The role of annexins in central nervous system development and disease.

Annexins, a group of Ca2+-dependent phospholipid-binding proteins, exert diverse roles in neuronal development, normal central nervous system (CNS) functioning, neurological disorders, and CNS tumors. This paper reviews the roles of individual annexins (A1-A13) in these contexts. Annexins possess unique structural and functional features, such as Ca2+-dependent binding to phospholipids, participating in membrane organization, and modulating cell signaling. They are implicated in various CNS processes, including endocytosis, exocytosis, and stabilization of plasma membranes. Annexins exhibit dynamic roles in neuronal development, influencing differentiation, proliferation, and synaptic formation in CNS tissues. Notably, annexins such as ANXA1 and ANXA2 play roles in apoptosis and blood-brain barrier (BBB) integrity. Neurological disorders, including Alzheimer's disease, multiple sclerosis, and depression, involve annexin dysregulation, influencing neuroinflammation, blood-brain barrier integrity, and stress responses. Moreover, annexins contribute to the pathogenesis of CNS tumors, either promoting or suppressing tumor growth, angiogenesis, and invasion. Annexin expression patterns vary across different CNS tumor types, providing potential prognostic markers and therapeutic targets. This review underscores the multifaceted roles of annexins in the CNS, highlighting their importance in normal functioning, disease progression, and potential therapeutic interventions.

Current Practices in LC-MS Untargeted Metabolomics: A Scoping Review on the Use of Pooled Quality Control Samples.

Untargeted metabolomics is an analytical approach with numerous applications serving as an effective metabolic phenotyping platform to characterize small molecules within a biological system. Data quality can be challenging to evaluate and demonstrate in metabolomics experiments. This has driven the use of pooled quality control (QC) samples for monitoring and, if necessary, correcting for analytical variance introduced during sample preparation and data acquisition stages. Described herein is a scoping literature review detailing the use of pooled QC samples in published untargeted liquid chromatography-mass spectrometry (LC-MS) based metabolomics studies. A literature query was performed, the list of papers was filtered, and suitable articles were randomly sampled. In total, 109 papers were each reviewed by at least five reviewers, answering predefined questions surrounding the use of pooled quality control samples. The results of the review indicate that use of pooled QC samples has been relatively widely adopted by the metabolomics community and that it is used at a similar frequency across biological taxa and sample types in both small- and large-scale studies. However, while many studies generated and analyzed pooled QC samples, relatively few reported the use of pooled QC samples to improve data quality. This demonstrates a clear opportunity for the field to more frequently utilize pooled QC samples for quality reporting, feature filtering, analytical drift correction, and metabolite annotation. Additionally, our survey approach enabled us to assess the ambiguity in the reporting of the methods used to describe the generation and use of pooled QC samples. This analysis indicates that many details of the QC framework are missing or unclear, limiting the reader's ability to determine which QC steps have been taken. Collectively, these results capture the current state of pooled QC sample usage and highlight existing strengths and deficiencies as they are applied in untargeted LC-MS metabolomics.

JNTX-101, a novel albumin-encapsulated gemcitabine prodrug, is efficacious and operates via caveolin-1-mediated endocytosis.

Albumin is an attractive candidate carrier for the development of novel therapeutic drugs. Gemcitabine has been FDA approved for the treatment of solid tumors; however, new drugs that optimize gemcitabine delivery are not available for clinical use. The aim of this study was to test the efficacy of a novel albumin-encapsulated gemcitabine prodrug, JNTX-101, and investigate whether Cav-1 expression predicts the therapeutic efficacy of JNTX-101. We first determined the treatment efficacy of JNTX-101 in a panel of pancreatic/lung cancer cell lines and found that increases in Cav-1 expression resulted in higher uptake of albumin, while Cav-1 depletion attenuated the sensitivity of cells to JNTX-101. In addition, decreased Cav-1 expression markedly reduced JNTX-101-induced apoptotic cell death in a panel of cells, particularly in low-serum conditions. Furthermore, we tested the therapeutic efficacy of JNTX-101 in xenograft models and the role of Cav-1 in JNTX-101 sensitivity using a Tet-on-inducible tumor model in vivo. Our data suggest that JNTX-101 effectively inhibits cell viability and tumor growth, and that Cav-1 expression dictates optimal sensitivity to JNTX-101. These data indicate that Cav-1 correlates with JNTX-101 sensitivity, especially under nutrient-deprived conditions, and supports a role for Cav-1 as a predictive biomarker for albumin-encapsulated therapeutics such as JNTX-101.

