A Unique Case of Intracranial Bifocal Germinoma.

Primary intracranial germ cell tumors are rare tumors that often occur in children and young adults. We report a case of a 17-year-old male, who presented with vomiting, headache, and blurring of vision of the left eye on the temporal aspect for two months. His biological assessment showed panhypopituitarism. Serum markers showed elevated beta human chorionic gonadotropin and lactate dehydrogenase. A solid cystic lesion was noted on imaging, involving the sella, parasellar region, and pineal region with calcifications within. Diagnosis of bifocal germinoma was confirmed by tumor biopsy. The treatment protocol for the patient involved four cycles of chemotherapy using etoposide and carboplatin, followed by a course of radiotherapy.

Signet ring cells and conditional survival after trimodality therapy for esophageal adenocarcinoma.

BACKGROUND AND METHODS: Although signet ring cell (SRC) histology is associated with resistance to neoadjuvant chemoradiotherapy and worse overall survival (OS) in esophageal adenocarcinoma (EAC), its prognostic relationship among patients who survive the early period following resection is unknown. EAC patients who underwent trimodality therapy at a single institution (2006-2018) were identified. Bayesian multivariable regression (BMR) analyses of OS and additional OS from a 3-year landmark were performed. RESULTS: Of 631 patients, SRCs were present in 16.0% (N = 101). SRC was associated with shorter median OS (45.8 [95% confidence interval: 31.0-96.7] vs. 79.8 [63.0-107.2] months; p = 0.014). In BMR analysis, the absence of an SRC component was moderately associated with improved OS (probability of beneficial effect, PBE = 0.879). Three-year conditional BMR analysis of additional OS (N = 357) showed that SRC status no longer had a prognostic effect (PBE = 0.546); higher pathological stage was strongly associated with worse additional OS (PBE < 0.001). CONCLUSIONS: The presence of SRC portends worse OS following trimodality therapy for EAC. However, this prognostic impact is dynamic and abates by 3 years postoperatively. In contrast, a higher pathological stage is strongly associated with poor overall and 3-year conditional survival. DISCUSSION: These findings may inform postoperative patient counseling and surveillance protocols.

The Right Gastroepiploic Artery as a Potential Organ at Risk in Neoadjuvant Chemoradiation for Esophageal and Gastroesophageal Cancers.

BACKGROUND: Preoperative chemoradiation is a standard of care for esophageal and gastroesophageal cancer. A gastric conduit is usually used for anastomosis with the right gastroepiploic artery (RGEA) being the sole arterial supply to the gastric remnant after such surgeries. Hence, lowering the radiation dose to this vessel may lower the risks of postoperative complications related to poor vasculature. Herein, we report our experience in contouring and replanning cases of distal esophageal/gastroesophageal carcinomas so that the radiation doses to the RGEA could be minimized. MATERIALS AND METHODS: Radiation plans of patients with lower esophageal/gastroesophageal carcinomas were retrieved from our database. Identification and delineation of the RGEA was done and replanning was performed with the aim to keep the maximal and mean doses as well as the V10Gy and V20Gy of the RGEA as low as possible without compromising target volume coverage.  Results: We achieved significant dose reductions in most of the dosimteric parameters in our selected cases without compromising target coverage. CONCLUSION: Lowering the dose to the RGEA, a potential organ-at-risk that may impact the postoperative course after neoadjuvant chemoradiation, is feasible.

Postoperative Adverse Events Following Neoadjuvant Therapy and Surgery for Borderline Resectable Pancreatic Cancer in a Phase 2 Clinical Trial (Alliance A021501).

