimilar trastuzumab) and pertuzumab with neoadjuvant chemotherapy. • pCR in 56% and node conversion in 68% of the patients. • pCR rate associated with ER-status and malignancy grade. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the most lethal gynecologic malignancy. The standard treatment involves chemotherapy with platinum-paclitaxel following cytoreductive surgery. For patients battling widespread and aggressive tumor spread, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery emerges as an encouraging alternative. However, the effectiveness of this strategy is often limited by advanced-stage diagnosis and high likelihood of recurrence. The high mortality rate necessitates the exploration of targeted therapies. Present results signal promising efficacy and acceptable toxicities of anti-angiogenic drugs, immunotherapy, or PARP inhibitors used in chemotherapy. However, the potential integration of these drugs into NACT raises questions about response rates, surgical outcomes, and adverse events. This review delves into the findings from all published articles and ongoing studies, aiming to summarize the clinical use of anti-angiogenic drugs, immunotherapy, or PARP inhibitors in NACT, highlight the positive and negative aspects, and outline future perspectives. [Display omitted] • AOC patients can benefit from NACT containing carboplatin, paclitaxel or bevacizumab. • The adverse events are acceptable when using bevacizumab in NACT. • Results of ongoing trials investigating the role of immunotherapy or PARP inhibitors in NACT for OC are eagerly awaited. [ABSTRACT FROM AUTHOR]

To evaluate the impact of multiple clinical features upon the outcome of interval cytoreductive surgery and thus upon the survival in patients with advanced ovarian cancer and primary peritoneal carcinoma. A retrospective analysis of patients receiving NACT followed by IDS between 2009 and 2017. Patients were analyzed according to the pre-NACT CA125, pre-IDS CA125, pre-IDS CA125 decline, patients' pre-IDS BMI, multisite bowel involvement and different working years of surgeons, for their influence upon the IDS outcome (e.g. optimal vs suboptimal) and the survival. After interval debulking surgery following 1–6 cycles of NACT, all patients analyzed were identified as optimal (n = 113) and suboptimal (n = 47) based on patients' record. The PFS/OS were 21/68 months and 9/26 months in optimal and suboptimal groups, respectively (p =.000 , p =.000). Although differential levels of pre-IDS CA125, pre-IDS CA125 decline, bowel involvement and surgeons' working years were found to be significantly different between the two groups, surgeons' working years and multisite bowel invasion were the independent factors for IDS outcome, and the latter one was also highly related to survival. Following NACT, the rate of optimal IDS might be improved for patients without multisite bowel involvement. For those with bowel involvement, management strategy made by well-experienced surgeons might be a key factor for the outcome of IDS. • Outcome of interval debulking surgery depends on multiple factors. • Surgeons' working years is pivotal in managing patients with bowel involvement. • Low pre-IDS and sharp decline of CA125 levels after NACT predict better IDS outcomes. [ABSTRACT FROM AUTHOR]

A systematic review of the studies where HIPEC combined with cytoreductive surgery was used in patients with primary advanced ovarian cancer was performed to understand is there a role for this treatment modality not only in recurrent but in primary advanced ovarian cancer. The results are controversial but there is a strong trend for improvement of the long-term outcomes of patients with primary advanced ovarian cancer after HIPEC. [ABSTRACT FROM AUTHOR]

Abstract: Neurons are known to express a high-affinity Na+-coupled dicarboxylate transporter(s) for uptake of tricarboxylic acid cycle intermediates, such as α-ketoglutarate and malate, which are precursors for neurotransmitters including glutamate and γ-aminobutyric acid. There is, however, little information available on the molecular identity of the transporters responsible for this uptake process in neurons. In the present study, we investigated the characteristics of Na+-dependent citrate transport in primary cultures of neurons from mouse cerebral cortex and established the molecular identity of this transport system as the Na+-coupled citrate transporter (NaC2/NaCT). Reverse transcriptase (RT)-PCR and immunocytochemical analyses revealed that only NaC2/NaCT was expressed in mouse cerebrocortical neurons but not in astrocytes. Uptake of citrate in neurons was Na+-dependent, Li+-sensitive, and saturable with the K t value of 12.3 μM. This K t value was comparable with that in the case of Na+-dependent succinate transport (K t = 9.2 μM). Na+-activation kinetics revealed that the Na+-to-citrate stoichiometry was 3.4:1 and concentration of Na+ necessary for half-maximal activation (K 0.5 Na) was 45.7 mM. Na+-dependent uptake of [14C]citrate (18 μM) was significantly inhibited by unlabeled citrate as well as dicarboxylates such as succinate, malate, fumarate, and α-ketoglutarate. This is the first report demonstrating the molecular identity of the Na+-coupled di/tricarboxylate transport system expressed in neurons as NaC2/NaCT, which can transport the tricarboxylate citrate as well as dicarboxylates such as succinate, α-ketoglutarate, and malate. [Copyright &y& Elsevier]

Citrate lies at a critical node of metabolism, linking tricarboxylic acid metabolism and lipogenesis via acetyl-coenzyme A. Recent studies have observed that deficiency of the sodium-dependent citrate transporter (NaCT), encoded by SLC13A5 , dysregulates hepatic metabolism and drives pediatric epilepsy. To examine how NaCT contributes to citrate metabolism in cells relevant to the pathophysiology of these diseases, we apply 13C isotope tracing to SLC13A5 -deficient hepatocellular carcinoma (HCC) cells and primary rat cortical neurons. Exogenous citrate appreciably contributes to intermediary metabolism only under hypoxic conditions. In the absence of glutamine, citrate supplementation increases de novo lipogenesis and growth of HCC cells. Knockout of SLC13A5 in Huh7 cells compromises citrate uptake and catabolism. Citrate supplementation rescues Huh7 cell viability in response to glutamine deprivation or Zn2+ treatment, and NaCT deficiency mitigates these effects. Collectively, these findings demonstrate that NaCT-mediated citrate uptake is metabolically important under nutrient-limited conditions and may facilitate resistance to metal toxicity. [Display omitted] • HCC cells utilize NaCT-mediated citrate uptake for lipogenesis • Citrate import supports lipogenesis and anaplerosis upon glutamine deprivation • NaCT-mediated citrate uptake facilitates protection against zinc toxicity Using isotope tracing, 13C MFA, and proliferation assays, Kumar et al. show that NaCT-mediated extracellular citrate is cytosolically catabolized, contributing to de novo lipogenesis (DNL) in HCC cells. Furthermore, extracellular citrate import by NaCT promotes growth in oxygen- and glutamine-limited conditions and protects against zinc-induced toxicity. [ABSTRACT FROM AUTHOR]