Non-Contact and Self-Calibrated Photopyroelectric Method for Complete Thermal Characterization of Porous Materials.

A general theory of a photopyroelectric (PPE) configuration, based on an opaque sample and transparent pyroelectric sensor, backing and coupling fluids is developed. A combined back-front detection investigation, based on a frequency scan of the phase of the PPE signals, followed by a self-normalization of the phases' behavior, leads to the possibility of simultaneously measuring both thermal effusivity and diffusivity of a solid sample. A particular case of this configuration, with no coupling fluid at the sample/backing interface and air instead of coupling fluid at the sample/sensor interface (non-contact method) is suitable for simultaneous measurement ofboth thermal diffusivity and effusivity (in fact complete thermal characterization) of porous solids. Compared with the already proposed configurations for investigations of porous materials, this novel configuration makes use of a fitting procedure with only one fitting parameter, in order to guarantee the uniqueness of the solution. The porous solids belong to a class of materials which are by far not easy to be investigated using PPE. To the best of our knowledge, porous materials represent the only type of compounds, belonging to condensed matter, which were not taken into consideration (until recently) as potential samples for PPE calorimetric investigations. Consequently, the method proposed in this paper complete the area of applications of the PPE method. Applications on some porous building materials and cellulose-based samples validate the theory.

Inhibition of RRM2 radiosensitizes glioblastoma and uncovers synthetic lethality in combination with targeting CHK1.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted ribonucleotide reductase subunit 2 (RRM2) with triapine to radiosensitize GBM. We found RRM2 is associated with increasing tumor grade, is overexpressed in GBM over lower grade gliomas and normal tissue, and is associated with worse survival. We found silencing or inhibition of RRM2 by siRNA or triapine sensitized GBM cells to ionizing radiation (IR) and delayed resolution of IR-induced γ-H2AX nuclear foci. In vivo, triapine and IR reduced tumor growth and increased mouse survival. Intriguingly, triapine led to RRM2 upregulation and CHK1 activation, suggesting a CHK1-dependent RRM2 upregulation following RRM2 inhibition. Consistently, silencing or inhibition of CHK1 with rabusertib abolished the triapine-induced RRM2 upregulation. Accordingly, combining rabusertib and triapine resulted in synthetic lethality in GBM cells. Collectively, our results suggest RRM2 is a promising therapeutic target for GBM, and targeting RRM2 with triapine sensitizes GBM cells to radiation and independently induces synthetic lethality of GBM cells with CHK1 inhibition. Our findings suggest combining triapine with radiation or rabusertib may improve therapeutic outcomes in GBM.

Validation of Sentinel Lymph Node Biopsy Technique Using Dual Tracer Technique in Post Lumpectomy Early Breast Cancer Patients.

Sentinel lymph node biopsy (SLNB) is the gold standard for the evaluation of axilla in clinically node-negative early breast cancers. There is limited data on the role and efficacy of the same in the post lumpectomy scenario. This prospective interventional study was conducted over 1 year on 30 post lumpectomy pT1/2 cN0 patients. SLNB was performed by preoperative lymphoscintigram using technetium-labeled human serum albumin followed by intraoperative blue dye injection. Sentinel nodes were identified based on blue dye uptake and gamma probe and sent for intra operative frozen section. Completion axillary nodal dissection was performed in all cases. The primary end point was sentinel node identification rate and accuracy of nodal frozen section. Sentinel node identification rate was 86.7% (n = 26/30) for scintigraphy alone and 96.7% (n = 29/30) using combined method. Average sentinel nodal yield/patient was 3.6 (range 0-7). Maximum yield was seen for hot and blue nodes (1.86). Sensitivity (n = 9/9) and specificity (n = 19/19) of frozen section were 100% with a false negative rate of 0% (0/19). Demographic factors such as age, body mass index, laterality, quadrant, biology, grade, and pathological T stage had no impact on the identification rate. Sentinel lymph node using dual tracer has a high identification rate and a low false negative rate post lumpectomy. Age, body mass index, laterality, quadrant, grade, biology, and pathological T size had no impact on the identification rate.

Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Improved Photopyroelectric (PPE) Configuration for Thermal Effusivity Investigations of Porous Solids.

A new photopyroelectric detection configuration is proposed in order to measure the thermal effusivity of porous solids. Compared with the previously reported detection scheme this configuration makes use of a transparent window in front of the pyroelectric sensor. In such a way, the heat losses by convection at the sensor's irradiated surface are eliminated, and consequently, the conduction remains the only process responsible for the heat propagation in the whole detection cell. In the paper, the mathematical model for this new configuration is developed, with the main conclusion that the sample's thermal effusivity can be finally obtained via a fitting procedure with only two fitting parameters (instead of three as previously reported); in such a way, the possible degeneracy of the results is eliminated. The suitability of the method is demonstrated with application on some porous building materials and cellulose-based pressed powders.