BACKGROUND: Postoperative adverse events (AEs) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR-PC) treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. We conducted a preplanned secondary analysis of patients enrolled on the Alliance A021501 clinical trial to quantify perioperative AE rates. METHODS: The A021501 phase 2 trial randomized patients with BR-PC to receive 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX and hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (December 31, 2016 to May 31, 2019). Adverse events were assessed 90 days after pancreatectomy. RESULTS: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n = 32, Arm 1; n = 19, Arm 2) at 28 institutions. Five (10%) patients required reoperation within 90 days; 56% of patients (n = 27/48) experienced at least one grade 3 or higher AE (50% vs. 67%, p = 0.37). Ninety-day mortality was 2.0%. Readmission was less frequent in Arm 1 (16% vs. 42%, p = 0.05), but there were no differences between study arms in rates of reoperation (13% vs. 5%), pancreatic fistula or intra-abdominal abscess requiring drainage (9% vs. 16%), or wound infection (6% vs. 16%). Pancreatic fistula or intra-abdominal abscess requiring drainage was associated with receipt of adjuvant therapy (p = 0.012). No difference in overall survival was observed based on occurrence of postoperative AEs (hazard ratio = 1.1; 95% confidence interval 0.5-2.6). CONCLUSIONS: In this multicenter study, rates of postoperative AEs were consistent with those previously reported. Multimodality trials of preoperative therapy for BR-PC may be performed in the cooperative group setting with careful quality assurance and safety monitoring. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02839343.

Dramatic Radiographic Response of Pelvis-Filling Locally Advanced Cervical Cancer Treated With Radiation and Chemotherapy.

Locally advanced cervical cancers are often treated with palliative intent due to concerns that the tumor is too far advanced or too large to be treated curatively. Also, patients greater than 65 years of age with cervical cancer are sometimes regarded as being too old or too frail to be cured with combined radiation and chemotherapy. These patients are often treated with radiation alone or with palliative therapy. Understanding the treatment modalities for cervical cancer is essential, as they can be complex and unique to each patient's specific diagnosis. This case report aims to describe the dramatic response to treatment with combined radiation and chemotherapy for a patient greater than 65 years of age with pelvis-filling cervical cancer with right-sided hydronephrosis. After a five-week course of concurrent chemoradiation, the cervical mass radiographically completely disappeared, with no evidence of disease noted on pelvic MRI.

Cancer treatments as paradoxical catalysts of tumor awakening in the lung.

Much of the fatality of tumors is linked to the growth of metastases, which can emerge months to years after apparently successful treatment of primary tumors. Metastases arise from disseminated tumor cells (DTCs), which disperse through the body in a dormant state to seed distant sites. While some DTCs lodge in pre-metastatic niches (PMNs) and rapidly develop into metastases, other DTCs settle in distinct microenvironments that maintain them in a dormant state. Subsequent awakening, induced by changes in the microenvironment of the DTC, causes outgrowth of metastases. Hence, there has been extensive investigation of the factors causing survival and subsequent awakening of DTCs, with the goal of disrupting these processes to decrease cancer lethality. We here provide a detailed overview of recent developments in understanding of the factors controlling dormancy and awakening in the lung, a common site of metastasis for many solid tumors. These factors include dynamic interactions between DTCs and diverse epithelial, mesenchymal, and immune cell populations resident in the lung. Paradoxically, among key triggers for metastatic outgrowth, lung tissue remodeling arising from damage induced by the treatment of primary tumors play a significant role. In addition, growing evidence emphasizes roles for inflammation and aging in opposing the factors that maintain dormancy. Finally, we discuss strategies being developed or employed to reduce the risk of metastatic recurrence.

NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma.

Background: The chemotherapeutic standard of care for patients with glioblastoma (GB) is radiation therapy (RT) combined with temozolomide (TMZ). However, during the twenty years since its introduction, this so-called Stupp protocol has revealed major drawbacks, because nearly half of all GBs harbor intrinsic treatment resistance mechanisms. Prime among these are the increased expression of the DNA repair protein O6-guanine-DNA methyltransferase (MGMT) and cellular deficiency in DNA mismatch repair (MMR). Patients with such tumors receive very little, if any, benefit from TMZ. We are developing a novel molecule, NEO212 (TMZ conjugated to NEO100), that harbors the potential to overcome these limitations. Methods: We used mouse models that were orthotopically implanted with GB cell lines or primary, radioresistant human GB stem cells, representing different treatment resistance mechanisms. Animals received NEO212 (or TMZ for comparison) without or with RT. Overall survival was recorded, and histology studies quantified DNA damage, apoptosis, microvessel density, and impact on bone marrow. Results: In all tumor models, replacing TMZ with NEO212 in a schedule designed to mimic the Stupp protocol achieved a strikingly superior extension of survival, especially in TMZ-resistant and RT-resistant models. While NEO212 displayed pronounced radiation-sensitizing, DNA-damaging, pro-apoptotic, and anti-angiogenic effects in tumor tissue, it did not cause bone marrow toxicity. Conclusions: NEO212 is a candidate drug to potentially replace TMZ within the standard Stupp protocol. It has the potential to become the first chemotherapeutic agent to significantly extend overall survival in TMZ-resistant patients when combined with radiation.

