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Triple-negative breast cancer (TNBC) poses a significant challenge in clinical oncology due to its aggressive nature and limited targeted therapeutic options. Neoadjuvant chemotherapy (NACT) has emerged as a promising strategy in the management of early-stage TNBC. This literature review aims to provide an in-depth analysis of the role of NACT in TNBC, focusing on its impact on early-stage disease and associated outcomes. The review synthesizes evidence from recent studies, clinical trials, and meta-analyses to present a comprehensive overview of the current landscape of NACT in early-stage TNBC. [ABSTRACT FROM AUTHOR]

In this study, we aimed to establish the role of regenerating islet-derived family member 4 (Reg IV) as an independent risk factor and prognostic predictor in patients with T2-3 stage breast cancer who exhibit a non-pathological complete response (non-pCR) following neoadjuvant chemotherapy (NACT). Additionally, we examined the potential correlation and interaction between Reg IV and epidermal growth factor receptor (EGFR). Methods: A total of 67 patients with T2-3 stage breast cancer exhibiting non-pCR after NACT between September 2019 and December 2021 were included in this study. The analysis involved Kaplan–Meier survival comparisons, pooled hazard ratios for risk quantification, Cox regression analysis to isolate the impact of Reg IV on prognosis, Riskplots for visualizing risk profiles, and SHAP analysis to assess the importance of variables in predicting outcomes. Results: The findings indicate that patients positive for Reg IV had a significantly poorer prognosis (HR: 2.62, 95% CI: 1.06– 6.47). Co-expression of Reg IV and EGFR was associated with the worst outcomes compared to patients negative for both markers. Cox regression analysis confirmed the independent prognostic impact of Reg IV (HR: 2.63, 95% CI: 1.66– 3.59). Riskplot analysis showed that patients positive for both Reg IV and EGFR predominantly experienced disease progression. SHAP analysis further reinforced the significant effect of Reg IV on the disease course, without substantial interaction with EGFR. Conclusion: Reg IV may serve as an independent risk factor and predictive marker for adverse outcomes in patients with T2-3 stage breast cancer who do not achieve non-pCR following NACT. [ABSTRACT FROM AUTHOR]

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Background: Moderately advanced and technically unresectable oral cavity cancers have a poor prognosis. Neoadjuvant chemotherapy might be beneficial in such patients by reducing tumour bulk and allowing definitive surgery. Aim: To evaluate the response of neoadjuvant chemotherapy in moderately advanced technically unresectable oral cavity cancers. Methodology: Prospective observational study - secondary data analysis of patients with moderately advanced oral cavity cancer, which were treated with neoadjuvant chemotherapy (NACT) during the period November 2014-April 2016. Data was analysed for information on patient characteristics, chemotherapy received, toxicity, clinical response rates, local treatment offered and pathological response rates. The statistical analysis was performed with SPSS version 20. Results: 30 patients, with a median age of 52 years were analyzed. Buccal mucosa was the most common sub site (50%). Three drug regimen was utilized in all patients. Resectability was achieved in 14 patients (46.67%). Febrile neutropenia was seen in 3 patients (10%). The overall response rate was 31%. Conclusion: NACT was effective in converting moderately advanced technically unresectable oral cavity cancers to operable disease in approximately 47% of patients. Post NACT, there is significant association between clinical and pathological findings of response rates. There is no increase in surgical complication rates following NACT. [ABSTRACT FROM AUTHOR]

We described a novel technique of marking the oral squamous cell carcinoma (OSCC) tumors before the pre-operative neoadjuvant chemotherapy (NACT). The pre-operative NACT may shrink the tumor, making it difficult for the oncosurgeon to identify the pre-NACT tumor area to be included in the surgical resection. Difficulty lies in exact topographic replication/documentation of examination findings on superficial or mucosal surface levels, primarily due to limited surface landmarks. This technique helps to identify the pre-NACT tumor margins during surgical resection and to achieve maximum oncological safety and refining surgical planning. [ABSTRACT FROM AUTHOR]

The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the intricacy and complexity of the latent human physiology, which is poorly captured by existing animal models. This review explores innovative technologies aimed at bridging such a knowledge gap. First, I provide an overview of SLC13A5 variants in the context of human disease and the specific cell types where the expression of the transporter has been observed. Next, I discuss current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids. Finally, I explore the relevance of these cellular models as platforms for delving into the intricate molecular and cellular mechanisms underlying SLC13A5-related disorders. [ABSTRACT FROM AUTHOR]