Novel genosensor for probing DNA mismatches and UV-induced DNA damage: Sequence-specific recognition.

Human genome is continuously susceptible to changes that may lead to undesirable mutations causing various diseases and cancer. Vast majority of techniques has investigated the discrimination between base-pair mismatched nucleic acid, but many of these techniques are time-consuming, complex, expensive, and limited to the detection of specific type of dsDNA mismatches. In this study, we introduce a simple mix-and-read assay for the sensitive and cost-effective analysis of DNA base mismatches and UV-induced DNA damage using Hoechst genosensor dye (H258). This dye is a minor groove binder that undergoes a drastic conformational change upon binding with mismatch DNA. The difference in binding affinity between perfectly matched and mismatched DNA was studied for sequences at different base mismatch locations and finally, extended for the detection of dsDNA damage by UVC radiation in calf thymus DNA. In addition, a comparative DNA damage kinetic study was performed using H258 (minor groove binder) and EvaGreen (intercalating) dye to get insight on assay selectivity and sensitivity with dye binding mechanism. The result shows good reproducibility making H258 genosensor a cheaper alternative for DNA mismatch and damage studies with possibility of extension for in-vitro detection of hot spots of DNA mutations.

Investigating stigma during the COVID-19 pandemic: Living conditions, social determinants and experiences of infection among employees at a tertiary referral cancer centre.

AIM: Healthcare workers (HCWs) have reported negative social experiences during the COVID-19 pandemic; however, this data is largely from medical personnel. We examined living conditions, social determinants, and experiences during the COVID-19 pandemic among all cadres of employees who had recovered from COVID-19 at a tertiary referral cancer hospital in India. METHODS: We conducted a mixed methods study combining a questionnaire-based survey followed by semi-structured interviews with open-ended questions, among hospital staff who recovered from COVID-19 between April and November 2020. We initially administered a 79-point survey to all participants; based on their responses, we used purposive sampling to identify 60 interview participants. The primary aim of the study was to examine the impact of socio-economic factors on experiences and potential stigma faced by staff during the COVID-19 pandemic. RESULTS: We surveyed 376 participants including doctors (10 %), nurses (20 %), support staff (29 %), administrators (18 %) and scientists/technicians (22 %). Of these, 126 (34 %) participants reported negative social experiences. Stigmatisation was lower among doctors compared to other professions, decreased in the second half of the study period, and was more among those living in less affluent surroundings. Interviews revealed 3 types of negative social experiences: neighbourhood tensions around restrictions of mobility, social distancing, and harassment. CONCLUSIONS: The first phase of the COVID-19 pandemic in India led to considerable negative social experiences among hospital employees, especially those lower in the socio-economic hierarchy, which was fuelled by restrictions imposed by the government and pressure on local neighbourhoods. POLICY SUMMARY: It is important to not just document and count stigma experiences during global pandemics, but also to examine sociologically the conditions under which and the processes through which stigma happens.

Reflecting the Quality Degradation of Engine Oil by the Thermal Diffusivity: Radiative and Nonradiative Analyses.

Ageing of engine oil is an important issue determining the engine life and performance. The present work attempts to delineate the ageing-induced changes in engine oil through the mode-mismatched dual-beam thermal lens (MMDBTL) technique and other conventional spectroscopic techniques. For the analyses, engine oil samples were collected after every 200 km of runtime. As the thermal diffusivity is related to the nonradiative deexcitation upon optical absorption, comprehensive radiative and nonradiative analyses were carried out. The Ultraviolet-Visible, Fourier transform infrared, and Nuclear magnetic resonance spectroscopic analyses point to the structural modification as a result of the breaking of the long-chain hydrocarbons into ketones, aldehydes, esters, and other compounds. This modifies the absorption pattern, which can also be understood from the nonlinear refractive index study using the Z-scan technique. The compositional variations associated with the degradation upon ageing, the length of the hydrocarbon chain, and the formation of newer molecules account for the enhancement of the thermal diffusivity revealed through the MMBDTL techniques. The complementary nature of the radiative and nonradiative emission is understood from the fluorescence study. Thus, the study reveals the possibility of thermal diffusivity measurement as an effective tool for the quality monitoring of engine oil.

Clinical Profile and Survival Outcome of Endometrial Cancer with p53 Mutation.