Response of various histological types of locally advanced rectal cancer to neoadjuvant multimodality therapy.

Objectives: To determine the response of various histological types of locally advanced rectal cancer to neoadjuvant multimodality therapy. METHODS: The non-randomised, quasi-experimental retrospective cohort study was conducted at the Combined Military Hospital, Rawalpindi, Pakistan, and comprised data of patients treated between January 1, 2020, to September 30, 2021. The data retrieved related to histologically proven and locally advanced rectal cancer patients aged 18-70 years receiving neoadjuvant chemoradiotherapy. Radiotherapy dose was 45 gray to pelvis with a boost to gross tumour of 5.4 gray in 3 fractions by using volumetric arc therapy concurrently with capecitabine 625mg/m² daily. A magnetic resonance imaging scan of pelvis with contrast was done at 5-10 weeks before surgery. Histological response to neoadjuvant treatment of various histological types was evaluated using the Rectal Cancer Regression Grade. Data was analysed using SPSS 22. RESULTS: Of the 182 patients evaluated, 108(59.34%) were included; 64(59.3%) males and 44(40.7%) females. The overall mean age was 45.4±5.2 years. Regression status was grade 1 in 24(22%) patients, grade 2 in 43(40%) and grade 3 in 41(38%) (p=0.074). There were 12(11.11%) patients with signet ring cell and 10(83.3%) showed pathological tumour regression. There were 17(15.74%) patients with mucinous variant, and 12(70.5%) had tumour regression. There were 79(73.15%) patients with adenocarcinoma, and 59(74.6%) of them showed tumour regression. . CONCLUSIONS: There was less tumour regression in mucinous and signet ring cell variants of adenocarcinoma. Modification and intensification of neoadjuvant therapy may be required in such histologies.

Results of the study of factors predicting the risk of the development of grade III radiation-induced mucositis during radiation or chemoradiation therapy in patients with oral cavity and oropharynx cancer.

