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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]

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]

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]

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]

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]

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]

Purpose: 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. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore the reliability of cell-free DNA (cfDNA) as an indicator for screening patients who benefit from neoadjuvant chemotherapy (NACT) in advanced gastric cancer (GC). 70 GC patients with TNM (Tumor, Lymph Node, Metastasis) stage II-III were enrolled. Plasma specimens of GC patients before and after NACT and of 50 healthy volunteers were collected. The concentration and integrity of cfDNA were detected by qRT-PCR. cfDNA concentration and integrity of different groups were analyzed to explore its relationship with clinical characteristics of gastric cancer patients. ROC (Receiver operating characteristic) curve was established to compare the cfDNA sensitivity and specificity with cancer antigen 724 (CA724), carcinoembryonic antigen (CEA), cancer antigen 199 (CA199) and alpha-fetoprotein (AFP). Factors affecting the prognosis of advanced GC patients were analyzed by COX univariate/multivariate analysis. The result showed that plasma cfDNA concentration and integrity of advanced GC patients before NACT were significantly higher than those of normal people. After receiving NACT, cfDNA concentration and integrity were significantly decreased (p < 0.05). There was a significant correlation between cfDNA concentration and TNM stage (p < 0.05). The values of area under curve (AUC) of ROC curve for cfDNA concentration and integrity were greater than those of CEA, CA724, CA199 and AFP. COX analysis showed that the tumor differentiation degree and cfDNA concentration were independent risk factors for the advanced GC patients prognosis. In conclusion, cfDNA can be used to predict the prognosis of advanced GC patients, and as a reliable indicator to evaluate for further NACT in advanced GC patients. [ABSTRACT FROM AUTHOR]

Objectives: High-grade serous carcinoma (HGSC) is the most common ovarian malignancy. The role of cytopathology in obtaining tissue diagnosis before institution of neoadjuvant chemotherapy (NACT) was evaluated.Methods: All histopathology-proven HGSC specimens between 2015 and 2018 with prior cytopathologic diagnosis by ascitic fluid evaluation or fine-needle aspiration (FNA) of ovarian mass were reviewed with cell block immunocytochemistry for CK7, CK20, PAX8, WT1, and p53.Results: Of 288 cases of HGSC, pre-NACT cytology diagnosis was established in 32% (93/288), with specific HGSC diagnoses made on ascitic fluid in 88% (82/93) and by ovarian mass FNA in 12% (11/93). The ascitic fluid showed moderate/high cellularity with papillary clusters in 76% (71/93) cases. Cell block immunocytochemistry showed tumor cells positive for CK7, PAX8, and WT1. p53 showed mutant or null-type positivity in 65% (33/51) and 33% (17/51) of cases, respectively, with 100% concordance with subsequent histopathology specimens. Poor/intermediate response to chemotherapy was shown in 75% of cases.Conclusions: Combined assessment of cytomorphology, cell block histomorphology, and ancillary immunohistochemical testing, including PAX8, WT1, and p53, allows for specific pre-NACT diagnoses of HGSC in ascitic fluid and ovarian FNA cytology. This practice allows for initiation of chemotherapy and diminution of disease burden prior to definitive surgical therapy. [ABSTRACT FROM AUTHOR]

Purpose: This retrospective study compared the efficacy and survival of patients with cervical adenocarcinoma (IB2/IIA2; FIGO2009) treated with neoadjuvant chemotherapy before radical surgery (NACT + RS), neoadjuvant chemoradiation therapy before radical surgery (NACRT + RS), or primary radical surgery (RS).Methods: Between January 2008 and November 2015, 91 patients diagnosed with stage IB2/IIA2 cervical adenocarcinoma were enrolled, including 29 patients who received RS, 24 patients who received NACT + RS, and 38 patients who received NACRT + RS.Results: The characteristics of patients were balanced among the three groups, and the median follow-up time was 72 months. The 5 year disease-free survival (DFS) rate was 75.8% and the 5 year overall survival (OS) rate was 85.0%. Univariate analysis revealed that effectiveness of neoadjuvant treatment, tumor size, lymph node metastases, and depth of stromal invasion were the factors predicting recurrence and mortality. Multivariate Cox proportional analysis revealed that the occurrence of a lymph node metastasis was an independent prognostic factor of DFS (hazard ratio [HR] = 0.223; 95% confidence interval [CI]: 0.060-0.827) and OS (HR = 0.088; 95% CI: 0.017-0.470). On survival analysis of preoperative adjuvant chemotherapy and primary surgery, the 5 year OS (P = 0.010) and DFS (P = 0.016) rates for the NACRT + RS group were significantly lower than those for the RS group.Conclusion: Stage IB2/IIA2 cervical adenocarcinoma patients who received primary RS had a better DFS and OS than those who received preoperative NACRT. There was no significant difference when compared to the preoperative NACT group. [ABSTRACT FROM AUTHOR]