Background and objective: To assess how patients with locally advanced breast cancer respond pathologically to neoadjuvant therapy. It is uncommon to have locally advanced breast cancer (LABC), and it poses significant clinical challenges. The purpose of the study was to look into the relationship between disease-free survival and the pathological response to neoadjuvant chemotherapy. Method: An observational study was conducted at Department of General Surgery, Deccan College of Medical Sciences, Hyderabad, Telangana, India from December 2022 to November 2023. on a sample of 40 persons to assess the pathological response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. The study received ethical approval from the committee. Result: Between the ages of 50 and 60, 33% of the population fell. About half of the patients exhibited negative human epidermal growth factor receptor 2 (HER2), positive progesterone receptor (PR), and positive oestrogen receptor (ER). Sixty-seven percent of tumours tested positive for both the progesterone receptor (PR) and the oestrogen receptor (ER). Forty percent of the tumours had HER2 positive results. Merely 17% of the patient cohort exhibited a pathological reaction to neoadjuvant chemotherapy (NACT). 83% of the total did not respond. Conclusion: Finding the cancers that are most likely to respond well to specific medications and treatment strategies might significantly improve the prognosis. The most recent developments in our knowledge of cancer biology and genetic analysis can be used to enhance the therapeutic therapy of locally advanced breast cancer (LABC), producing a very effective individualised strategy. [ABSTRACT FROM AUTHOR]

Craniofacial osteosarcoma is a relatively rare disease entity. In the craniofacial region, mandible is the commonest site followed by maxilla and skull bone. Due to its rare occurrence standard treatment guidelines are not formulated as in long bone or extremity sarcoma. Here we have reported a locally advanced case of a maxillary osteosarcoma of chondroblastic variant who was initially considered for neoadjuvant chemotherapy. However there was radiological evience of disease progression. Then the patient was considered for surgery followed by adjuvant radiotherapy. A literature review of the published cases of maxillary chondroblastic osteosarcoma has also been done here. [ABSTRACT FROM AUTHOR]

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1–5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts' specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment. [ABSTRACT FROM AUTHOR]

Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies. These studies evaluated stromal (sTILs) and intra-epithelial (ieTILs) TILs before and after NACT. sTIL responses varied, impacting prognostic outcomes, and ieTILs increased in some patients without clear survival associations. PD-L1 expression after NACT correlated with improved overall survival (OS), and increases in granzyme B+ and PD-1 correlated with longer progression-free survival (PFS). Remarkably, reduced FoxP3+ TILs post-NACT correlated with better prognosis. NACT often increases sTIL/ieTIL and CD8+ subpopulations, but their correlation with improved PFS and OS varies. Upregulation of co-inhibitory molecules, notably PD-L1, suggests an immunosuppressive response to chemotherapy. Ongoing trials exploring neoadjuvant ICIs and chemotherapy offer promise for advancing OC treatment. Standardized measurements assessing TIL density, location, and heterogeneity are crucial for addressing genetic complexity and immunological heterogeneity in OC.

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.

Compared with the early symptoms of non-pregnancy, the early pregnancy with cervical cancer is often confused with threatened abortion, so it is difficult to diagnose and delay the time of treatment. At present, compared with cervical cancer, there is no clear and standard treatment for cervical cancer in pregnancy. At present, the diagnosis and treatment plan is mainly made according to the pathological examination, staging, fetal development (whether there is abnormality on ultrasound and whether the chromosome karyotype is normal or not) and the pregnant women and their family members’ pregnancy wishes. A case of pregnancy complicated with cervical cancer who was terminated by planned cesarean section after neoadjuvant chemotherapy (NACT) with irregular vaginal bleeding as the first symptom was analyzed retrospectively.

Background: Any treatment protocol that leads to complete elimination of surgery may lead to a better patient acceptance of breast cancer treatments. Objectives: We conducted this study to assess the feasibility of preoperative vacuum-assisted biopsies in identifying pathological complete response (pCR) and its accuracy in correlation to final histopathology report (HPR), in an Indian setting. Methods: This was a prospective study conducted between October 1, 2019, and March 31, 2021. Patients with early breast cancer, estrogen and progesterone receptors negative and either Her2 positive or negative, and who were fit to undergo marker placement at the centre of the tumour and to receive third-generation chemotherapy (4 cycles of 3 weekly doxorubicin and cyclophosphamide followed by 4 cycles of 3 weekly docetaxel) were included in the study. Following the enrolment, a tissue marker was placed at the centre of the tumour and appropriate chemotherapy was started. Patients who achieved clinical complete response were subjected to ultrasound-guided vacuum-assisted biopsy (VAB) from the tumour bed before surgery. Pathology results of the VAB and resected specimen were then compared. Descriptive statistics were used in the study. Results: Eighteen patients were enrolled in the study, with a mean age of 43.6 ± 9.8 years. However, only 10 were eligible for VAB procedure, and sensitivity and specificity were calculated based on the results of these 10 patients only. Vacuum-assisted biopsy showed sensitivity of 50% and specificity of 100% in identifying pCR. Combination of mammography, ultrasonography, and VAB showed sensitivity of 77.8% and specificity of 66.7% in identifying pCR. Conclusion: Vacuum-assisted biopsy of tumour bed may not be sensitive enough to eliminate surgery even in patients who have had exceptional response to neo-adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

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]