BACKGROUND: Today, a number of methods and ways of prevention and treatment of radiation- -induced mucositis of the oral cavity and oropharynx have been developed, but the represented approaches are still not effective enough. Therefore, to increase the effectiveness of the prevention and treatment of radiation-induced mucositis, it is necessary to approach this problem comprehensively and individually, and to evaluate the factors affecting the development of mucositis. MATERIALS AND METHODS: In this single-center prospective controlled non-randomized clinical trial, the results of clinical observation of the development of complications of radiation and chemoradiation therapy in 105 patients with a newly diagnosed squamous cell cancer of the oral cavity and oropharynx were analyzed. Factors affecting the risk of the development of grade III radiation-induced mucositis including the age, gender of the patients, their general condition before the treatment according to World Health Organisation scales, type of the treatment and its doses, additional use of immunotherapy with alpha/beta defensins, characteristic signs of the tumor process and all indices of the immune status of the patients before the treatment have been analyzed. RESULTS: The method of construction and analysis of one-factor logistic regression models, where 24 indices were analyzed as factorial features, showed that the reduction of the risk of the development of grade III radiation-induced mucositis is predicted by several factors: immunotherapy, gender, serum concentrations of IgG and IgA. A decrease (P < 0.001) in the risk of the development of grade III radiation-induced mucositis was revealed if immunotherapy with alpha/beta defensins (with a total dose of 40 mg) was included into the treatment scheme (relative odds (RO) 0.05; 95% reference interval (RI) 0.02-0.18), in comparison with patients of the groups where it was not present or this immune agent was used in a total dose of 60 mg (P = 0.001, RO 0.06; 95% RI 0.01-0.30). The next factorial sign was gender, namely the risk of the development of grade III radiation-induced mucositis was lower for men (P = 0.003; RO 0.15; 95% RI 0.04-0.53) compared to women. An increase (P = 0.024) in the risk of the development of grade III radiation-induced mucositis with an increase in the initial level of IgG serum concentration was revealed, (RO 1.08; 95% RI 1.01-1.16) for each 1 mg/mL, as well as an increase (P = 0.044) in the possibility of the appearance of grade III radiation-induced mucositis with an increase in the serum concentration of IgA (RO 1.23; 95% RI 1.01-1.50) for every 1 mg/mL also before the beginning of the treatment. Multifactorial analysis has also confirmed that the risk of the development of grade III radiation-induced mucositis increases (P = 0.008) with a high serum IgG concentration before the treatment or with an increase in this index during therapy (RO 1.13; 95% RI 1.03-1.09) for every 1 mg/mL (when standardized by other risk factors). It was determined that when standardizing according to other factors (gender, IgG level), the risk of the development of grade III radiation-induced mucositis in the use of the immune agent alpha/beta defensins in a total dose of 40 mg per course decreases (P < 0.001; RO 0.08; 95% RI 0.02-0.27) compared to patients with oral cavity and oropharynx cancer who were not treated with immunotherapy. The risk of the development of grade III radiation-induced mucositis also decreases (P = 0.001) in the use of immunotherapy in a higher dose, i.e. 60 mg per course (RO 0.03; 95% RI 0.004-0.24 compared to patients whose treatment did not include immunotherapy (when standardized by other factors). CONCLUSION: As a result of this controlled clinical study, some factors were determined in addition to the radiation as those affecting the risk of the development of grade III radiation-induced mucositis in patients with oral cavity and oropharynx cancer during special treatment. These factors comprise the inclusion of immunotherapy with alpha/beta defensins into the specific treatment; gender, and baseline levels of serum IgG and IgA concentrations suggest a pattern in which the higher the serum IgG and IgA concentrations are before the start of the treatment, the greater is the likelihood of severe radiation-induced mucositis degree during special therapy. The results of the study of humoral state of the immune system in patients with oral cavity and oropharynx cancer before the beginning of chemoradiation therapy can be used as prognostic risk factors for the development of severe gamma-irradiation-induced mucositis of the oropharyngeal area, as well as an indication for the use of immunotherapeutic agents (in particular, alpha/beta defensins) that are able to polarize the immune response towards type 1 T-helpers through their immunomodulatory action.

Case series on the management and outcomes of Bartholin gland carcinoma.

OBJECTIVE: To evaluate the management and outcomes of Bartholin gland cancer at a single tertiary institution. STUDY DESIGN: A single institution retrospective review of 9 cases of BGC between 2004 and 2022 was conducted. Demographics, pathological characteristics, treatment, follow up and oncologic outcomes were extracted from clinical records. Data are summarised using descriptive statistics and survival probabilities are presented with Kaplan Meier graphs. RESULTS: Ten cases of BGC were identified at our institution over a period of 18 years. Nine out of ten clinical records were available for analysis. Eight patients presented with vulval swelling and four were treated initially for Bartholin cyst or abscess. One patient had a histological diagnosis of adenoid cystic carcinoma while the remaining were squamous cell carcinomas. With the exception of stage I disease chemoradiation was the primary mode of treatment. Adverse events included skin desquamation (4/9), venous thrombo-embolism (2/9), gastro-intestinal (1/9) and neurotoxicity (1/9). Median follow up was 60 months with a 5-year recurrence free and overall survival at 76 % and 64 % respectively. CONCLUSION: BGC may present after a long duration of symptoms and at advanced stages. Primary chemoradiation appears to be a feasible treatment option in advanced disease with the benefit of decreased morbidity.

Radiotherapy for Rectal Cancer: How Much is Enough?