Clinicopathologic classification of endometrial cancer imperfectly reflects the tumor biology. Pathologic categorization - especially in high-grade tumors - results in an imprecise estimation of the risk of disease, recurrence, and death. Molecular subtyping is emerging as the standard of care in diagnosis and treatment of endometrial cancers. Molecular markers are important prognostic factors in tumor dissemination and early recurrence of endometrial cancers. TP53 mutation is an important prognostic factor for both serous and endometrioid cancers. The study aims to compare the clinical profile and overall survival of endometrial cancers with and without p53 mutation. Sixty-three patients who underwent surgical staging for carcinoma endometrium were included in the study.TP53 mutation status was determined based on p53 expression by immunohistochemistry (IHC) as a p53 wild or p53 mutant type. Data were analyzed for the clinical profile, p53 mutation status on IHC, histological pattern, tumor grade, stage of the disease, lymph node spread, recurrence pattern, treatment received, 2-year disease-free survival, and overall survival. Recurrence was noted in 12.7% patients after 2-year follow-up, of which 75% patients had p53 mutation. Significant association was seen between p53 expression and high-grade tumors, stage, cervical involvement, and adnexal involvement. The 2-year overall survival of the p53 wild type was 97.2% and the p53 mutant type was 91.7%. The 2-year disease-free survival for the p53 wild type was 94.3% and the disease-free survival of the p53 mutant variety was 83.5%. The 2-year disease-free survival for endometrioid carcinoma with p53 wild type was 100% and p53 mutant variety was 86.2% (p value 0.033). About 15.9% (10) patients were reassigned to the high-risk group needing chemotherapy and radiation according to the ESGO ESTRO 2021 consensus classification, due to their p53 mutation status. IHC to assess somatic p53 mutation may be done in endometrial biopsies irrespective of their histology. This may help to identify that the aggressive tumors thereby help in tailoring surgery, planning adjuvant treatment, and follow-up.

A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer.

PURPOSE: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. PATIENTS AND METHODS: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. RESULTS: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. CONCLUSIONS: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Two novel "release-on-demand" fluorescent biosensors for probing UV-induced DNA damage induced in single stranded and double stranded DNA: Comparative study.

Light in the UVC spectral region damages both single-strand (ssDNA) and double-strand DNA (dsDNA), and contributes to the formation of mutagenic photoproducts. In-vivo studies show greater damage for ssDNA compared to dsDNA. However, excited-state spectroscopy shows that dsDNA has longer excited-state lifetime than ssDNA, which increases the probability of damage for dsDNA. However, lack of a direct comparison of in-vitro ssDNA and dsDNA damage rates precludes the development of a model that elucidates the molecular factors responsible for damage. In this work, two novel sensitive "release-on-demand" biosensors are developed for the selective probing of DNA-damage and comparing the rate of DNA damage in ssDNA and dsDNA. The two biosensors involve the use of EvaGreen and Hoechst dyes for the sensitive probing of DNA-damage. The results show that ssDNA is damaged at a faster rate than dsDNA in the presence of UVC light (200-295 nm). Furthermore, we examined the effect of G/C composition on the damage rate for mostly A/T ssDNA and dsDNA oligonucleotides. Our results show that DNA damage rates are highly dependent on the fraction of guanines in the sequence, but that in-vitro dsDNA always exhibits an overall slower rate of damage compared to ssDNA, essentially independent of sequence.

Transglottic intralaryngeal papillary thyroid carcinoma.

BACKGROUND: Malignant change of intralaryngeal ectopic thyroid tissues to papillary thyroid cancer is extremely rare. METHOD: A case that was successfully managed with a conservation surgery of the larynx and an interval total thyroidectomy is presented. CONCLUSION: High index of suspicion and optimised surgery yields the best outcome as demonstrated in the description.

Outcomes of COVID-19 and risk factors in patients with cancer.

Patients with cancer are at higher risk for adverse coronavirus disease 2019 (COVID-19) outcomes. Here, we studied 1,253 patients with cancer, who were diagnosed with severe acute respiratory syndrome coronavirus 2 at a tertiary referral cancer center in India. Most patients had mild disease; in our settings, recent cancer therapies did not impact COVID-19 outcomes. Advancing age, smoking history, concurrent comorbidities and palliative intent of treatment were independently associated with severe COVID-19 or death. Thus, our study provides useful insights into cancer management during the COVID-19 pandemic.

EGFR Mutations in Head and Neck Squamous Cell Carcinoma.