Neutrophil–Lymphocyte Ratio (NLR) provides an understanding of the systemic inflammatory conditions. NLR plays an important role as a predictor of mortality in breast and other malignancies. The application of NLR to predict prognosis of Locally Advanced Breast Cancer (LABC) has not been well developed. In this retrospective study, we establish a relationship of pre-treatment NLR with the Pathological Complete Response (pCR) in LABC patients to enhance decision-making and treatment protocols. Data of women diagnosed with carcinoma breast between January 2015 and December 2017 was retrieved from hospital records of a tertiary medical centre in Bangalore, India, after obtaining institutional ethical clearance. LABC patients were categorized into pCR(+) and pCR(−). NLR was calculated and divided into quartiles. The cutoff NLR was determined using the Receiver Operating Characteristic (ROC) curve. Statistical analysis was performed on 119 LABC patients, of which 25 (21%) achieved pCR. Oestrogen Receptor (ER) positivity was significantly lower in pCR(+) than in pCR(−) (p = 0.012). NLR of 2.46 (AUC, 0.744; 95% CI [0.201–0.584]; p = 0.056) was considered the optimum cutoff for pCR(+). A sensitivity of 54%, specificity of 8%, positive predictive value of 1% and high Negative Predictive Value (NPV) of 84% was achieved in the study. A relationship between pCR and the pre-treatment NLR determined a significantly high NPV. Poor pCR in luminal A/B subtype presents with elevated NLR. Therefore, in luminal type A/B (ER- and PR-positive) with elevated NLR (poor outcome) and low pCR (poor response to NACT), the decision of eliminating NACT could be considered, thereby recommending surgical intervention. [ABSTRACT FROM AUTHOR]

The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder. [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 FROM AUTHOR]

The advantages of neoadjuvant chemotherapy are the ability to 1) increase the rate of breast conservation and improve operability, 2) to reduce mortality by recognizing resistance mechanisms early, and 3) to investigate the activity of new agents by assessing the pathological complete response rate as a surrogate marker for clinical efficacy. The German Breast Group (GBG) is a cooperative study group which focuses on neoadjuvant therapy for breast cancer. This group cooperates closely with the German Gynecological Oncology Working Group-Breast (AGO-B). Additionally, these two German study groups maintain close ties with other national and international study groups, such as the Breast International Group (BIG), Austrian Breast and Colorectal Cancer Study Group (ABCSG), Central European Cooperative Oncology Group (CECOG), International Cooperative Cancer Group (ICCG) and National Surgical Adjuvant Breast Project (NSABP). A series of clinical trials evaluating the role of neoadjuvant therapy in women with primary breast cancer have been designed, performed and published over the last 10 years. This article summarizes the results of the neoadjuvant trials that have been conducted by the German study groups, outlines ongoing clinical research projects, and discusses concepts for future clinical trials. [ABSTRACT FROM AUTHOR]

We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive dysfunction. Additionally, most patients lack tooth enamel (amelogenesis imperfecta). However, patients have not had their overall health and growth described in detail. Here we characterized the non-neurologic health of 15 patients with medical records uploaded to Ciitizen, a cloud-based patient medical records portal. Ciitizen used a query method for data extraction. Overall, the patients' records suggested a moderate number of gastrointestinal issues related to feeding, reflux, vomiting and weight gain and a diverse number of respiratory complaints. Other organ systems had single or no abnormal diagnoses, including liver, renal and cardiac. Growth parameters were mostly in the normal range during early life, with a trend toward slower growth in the few adolescent patients with data available. The gastrointestinal and pulmonary issues may at least partially be explained by the severity of the neurologic disorder. More data are needed to clarify if growth is impacted during adolescence and if adult patients develop or are protected from non-neurologic disorders. [ABSTRACT FROM AUTHOR]

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]