The sodium dependent SLC13 family transporters comprise of five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them, NaDC1, NaDC3 and NaCT are sodium dependent transporters belonging to family of dicarboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, therefore structural information is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as a precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these transporters and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of genes coding for citrate transport present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporters are required for the development of citrate inhibitors. This review discusses the structure, function, and regulation of the NaCT transporter. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT transporters is succinctly summarized. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most frequent cancer affecting women, and axillary lymph nodes (ALNs) are the most common initial site of metastatic spread. In patients with positive ALNs undergoing neoadjuvant chemotherapy (NACT), it is necessary to localize and identify the lymph node metastases in order to perform less invasive axillary surgery, such as targeted axillary dissection (TAD). In this setting, the choice of the most appropriate localization methods is crucial to correctly orientate the removal of the pathological ALNs. This is more important considering that ALNs can become non-palpable after NACT. National Comprehensive Cancer Network (NCCN) guidelines also suggest their possible use in a non-NACT setting, particularly in patients candidate to SLNB with limited numbers of positive ALNs in whom ALNs have been biopsied. Targeted axillary dissection (TAD) is an axillary staging technique after NACT that involves the removal of biopsy-proven metastatic lymph nodes in addition to sentinel lymph node biopsy (SLNB). This technique avoids the morbidity of traditional axillary lymph node dissection and has shown a lower false-negative rate than SLNB alone. Therefore, marking positive axillary lymph nodes before NACT is critical in order to locate and remove them in the subsequent surgery. Current localization methods include clip placement with intraoperative ultrasound, carbon-suspension liquids, localization wires, radioactive tracer-based localizers, magnetic seeds, radar reflectors, and radiofrequency identification devices. The aim of this paper is to illustrate the management of axillary lymph nodes based on current guidelines and explain the features of axillary lymph node markers, with relative advantages and disadvantages. [ABSTRACT FROM AUTHOR]

Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation. Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed. Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes. Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders. [ABSTRACT FROM AUTHOR]

The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the "multiple-hit theory" and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders. [ABSTRACT FROM AUTHOR]

The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the intricacy and complexity of the latent human physiology, which is poorly captured by existing animal models. This review explores innovative technologies aimed at bridging such a knowledge gap. First, I provide an overview of SLC13A5 variants in the context of human disease and the specific cell types where the expression of the transporter has been observed. Next, I discuss current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids. Finally, I explore the relevance of these cellular models as platforms for delving into the intricate molecular and cellular mechanisms underlying SLC13A5-related disorders.

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1–5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts’ specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.

Autophagy plays a dual role in oncogenesis processes. On one hand, autophagy enhances the cell resistance to oncogenic factors, and on the other hand, it participates in the tumor progression. The aim of the study was to find the associations between the effectiveness of the FLOT regimen in resectable gastric cancers (GCs) with the key autophagy-related proteins. Materials and Methods: The study included 34 patients with morphologically verified gastric cancer. All patients had FLOT neoadjunvant chemotherapy (NACT) (fluorouracil, leucovorin, oxaliplatin, and docetaxel) followed by gastrectomy. The studied tissue material was the non-transformed and tumor tissues obtained during diagnostic video gastroscopy in patients before the start of the combined treatment and after surgical treatment, frozen after collection. The LC3B, mTOR, and AMPK expression was determined by real-time PCR. The content of the LC3B protein was determined by Western blotting analysis. Results: The mRNA level and the content of the LC3B protein were associated with the tumor stage and the presence of signet ring cells. The AMPK mRNA level was increased in patients with the T4N0-2M0 stage by 37.7 and 7.33 times, which was consequently compared with patients with the T2N0M0 and T3N0-1M0 stages. The opposite changes in the mTOR and AMPK in the GCs before anti-cancer therapy were noted. The tumor size and regional lymph node affections were associated with a decrease in the mTOR mRNA level. A decrease in the mTOR expression was accompanied by an increase in the AMPK expression in the GCs. The mTOR expression was reduced in patients with a cancer spreading; in contrast, AMPK grew with the tumor size. There was an increase in the LC3B expression, which can probably determine the response to therapy. An increase in LC3B mRNA before the start of treatment and the protein content in cancers after NACT with a decrease in therapy effectiveness was recorded. There was an increase in the protein level in patients with partial regression and stabilization by 3.65 and 5.78 times, respectively, when compared with patients with complete tumor regression was noted. Conclusions: The anticancer effectiveness in GCS is down to the LC3B, mTOR, and AMPK expression. These were found to be entire molecular targets affecting the cancer progression and metastasis as well as the NACT effectiveness.

Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation.Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed.Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes.Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders.