EGFR is a prototypical receptor tyrosine kinase that is overexpressed in multiple cancers including head and neck squamous cell carcinoma (HNSCC). The standard of care for HNSCC remains largely unchanged despite decades of research. While EGFR blockade is an attractive target in HNSCC patients and anti-EGFR strategies including monoclonal antibodies and kinase inhibitors have shown some clinical benefit, efficacy is often due to the eventual development of resistance. In this review, we discuss how the acquisition of mutations in various domains of the EGFR gene not only alter drug binding dynamics giving rise to resistance, but also how mutations can impact radiation response and overall survival in HNSCC patients. A better understanding of the EGFR mutational landscape and its dynamic effects on treatment resistance hold the potential to better stratify patients for targeted therapies in order to maximize therapeutic benefits.

Investigation of nucleic acid damage induced by a novel ruthenium anti-cancer drug using multiple analytical techniques: Sequence specificity and damage kinetics.

Cis-diacetonitrilo-bis(bipyridine) ruthenium(II) chloride is a recently introduced cis-platin analogue that has anti-cancer properties with lower side effects. However, the sequence dependence of its DNA damaging mechanism is unclear. Here, we present a simple, sensitive, multiplexed mix-and-read assay for ascertaining the molecular mechanism of DNA damage induced by the studied ruthenium complex (Ru-complex). The damage kinetics and sequence specificity for the Ru-complex induced DNA damage are examined by studying the induced damage in various oligonucleotide sequences by EvaGreen-DNA intercalator probe. High-through-put measurements were established using a 96-well microplate platform that allows multiple sequences to be measured simultaneously. The results show that the extent of damage increases with an increasing number of guanines, with considerable amount of damage at GA, GT and GC sites, in particular. Furthermore, the interaction of Ru-complex with DNA was confirmed using thermal analysis and MALDI-TOF-MS. Results indicate that the activated Ru-complex preferentially binds via both mono- and di-adduct formation at G and GG sites, respectively. Moreover, the developed method was successfully applied for the determination of the potency of the studied Ru-complex to induce DNA damage in K-Ras and N-Ras family of genes, one of the most common oncogenic events in cancer.

Successful Treatment of Late Isolated Bone Metastasis in a Patient with Bilateral Retinoblastoma Using an Unconventional Method.

Though survival in bilateral retinoblastoma (RB) has improved due to advancement in diagnostics and treatment modalities, children require long-term follow-ups for recurrence and second malignancies. We report a case of bilateral RB in a 7-month-old baby who was treated with chemotherapy, transpupillary thermotherapy, and periocular carboplatin for both eyes following which there was complete regression of tumour. Six and a half years after treatment, the child presented with metastatic recurrence of tumour in the left ulna. He was treated successfully with chemotherapy, extracorporeal radiation and reimplantation therapy. A less aggressive treatment approach for isolated bone relapse may be considered in selected cases.

ANETT: PhAse II trial of NEoadjuvant TAK-228 plus Tamoxifen in patients with hormone receptor-positive breast cancer.

INTRODUCTION: Neoadjuvant endocrine therapy is often utilized to downstage Estrogen Receptor-positive (ER+) breast cancer prior to surgery. However, this approach is sometimes met with endocrine resistance mechanisms within the tumor. This trial examines the safety and efficacy of tamoxifen in combination with an mTORC1/2 inhibitor, TAK-228, in the neoadjuvant treatment of ER+ breast cancer. METHODS: In this single-arm, open-label trial, pre- and post-menopausal women were enrolled to receive neoadjuvant tamoxifen (20 mg daily) with TAK-228 (30 mg weekly) for 16 weeks prior to surgery. Patient had tissue sampling at baseline, week 6, and week 16. The primary endpoint was change in Ki-67 from baseline to 6 weeks. The toxicity, change in tumor size, pathologic complete response rate, PEPI score, and baseline Oncotype Dx score were also assessed. RESULTS: Twenty-eight women were enrolled on the trial, and 25 completed the entire study course. The combination of tamoxifen and TAK-228 resulted in a significant reduction in Ki-67 from 18.3 to 15.2% (p = 0.0023). The drug was also found to be safe and tolerable. While nausea and hyperglycemia were common side effects, these were manageable. The tumor size also significantly decreased with the treatment, with a median decrease of 0.75 cm (p < 0.0001). There were no pathologic complete responses. CONCLUSION: Tamoxifen and TAK-228 was safe and well tolerated neoadjuvant treatment for ER+ breast cancer, preliminary evidence of activity with significant reduction in both Ki-67 and tumor size, warranting further evaluation in a larger study.