Background: Askin tumour or peripheral primitive neuroectodermal tumour (PNET) of Thoraco-pulmonary region is a rare, highly aggressive tumour belonging to Ewings sarcoma family of tumour (EFT). A paradigm shift to successful outcomes was possible in recent times due to introduction of Multimodality management .We present our experience of treating 24 cases of PNET with multimodality management. Materials and method : Data of Histo-pathologically proven cases of PNET involving chest wall was extracted from the prospectively maintained Computerized soft tissue sarcoma data base and analysed for clinical profile, details of multimodality management and relapse patters. Result: A total of 24 cases of PNET chest wall were treated between 2010 to 2015. The mean age was 24Years (range 12 to 37 yrs) . Disease was equally distributed in both sexes. Most common presentation was chest pain ( 61 %) followed by Chest wall mass. All patient except one received Neo adjuvant chemotherapy followed by surgery with or without radiotherapy . VAC ( vincristine, Actinomycin D, cyclophosphamide ) alternating with IE ( ifosamide, etoposide ) was the chemotherapeutic regimen given. All patients responded to NACT and had chest wall resection and reconstruction . Three 3 patients required lung resections. Radiotherapy was given in 6 Patients Out of 14 Patients . At a median follow-up of 22.5 months .8 Patients had relapse of disease . Conclusion: Askins tumours are highly aggressive type of tumors affecting younger population . These tumors are highly chemosensitive hence NACT followed by radical surgery results in optimal outcomes. These cases should ideally be treated in tertiary care cancer centres with expertise for successful outcomes. [ABSTRACT FROM AUTHOR]

Carboplatin/paclitaxel is the reference regimen in the treatment of advanced high-grade serous ovarian cancer (HGSOC) in neo-adjuvant chemotherapy (NACT) before interval debulking surgery (IDS). To identify new genetic markers of platinum-resistance, next-generation sequencing (NGS) analysis of 26 cancer-genes was performed on paired matched pre- and post-NACT tumor and blood samples in a patient with stage IV HGSOC treated with NACT-IDS, showing platinum-refractory/resistance and poor prognosis. Only the TP53 c.375+1G>A somatic mutation was identified in both tumor samples. This variant, associated with aberrant splicing, was in trans configuration with the 72Arg allele of the known germline polymorphism TP53 c.215C>G (p. Pro72Arg). In the post-NACT tumor sample we observed the complete expansion of the TP53 c.375+1G>A driver mutant clone with somatic loss of the treatment-sensitive 72Arg allele. NGS results were confirmed with Sanger method and immunostaining for p53, BRCA1, p16, WT1, and Ki-67 markers were evaluated. This study showed that (i) the splice mutation in TP53 was present as an early driver mutation at diagnosis; (ii) the mutational profile was shared in pre- and post-NACT tumor samples; (iii) the complete expansion of a single dominant mutant clone through loss of heterozygosity (LOH) had occurred, suggesting a possible mechanism of platinum-resistance in HGSOC under the pressure of NACT. [ABSTRACT FROM AUTHOR]

The optimal therapeutic strategy for locally advanced pancreatic cancer patients (LAPC) has not yet been established. Our aim is to evaluate how surgery after neoadjuvant treatment with either FOLFIRINOX (FFN) or Gemcitabine-NabPaclitaxel (GemNab) affects the clinical outcome in these patients. LAPC patients treated at our institution were retrospectively analysed to reach this goal. The group characteristics were similar: 35 patients were treated with the FOLFIRINOX regimen and 21 patients with Gemcitabine Nab-Paclitaxel. The number of patients undergoing surgery was 14 in the FFN group (40%) and six in the GemNab group (28.6%). The median Disease-Free Survival (DFS) was 77.10 weeks in the FFN group and 58.65 weeks in the Gem Nab group (p = 0.625), while the median PFS in the unresected group was 49.4 weeks in the FFN group and 30.9 in the GemNab group (p = 0.0029, 95% CI 0.138–0.862, HR 0.345). The overall survival (OS) in the resected population needs a longer follow up to be completely assessed, while the median overall survival (mOS) in the FFN group was 72.10 weeks and 53.30 weeks for the GemNab group (p = 0.06) in the unresected population. Surgery is a valuable option for LAPC patients and it is able to induce a relevant survival advantage. FOLFIRINOX and Gem-NabPaclitaxel should be offered as first options to pancreatic cancer patients in the locally advanced setting. [ABSTRACT FROM AUTHOR]

The biological properties of circulating tumor cells (CTCs), and their dynamics during neoadjuvant chemotherapy are important, both for disease progression prediction and therapeutic target determination, with the aim of preventing disease progression. The aim of our study was to estimate of different CTC subsets in breast cancer during the NACT (neoadjuvant chemotherapy). The prospective study includes 27 patients with invasive breast cancer, T2-4N0-3M0, aged 32 to 60 years. Venous heparinized blood samples, taken before and after biopsy, after each courses of chemotherapy (on days 3–7), and before surgical intervention, served as the material for this study. Different subsets of circulating tumor cells were determined on the basis of the expression of EpCAM, CD45, CD44, CD24, and N-Cadherin using flow cytometry. As the result of this study, it has been observed that significant changes in the quantity of the different subsets of circulating tumor cells in patients’ blood were observed after carrying out the 3rd course of NACT. NACT causes significant changes in the quantity of six CTC subsets, with various combinations of stemness and epithelial-mesenchymal transition (EMT) properties. [ABSTRACT FROM AUTHOR]