[Display omitted] • NaCT (SLC13A5) supplies citrate to neuronal cells vital for brain function. • SLC13A5 mutations characterized as Class I abolish citrate transport. • Class II mutations display low protein expression and ER retention. • Mutant mRNA levels are normal; thus, defects lie in protein folding and stability. • Class II mutations suffer trafficking defects, and are targeted for degradation. The sodium-coupled citrate transporter (NaCT, SLC13A5) mediates citrate uptake across the plasma membrane via an inward Na+ gradient. Mutations in SLC13A5 cause early infantile epileptic encephalopathy type-25 (EIEE25, SLC13A5 Epilepsy) due to impaired citrate uptake in neurons and astrocytes. Despite clinical identification of disease-causing mutations, underlying mechanisms and cures remain elusive. Here we mechanistically classify six frequent SLC13A5 mutations by phenotyping their protein cell surface expression and citrate transport functions. Mutants C50R, T142M, and T227M exhibit impaired citrate transport despite normal expression at the cell surface. In contrast, mutations G219R, S427L, and L488P show low total protein expression levels, absence of mature, glycosylated proteins at the cell surface, retention of the proteins in the endoplasmic reticulum, and diminished transport activity. This mechanistic classification divides SLC13A5 mutants into two groups, Class I (C50R, T142M, and T227M) and Class II (G219R, S427L, and L488P). Importantly, mutants' mRNA levels resemble wildtype, suggesting post-translational defects. Class II mutations display immature core-glycosylation and shortened half-lives, indicating protein folding defects. Together, these experiments provide a comprehensive understanding of the disease-causing mutation's defects in SLC13A5 Epilepsy at the biochemical and molecular level and shed light into the trafficking pathway(s) of NaCT. The two classes of mutations will require fundamentally different approaches for treatment to either restore transport function of the mutant protein that is capable of reaching the cell surface (Class I), or therapies that enable the correction of protein folding defects to enable escape to the cell surface where it may restore transport function (Class II). [ABSTRACT FROM AUTHOR]

Aim: To assess the response of neoadjuvant chemotherapy in carcinoma breast patients by high-frequency ultrasound. Material and Method: The current single blind, observational study was conducted at rural tertiary healthcare center of Acharya Vinoba Bhave Rural Hospital from October 2018 to Sept 2020. We incorporated breast cancer patients with TNM stages IIIA and IIIB who received neoadjuvant chemotherapy with Cyclophosphamide/Adriamycin/5 FU and Paclitaxel respectively followed by standard surgical procedure modified radical mastectomy. Successive ultrasound examination of the breast malignancy and the axilla was done after 21 days of either of any neoadjuvant chemotherapy for 3 cycles. Assessment of response to neoadjuvant chemotherapy was applied in terms of reduction in the breast tumour volume on ultrasound and percentage of tumour response calculated by Response Evaluation Criteria for Solid Tumours (RECIST). Data were analysed using SPSS version 24.0. Results: Higher frequency of patients was invasive ductal breast cancer. In our study, Paclitaxel group showed better response in terms of CR and PR than CAF group. Our study noticed a consistent decrement in tumour volume after every cycle of either CAF or Paclitaxel NACT. Axillary ultrasound was able to predict the response of axillary lymph nodes in terms of increase or decrease in number and morphological changes after 3 cycles of NACT with similarity on final histopathology. Conclusion: It can be concluded from the results of the present study that high-frequency ultrasound is appropriate tool for assessment of response of primary breast malignancy and lymphnode metastasis in the axilla after neoadjuvant chemotherapy.

Objective: In this study, we aimed to establish the role of regenerating islet-derived family member 4 (Reg IV) as an independent risk factor and prognostic predictor in patients with T2-3 stage breast cancer who exhibit a non-pathological complete response (non-pCR) following neoadjuvant chemotherapy (NACT). Additionally, we examined the potential correlation and interaction between Reg IV and epidermal growth factor receptor (EGFR)., Methods: A total of 67 patients with T2-3 stage breast cancer exhibiting non-pCR after NACT between September 2019 and December 2021 were included in this study. The analysis involved Kaplan-Meier survival comparisons, pooled hazard ratios for risk quantification, Cox regression analysis to isolate the impact of Reg IV on prognosis, Riskplots for visualizing risk profiles, and SHAP analysis to assess the importance of variables in predicting outcomes., Results: The findings indicate that patients positive for Reg IV had a significantly poorer prognosis (HR: 2.62, 95% CI: 1.06-6.47). Co-expression of Reg IV and EGFR was associated with the worst outcomes compared to patients negative for both markers. Cox regression analysis confirmed the independent prognostic impact of Reg IV (HR: 2.63, 95% CI: 1.66-3.59). Riskplot analysis showed that patients positive for both Reg IV and EGFR predominantly experienced disease progression. SHAP analysis further reinforced the significant effect of Reg IV on the disease course, without substantial interaction with EGFR., Conclusion: Reg IV may serve as an independent risk factor and predictive marker for adverse outcomes in patients with T2-3 stage breast cancer who do not achieve non-pCR following NACT., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Li et al.)