Though resection has been the mainstay of treatment for nonmetastatic rectal cancer over the past century, radiation has become an increasingly integral component of care for locally advanced disease. Today, two predominant radiotherapy approaches-hyperfractionated chemoradiotherapy and "short-course" radiation-are widely utilized to reduce local recurrence and, in some cases, cure disease. Both have been incorporated into total neoadjuvant therapy (TNT) regimens and achieved excellent local control and superior complete response rates compared to chemoradiation alone. Additionally, initial results of "watch and wait" protocols utilizing either radiation modality have been promising. Yet, differences do exist; though short course is cheaper and more convenient for patients, recently published data may show superior complete response and local recurrence rates with chemoradiation. Ultimately, direct comparisons of short-course radiotherapy against chemoradiation within the TNT framework are needed to identify optimal radiation regimens in the treatment of locally advanced rectal cancer.

Chemoradiation, Consolidation Chemotherapy, and Watch and Wait for Early Rectal Cancer.

As watch and wait has become an attractive management alternative among patients with rectal cancer who achieve a clinical complete response to neoadjuvant chemoradiation, the focus of organ preservation has now shifted toward the use of this approach in patients with early rectal cancer. These patients would otherwise be treated without the use of neoadjuvant therapy for oncological reasons. The sole purpose of any neoadjuvant treatment here would be the achievement of a complete clinical response in an attempt to avoid total mesorectal excision. This has become particularly interesting after the incorporation of total neoadjuvant therapy regimens. These regimens have resulted in significantly higher rates of complete tumor regression and therefore become an interesting alternative among early rectal cancer patients where organ preservation is desired. The present review provides an overview of the currently available evidence and the preliminary experience with this rather controversial approach.

Surveillance after Total Neoadjuvant Therapy: What to do for Near-Complete Responders.

A proportion of patients who undergo total neoadjuvant therapy for rectal cancer will achieve what is classified as a near-complete response. Significant debate exists as to the optimal management strategy for these patients with large heterogeneity in management. This article will examine the therapeutic and surveillance options for these patients as well as the relevant outcomes data.

External auditory canal metastasis revealing bronchogenic carcinoma: A case report and literature review.

This report presents a rare case of bronchogenic adenocarcinoma with initial metastasis in the external auditory canal. The patient, a 64-year-old man with a history of bladder urothelial carcinoma, initially presented with a persistent right otitis externa. Otoscopic examination revealed a mass obstructing the right external auditory canal. The temporal bone computed tomography scan revealed a mass that completely obstructed the right external auditory canal and extended into the middle ear. A biopsy showed a poorly differentiated adenocarcinoma of bronchogenic origin, confirmed by positive immunohistochemical staining for cytokeratin 7 and Thyroid transcription factor-1. Further imaging revealed a large tumor mass in the lung involving the mediastinum and parenchyma, along with carcinomatous lymphangitis and cerebral metastasis. Histopathological examination of the primary lung tumor confirmed a poorly differentiated adenocarcinoma with similar features to the metastasis in the external auditory canal. The tumor was staged as T4N2M1c, and the patient underwent local external-beam radiation therapy with chemotherapy.

Can Pretreatment MRI and Planning CT Radiomics Improve Prediction of Complete Pathological Response in Locally Advanced Rectal Cancer Following Neoadjuvant Treatment?

OBJECTIVE(S): The treatment response to neoadjuvant chemoradiation (nCRT) differs largely in individuals treated for rectal cancer. In this study, we investigated the role of radiomics to predict the pathological response in locally advanced rectal cancers at different treatment time points: (1) before the start of any treatment using baseline T2-weighted MRI (T2W-MR) and (2) at the start of radiation treatment using planning CT. METHODS: Patients on nCRT followed by surgery between June 2017 to December 2019 were included in the study. Histopathological tumour response grading (TRG) was used for classification, and gross tumour volume was defined by the radiation oncologists. Following resampling, 100 and 103 pyradiomic features were extracted from T2W-MR and planning CT images, respectively. Synthetic minority oversampling technique (SMOTE) was used to address class imbalance. Four machine learning classifiers built clinical, radiomic, and merged models. Model performances were evaluated on a held-out test dataset following 3-fold cross-validation using area under the receiver operator characteristic curves (AUC) with bootstrap 95% confidence intervals. RESULTS: One hundred and fifty patients were included; 58/150 with TRG 1 were classified as complete responders, and rest were incomplete responders (IR). Clinical models performed better (AUC = 0.68) compared to radiomics models (AUC = 0.62). Overall, the clinical + T2W-MR model showed best performance (AUC = 0.72) in predicting the pathological response prior to therapy. Clinical + Planning CT-merged models could only achieve the highest AUC of 0.66. CONCLUSION: Merging clinical and baseline T2W-MR radiomics enhances predicting pathological response in rectal cancer. Validation in larger cohorts is warranted, especially for watch and wait strategies.