Pingping Ye,1 Hongbo Duan,1 Zhenya Zhao,2 Shibo Fang1 1Department of Ultrasonography, The Sixth Hospital of Ningbo City of Zhejiang Province, Ningbo, 315100, People’s Republic of China; 2Department of Imaging, The First Hospital of Ningbo City of Zhejiang Province, Ningbo, 315010, People’s Republic of ChinaCorrespondence: Shibo FangDepartment of Ultrasonography, The Sixth Hospital of Ningbo City of Zhejiang Province, 1059 Zhongshan East Road, Ningbo, Zhejiang Province, People’s Republic of ChinaTel +86 0574-87996115Email yepingping321@163.comPurpose: Clinical responses of neoadjuvant chemotherapy (NACT) are associated with prognosis in patients with breast cancer. The selection of suitable variables for the prediction of clinical responses remains controversial. Herein, we developed a predictive model based on ultrasound imaging and clinical indices to identify patients most likely to benefit from NACT.Patients and Methods: We recruited a total of 225 consecutive patients who underwent NACT followed by surgery and axillary lymph node dissection at the Sixth Hospital of Ning Bo City of Zhe Jiang Province between January 1, 2018, and March 31, 2021. All patients had been diagnosed with breast cancer following the clinical examination. First, we created a training cohort of patients who underwent NACT+surgery (N=180) to develop a nomogram. We then validated the performance of the nomogram in a validation cohort of patients who underwent NACT+ surgery (N=45). Multivariate logistic regression was then used to identify independent risk factors that were associated with the response to NACT; these were then incorporated into the nomogram.Results: Multivariate logistic regression analysis identified several significant differences as to clinical responses of NACT, including neutrophil–lymphocyte ratio (NLR), body mass index (BMI), pulsatility index (PI), resistance index (RI), blood flow, Ki67, histological type, molecular subtyping, and tumor size. The performance of the nomogram score exhibited a robust C-index of 0.89 (95% confidence interval [CI]: 0.83 to 0.95) in the training cohort and a high C-index of 0.87 (95% CI: 0.81 to 0.93) in the validation cohort. Clinical impact curves showed that the nomogram had a good predictive ability.Conclusion: We successfully established an accurate and optimized nomogram incorporated ultrasound imaging and clinical indices that could be used preoperatively to predict clinical responses of NACT. This model can be used to evaluate the risk of clinical responses to NACT and therefore facilitate the choice of personalized therapy.Keywords: breast cancer, NACT, clinical response, nomogram prediction

Aim: To assess the response of neoadjuvant chemotherapy in carcinoma breast patients by high-frequency ultrasound. Material and Method: The current single blind, observational study was conducted at rural tertiary healthcare center of Acharya Vinoba Bhave Rural Hospital from October 2018 to Sept 2020. We incorporated breast cancer patients with TNM stages IIIA and IIIB who received neoadjuvant chemotherapy with Cyclophosphamide/Adriamycin/5 FU and Paclitaxel respectively followed by standard surgical procedure modified radical mastectomy. Successive ultrasound examination of the breast malignancy and the axilla was done after 21 days of either of any neoadjuvant chemotherapy for 3 cycles. Assessment of response to neoadjuvant chemotherapy was applied in terms of reduction in the breast tumour volume on ultrasound and percentage of tumour response calculated by Response Evaluation Criteria for Solid Tumours (RECIST). Data were analysed using SPSS version 24.0. Results: Higher frequency of patients was invasive ductal breast cancer. In our study, Paclitaxel group showed better response in terms of CR and PR than CAF group. Our study noticed a consistent decrement in tumour volume after every cycle of either CAF or Paclitaxel NACT. Axillary ultrasound was able to predict the response of axillary lymph nodes in terms of increase or decrease in number and morphological changes after 3 cycles of NACT with similarity on final histopathology. Conclusion: It can be concluded from the results of the present study that high-frequency ultrasound is appropriate tool for assessment of response of primary breast malignancy and lymphnode metastasis in the axilla after neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Mammalian INDY (mINDY, NaCT, gene symbol SLC13A5) is a potential target for the treatment of metabolically associated fatty liver disease (MAFLD). This study evaluated the effects of a selective, cross-species active, non-competitive, non-substrate-like inhibitor of NaCT. First, the small molecule inhibitor ETG-5773 was evaluated for citrate and succinate uptake and fatty acid synthesis in cell lines expressing both human NaCT and mouse Nact. Once its suitability was established, the inhibitor was evaluated in a diet-induced obesity (DIO) mouse model. DIO mice treated with 15 mg/kg compound ETG-5773 twice daily for 28 days had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Liver triglycerides were significantly reduced, and body composition was improved by reducing fat mass, supported by a significant reduction in the expression of genes for lipogenesis such as SREBF1 and SCD1. Most of these effects were also evident after a seven-day treatment with the same dose. Further mechanistic investigation in the seven-day study showed increased plasma β-hydroxybutyrate and activated hepatic adenosine monophosphate-activated protein kinase (AMPK), reflecting findings from Indy (−/−) knockout mice. These results suggest that the inhibitor ETG-5773 blocked citrate uptake mediated by mouse and human NaCT to reduce liver steatosis and body fat and improve glucose regulation, proving the concept of NaCT inhibition as a future liver treatment for MAFLD. [ABSTRACT FROM AUTHOR]

Ovarian cancer remains the leading cause of death from gynecological cancer. Survival is significantly related to the stage of the disease at diagnosis. Of quite importance is primary cytoreductive surgery, having as a goal to remove all visible tumor tissue, and is the standard primary treatment in combination with platinum-based chemotherapy for patients with advanced ovarian carcinoma. Neo-adjuvant chemotherapy (NACT) has been implemented mostly in treating advanced disease, with studies performed having numerous limitations. Data extrapolated from these studies have not shown inferiority survival of NACT, compared to primary debulking surgery. The role of NACT is of particular interest because of the intrinsic mechanisms that are involved in the process, which can be proven as therapeutic approaches with enormous potential. NACT increases immune infiltration and programmed death ligand-1 (PDL-1) expression, induces local immune activation, and can potentiate the immunogenicity of immuneexclude high grade serous ovarian tumors, while the combination of NACT with bevacizumab, PARP inhibitors or immunotherapy remains to be evaluated. This article summarizes all available data on studies implementing NACT in the treatment of ovarian cancer, focusing on clinical outcomes and study limitations. High mortality rates observed among ovarian cancer patients necessitates the identification of more effective treatments, along with biomarkers that will aid treatment individualization. [ABSTRACT FROM AUTHOR]

Esophageal cancer is a complex gastrointestinal malignancy with an extremely poor outcome. Approximately 80% of cases of this malignancy in Asian countries including India are of squamous cell origin, termed Esophageal Squamous Cell Carcinoma (ESCC).The five-year survival rate in ESCC patients is less than 20%. Neo-adjuvant chemo-radiotherapy (NACRT) followed by surgical resection remains the major therapeutic strategy for patients with operable ESCC. However, resistance to NACRT and local recurrence after initial treatment are the leading cause of dismal outcomes in these patients. Therefore, an alternative strategy to promote response to the therapy and reduce the post-operative disease recurrence is highly needed. At the molecular level, wide variations have been observed in tumor characteristics among different populations, nevertheless, several common molecular features have been identified which orchestrate disease progression and clinical outcome in the malignancy. Therefore, determination of candidate molecular pathways for targeted therapy remains the mainstream idea of focus in ESCC research. In this review, we have discussed the key signaling pathways associated with ESCC, i.e., Notch, Wnt, and Nrf2 pathways, and their crosstalk during disease progression. We further discuss the recent developments of novel agents to target these pathways in the context of targeted cancer therapy. In-depth research of the signaling pathways, gene signatures, and a combinatorial approach may help in discovering targeted therapy for ESCC. [ABSTRACT FROM AUTHOR]

Background: Oral cancer (OC) ranks as the sixth most prevalent kind of cancer in the United States, according to researchers. According to many studies, the head and neck account for 40% of all cancer cases in India. Low rates of survival after surgery and postoperative irradiation (PORT) for advanced malignancies have prompted researchers to consider NACT as a viable treatment option. Objectives: To evaluate the role of NACT in LAOC. Methodology: We gathered demographic data, clinical history, prior medical history, family history, and social history using standard, semi-structured questionnaires and required investigations in 40 patients using a prospective analytical type of research. All patients received NACT and were followed for six months. Result and Conclusion: We found that nausea-vomiting was the most prevalent adverse event after NACT, followed by neutropenia (11.66%), diarrhea (8.33%), and anemia (up to 3.33%). Thus, we conclude that, during the 6-month follow-up, we found no disease recurrence. The buccal-alveolar complex was also affected in several patients. The utilization of induction CT in cases of T4b unresectable cancer has been found to slow disease development, yield a partial macroscopic response, and be safe and feasible. This strategy should increase survival rates for patients who have surgery. [ABSTRACT FROM AUTHOR]

BackgroundPathological complete response (pCR) is considered a surrogate for favorable survival in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NACT), which is the goal of NACT. This study aimed to develop and validate a nomogram for predicting the pCR probability of BC patients after NACT based on the clinicopathological features.MethodsA retrospective analysis of 527 BC patients treated with NACT between January 2018 and December 2021 from two institutions was conducted. Univariate and multivariate logistic regression analyses were performed to select the most useful predictors from the training cohort (n = 225), and then a nomogram model was developed. The performance of the nomogram was evaluated with respect to its discrimination, calibration, and clinical usefulness. Internal validation and external validation were performed in an independent validation cohort of 96 and 205 consecutive BC patients, respectively.ResultsAmong the 18 clinicopathological features, five variables were selected to develop the prediction model, including age, American Joint Committee on Cancer (AJCC) T stage, Ki67 index before NACT, human epidermal growth factor receptor 2 (HER2), and hormone receptor (HR) status. The model showed good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.825 (95% CI, 0.772 to 0.878) in the training cohort, and 0.755 (95% CI, 0.658 to 0.851) and 0.79 (95% CI, 0.724 to 0.856) in the internal and external validation cohorts, respectively. The calibration curve presented good agreement between prediction by nomogram and actual observation, and decision curve analysis (DCA) indicated that the nomogram had good net benefits in clinical scenarios.ConclusionThis study constructed a validated nomogram based on age, AJCC T stage, Ki67 index before NACT, HER2, and HR status, which could be non-invasively applied to personalize the prediction of pCR in BC patients treated with NACT.