Avelumab maintenance therapy for node-positive muscle invasive bladder cancer: a report of two cases.

Background: Muscle-invasive bladder cancer (MIBC) with nodal involvement is associated with poor prognosis and high mortality. Treatment of node-positive MIBC is complex due to disease heterogeneity and a lack of evidence-based treatment options, especially alternatives to radical cystectomy. We describe a bladder-sparing management approach involving systemic therapy followed by maintenance therapy, illustrated with two cases of node-positive MIBC. Case presentation: Two patients with node-positive MIBC received upfront gemcitabine/cisplatin chemotherapy, concurrent chemoradiotherapy (cCRT), and avelumab (immune checkpoint inhibitor) maintenance therapy. Both patients achieved complete remission without recurrence or distant metastasis post-avelumab maintenance therapy. At the last follow-up, Patient 1 (45-year-old male) was in remission for over two years, and Patient 2 (57-year-old male) was in complete remission for over one year post-chemotherapy. Avelumab treatment was well-tolerated, with no immune-related adverse events, and quality of life (QoL) was maintained. Conclusion: Both cases showed a good response and extended remission on avelumab maintenance, supporting its use in conjunction with local consolidation therapy as a bladder-preserving approach in node-positive MIBC. Further research, such as the ongoing INSPIRE trial, is required to refine treatment strategies for this patient group.

Correlation of maintenance chemotherapy and improved survival in patients with locally advanced unresectable pancreatic head adenocarcinoma receiving neoadjuvant chemotherapy and concurrent chemoradiotherapy.

To assess the efficacy of maintenance chemotherapy in the management of unresectable locally advanced pancreatic head adenocarcinoma (PHA) cancer after neoadjuvant chemotherapy and concurrent chemoradiation therapy (CCRT). This study, a large-scale head-to-head propensity score matching (PSM) cohort study, employed real-world data. PSM was used to evaluate the impact of maintenance chemotherapy on overall survival and cancer-specific survival in patients with unresectable locally advanced PHA who underwent neoadjuvant chemotherapy and CCRT. A total of 148 patients with locally advanced pancreatic head adenocarcinoma were included in the study after PSM. These patients were equally divided into two groups, those receiving maintenance chemotherapy and those who did not. Confounding factors were balanced between the groups. The adjusted hazard ratios for all-cause mortality and cancer-specific mortality were 0.56 (95% CI: 0.40-0.77; P = 0.0005) and 0.56 (95% CI: 0.40-0.78; P = 0.0007), respectively, in patients receiving maintenance chemotherapy compared to those who did not. Our large-scale, real-world study demonstrates that maintenance chemotherapy may enhance survival outcomes for patients with unresectable locally advanced pancreatic head adenocarcinoma who underwent neoadjuvant chemotherapy and concurrent chemoradiation therapy.

Utilization and survival outcomes of neoadjuvant chemotherapy for early-stage gastric cancer.

BACKGROUND AND OBJECTIVES: Given increased utilization of neoadjuvant therapy (NAT) for gastric adenocarcinoma, practice patterns deviating from standard of care (upfront resection) remain unknown. We sought to identify factors associated with NAT use and survival outcomes among early-stage gastric cancers. METHODS: The National Cancer Database identified patients with early-stage (T1N0M0) gastric cancer (2010-2020). Multivariable logistic regression assessed characteristics associated with NAT utilization compared to upfront surgery. After 1:1 propensity score matching, Kaplan-Meier methods and Cox regression assessed overall survival (OS). RESULTS: Of 6452 patients with early-stage gastric cancer, 626 (9.7%) received NAT. Patients who received NAT were more likely treated at community hospitals, had moderate to poorly differentiated disease, and tumors located in the cardia (all p < 0.05). After propensity score matching, 1,248 patients remained. Median OS for NAT was 37.1 months (IQR 20.2-64.0) versus 45.6 months (IQR 22.5-72.8) for resection (p < 0.001). Treatment with NAT remained independently predictive of worse OS on Cox regression (hazard ratio 1.19; 95% confidence interval 1.05-1.34). CONCLUSIONS: Although patients who received NAT had more aggressive prognostic features, NAT was associated with worse OS despite accounting for this selection bias. These results highlight the importance of adhering to guidelines, regardless of differing disease characteristics, which has significant implications on outcomes.