Ovarian cancer remains the leading cause of death from gynecological cancer. Survival is significantly related to the stage of the disease at diagnosis. Of quite importance is primary cytoreductive surgery, having as a goal to remove all visible tumor tissue, and is the standard primary treatment in combination with platinum-based chemotherapy for patients with advanced ovarian carcinoma.Neo-adjuvant chemotherapy (NACT) has been implemented mostly in treating advanced disease, with studies performed having numerous limitations. Data extrapolated from these studies have not shown inferiority survival of NACT, compared to primary debulking surgery. The role of NACT is of particular interest because of the intrinsic mechanisms that are involved in the process, which can be proven as therapeutic approaches with enormous potential. NACT increases immune infiltration and programmed death ligand-1 (PDL-1) expression, induces local immune activation, and can potentiate the immunogenicity of immune-exclude high grade serous ovarian tumors, while the combination of NACT with bevacizumab, PARP inhibitors or immunotherapy remains to be evaluated. This article summarizes all available data on studies implementing NACT in the treatment of ovarian cancer, focusing on clinical outcomes and study limitations. High mortality rates observed among ovarian cancer patients necessitates the identification of more effective treatments, along with biomarkers that will aid treatment individualization.

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]

Background: 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. Method: 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. Results: 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. Conclusion: 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.

Eighty-five percent of oral cavity cancers present as locally advanced disease and are treated with multimodality approach. Patients who can undergo radical resection have the best outcomes, although the overall results are still unsatisfactory. Neoadjuvant chemotherapy (NACT) has been studied in oral cavity cancers with the aim of improving locoregional control and overall survival (OS) and as an organ preservation tool in resectable oral cavity cancers, It has also been studied in borderline resectable/technically unresectable tumors in order to reduce surgical margins, increase resectability, and achieve R0 resection and in unresectable tumors in order to improve disease-free survival and OS. In this review, we will critically analyze the current evidence for the use of NACT in oral squamous cell carcinoma (OSCC) and suggest an approach to select a patient who might benefit from NACT.

The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the “multiple-hit theory” and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders.

TESS Research Foundation (TESS) is a patient-led nonprofit organization seeking to understand the basic biology and clinical impact of pathogenic variants in the SLC13A5 gene. TESS aims to improve the fundamental understanding of citrate's role in the brain, and ultimately identify treatments and cures for the associated disease. TESS identifies, organizes, and develops collaboration between researchers, patients, clinicians, and the pharmaceutical industry to improve the lives of those suffering from SLC13A5 citrate transport disorder. TESS and its partners have developed multiple molecular tools, cellular and animal models, and taken the first steps toward drug discovery and development for this disease. However, much remains to be done to improve our understanding of the disorder associated with SLC13A5 variants and identify effective treatments for this devastating disease. Here, we describe the available SLC13A5 resources from the community of experts, to foundational tools, to in vivo and in vitro tools, and discuss unanswered research questions needed to move closer to a cure., Competing Interests: TLB is employed by TESS Research Foundation. MAB, GZ, and BEP are advisors to TESS Research Foundation. KLN is volunteer Executive Director and Founder of TESS Research Foundation. GZ is a minor shareholder and employee of Eternygen GmbH., (© The Author(s), 2024.)

Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies. These studies evaluated stromal (sTILs) and intra-epithelial (ieTILs) TILs before and after NACT. sTIL responses varied, impacting prognostic outcomes, and ieTILs increased in some patients without clear survival associations. PD-L1 expression after NACT correlated with improved overall survival (OS), and increases in granzyme B+ and PD-1 correlated with longer progression-free survival (PFS). Remarkably, reduced FoxP3+ TILs post-NACT correlated with better prognosis. NACT often increases sTIL/ieTIL and CD8+ subpopulations, but their correlation with improved PFS and OS varies. Upregulation of co-inhibitory molecules, notably PD-L1, suggests an immunosuppressive response to chemotherapy. Ongoing trials exploring neoadjuvant ICIs and chemotherapy offer promise for advancing OC treatment. Standardized measurements assessing TIL density, location, and heterogeneity are crucial for addressing genetic complexity and immunological heterogeneity in OC.

Summary: 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.

Cervical cancer continues to be a major public health concern in India and other low- and middle-income countries. Tata Memorial Centre, India, has been at the forefront in providing treatment, developing best practice guidelines for low-cost efficacious interventions, conducting practice-changing randomized trials and engaging in regional and international collaborations for education and research in cervical cancer. This review summarizes how cervical cancer research and clinical care has evolved over the past two decades at the Tata Memorial Centre, right from testing low-cost public health screening of cervical cancers to the incorporation of the latest technological advancements and providing high-quality evidence for therapeutic management of cervical cancer. The various ongoing strategies for improving survival, toxicity reduction, translational research studies, educational activities and teaching programmes initiated by the Tata Memorial Centre at both national and international levels are discussed. [ABSTRACT FROM AUTHOR]

Breast cancer incidence is on the rise in India as in rest of the world. While the advances in overall cancer care are at par, the surgical interventions have not been changing at the same pace in India, as in the rest of the developed world. Partly, this is due to the relatively more advanced state of cancer at detection and partly due to lack of awareness resulting in apprehension and slow acceptance of de-escalation of surgical interventions by the treating surgeons, and the beneficiaries, the patients. The article looks at the current scenario, available evidence on the practices and pitfalls with possible solutions for advancing surgical care of breast cancer in India. [ABSTRACT FROM AUTHOR]

Background: Breast cancer patients with skin ulcerations, satellite nodules or Peau d'orange at presentation are classified with stage 4 breast cancer (T4b). Neoadjuvant chemotherapy (NACT), followed by mastectomy, is the commonly accepted treatment in such patients for fear of adverse outcomes with breast conservation surgery (BCS) and uncertainty over sparing initially involved skin irrespective of the response to chemotherapy. Identifying patients with skin resolution post-NACT can help surgeons in decision-making. Aim: To assess skin response in T4b breast cancer patients post-NACT and find the correlation between various clinical and pathological factors associated with no skin involvement on final histology. Methodology: Records of breast cancer patients managed at the Tata Medical Center, Kolkata, with NACT for T4b breast carcinoma patients who underwent mastectomy were reviewed between January 2014 and December 2018. Final histology was checked for dermal involvement with the tumour. The Mann-Whitney U test was used for continuous variables for descriptive data, and Pearson's chi-squared and Fischer's exact tests were applied for categorical data. p-value < 0.05 was taken as significant. Results: A total of 285 records mentioning skin involvement were reviewed, out of which 111 patients fulfilled the AJCC criterion. The median age at diagnosis of T4b breast cancer was 50 years. The median clinical size pre-chemotherapy was 7 cm. Residual median tumour size on final histology was reported as 1 cm. 78/111 patients showed a post-NACT response of 50% or more, and 43/111 showed a response of more than 90%. 57 (51.4%) patients showed skin involvement on final histopathology, while 54 (48.6%) patients did not. ER negative tumours were more likely to show no dermal involvement (p = 0.006). Residual tumour size of less than 1 cm on final histology (p < 0.05) and nodal stage were significant predictors of dermal response. Conclusion: Approximately half of the T4b breast cancer patients showed resolution of dermal skin involvement post-NACT. ER negative and those with residual tumour size less than 1 cm post-NACT are more likely to show dermal resolution. This can help surgeons plan a BCS or skin sparing mastectomy for such patients who usually end up having a mastectomy. [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]

The SLC13 family in humans and other mammals consists of sodium-coupled transporters for anionic substrates: three transporters for dicarboxylates/citrate and two transporters for sulfate. This review will focus on the di- and tricarboxylate transporters: NaDC1 (SLC13A2), NaDC3 (SLC13A3), and NaCT (SLC13A5). The substrates of these transporters are metabolic intermediates of the citric acid cycle, including citrate, succinate, and α-ketoglutarate, which can exert signaling effects through specific receptors or can affect metabolic enzymes directly. The SLC13 transporters are important for regulating plasma, urinary and tissue levels of these metabolites. NaDC1, primarily found on the apical membranes of renal proximal tubule and small intestinal cells, is involved in regulating urinary levels of citrate and plays a role in kidney stone development. NaDC3 has a wider tissue distribution and high substrate affinity compared with NaDC1. NaDC3 participates in drug and xenobiotic excretion through interactions with organic anion transporters. NaCT is primarily a citrate transporter located in the liver and brain, and its activity may regulate metabolic processes. The recent crystal structure of the Vibrio cholerae homolog, VcINDY, provides a new framework for understanding the mechanism of transport in this family. This review summarizes current knowledge of the structure, function, and regulation of the di- and tricarboxylate transporters of the SLC13 family.

Abstract Background Neuroendocrine cervical carcinoma (NECC) is a rare but aggressive form of cervical cancer representing less than 3% of all cervical cancer cases. The objective of this study is to evaluate the effects of the clinicopathologic features and treatment modalities on the survival of patients with NECC. Methods In all, 89 stage I-IV patients with NECC that were diagnosed and treated between 2006 and 2014 at the Zhejiang Cancer Hospital were retrospectively recruited in this study. The Kaplan-Meier method, Cox regression analysis models and the log-rank test were used for the statistical analyses. Results NECC patients with advanced FIGO stage, tumor size > 4 cm, lymph node metastasis (LNM) and lymph-vascular space invasion (LVSI) were more likely to have significantly worse survival. Neither neo-adjuvant chemotherapy (NACT) nor radiotherapy (RT) was associated with improved overall survival. In the stratified analysis of stage I-IIA patients, those with advanced FIGO stage (P = 0.018), LNM (P = 0.008) and LVSI (P = 0.024) were associated with significantly worse survival. Patients without LNM who did not receive RT had significantly better survival rates than those who received RT (HR = 3.363, 95%CI = 1.245–10.619; P = 0.018). Moreover, for stage I-IIA patients with tumor size > 4 cm, NACT was not associated with a significantly better survival rate compared with no NACT (P = 0.600). None of the clinicopathologic features or treatment modalities was an independent prognostic factor in the multivariate analysis. Conclusions In conclusion, advanced FIGO stage, tumor size > 4 cm, LNM and LVSI were associated with poor survival. For stage I-IIA patients, RT should be carefully used in patients who are negative for LNM, and NACT may not be the optimal treatment for patients with tumor size > 4 cm.