Exploring the combined impact of cisplatin and copper-cysteamine nanoparticles through Chemoradiation: An in-vitro study.

Copper-Cysteamine nanoparticles (Cu-Cy NPs) have emerged as promising radiosensitizers in cancer treatment. This study aims to investigate the combined therapeutic effect of these nanoparticles and cisplatin using a clinical linear accelerator to enhance the efficacy of chemoradiation therapy for cervical cancer. Following successful synthesis and characterization of Cu-Cy NPs, the cytotoxicity effect of these nanoparticles and cisplatin in various concentrations was evaluated on HeLa cancer cells, individually and in combination. Additionally, the radiobiological effects of these agents were investigated under a 6MV linear accelerator. At a concentration of 25 mg/L, Cu-Cy NPs displayed no significant cytotoxicity toward HeLa cancer cells. However, when combined with 2Gy X-ray irradiation at this concentration, the nanoparticles demonstrated a potent radiosensitizing effect. Notably, cell viability and migration rate in the combination group (Cu-Cy NPs + cisplatin + radiation) were significantly reduced compared to the radiation-alone group. Additionally, the combination treatment induced a significantly higher rate of apoptosis compared to the radiation-alone group. Overall, Cu-Cy NPs exhibited a significant dose-dependent synergistic enhancement of radiation efficacy when combined with cisplatin under X-ray exposure, and may provide a promising approach to improve the therapeutic effect of conventional radiation therapy.

BUB1 Inhibition Sensitizes TNBC Cell Lines to Chemotherapy and Radiotherapy.

BUB1 is overexpressed in most human solid cancers, including breast cancer. Higher BUB1 levels are associated with a poor prognosis, especially in patients with triple-negative breast cancer (TNBC). Women with TNBC often develop resistance to chemotherapy and radiotherapy, which are still the mainstay of treatment for TNBC. Our previous studies demonstrated that a BUB1 kinase inhibitor (BAY1816032) reduced tumor cell proliferation and significantly enhanced radiotherapy efficacy in TNBC. In this study, we evaluated the effectiveness of BAY1816032 with a PARP inhibitor (olaparib), platinum agent (cisplatin), and microtubule poison (paclitaxel) alone or in combination with radiotherapy using cytotoxicity and clonogenic survival assays. BUB1 inhibitors sensitized BRCA1/2 wild-type SUM159 and MDA-MB-231 cells to olaparib, cisplatin, and paclitaxel synergistically (combination index; CI < 1). BAY1816032 significantly increased the radiation sensitization of SUM159 and MDA-MB-231 by olaparib, cisplatin, or paclitaxel at non-toxic concentrations (doses well below the IC50 concentrations). Importantly, the small molecular inhibitor of BUB1 synergistically (CI < 1) sensitized the BRCA mutant TNBC cell line HCC1937 to olaparib. Furthermore, the BUB1 inhibitor significantly increased the radiation enhancement ratio (rER) in HCC1937 cells (rER 1.34) compared to either agent alone (BUB1i rER 1.19; PARPi rER 1.04). The data presented here are significant as they provide proof that inhibition of BUB1 kinase activity sensitizes TNBC cell lines to a PARP inhibitor and radiation, irrespective of BRCA1/2 mutation status. Due to the ability of the BUB1 inhibitor to sensitize TNBC to different classes of drugs (platinum, PARPi, microtubule depolarization inhibitors), this work strongly supports the role of BUB1 as a novel molecular target to improve chemoradiation efficacy in TNBC and provides a rationale for the clinical evaluation of BAY1816032 as a chemosensitizer and chemoradiosensitizer in TNBC.