ESR1 and p53 interactome alteration defines mechanisms of tamoxifen response in luminal breast cancer.

The canonical mechanism behind tamoxifen's therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I-III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy.

Update on Management of Ductal Carcinoma in Situ.

Ductal carcinoma in situ (DCIS) represents 18% to 25% of all diagnosed breast cancers, and is a noninvasive, nonobligate precursor lesion to invasive cancer. The diagnosis of DCIS represents a wide range of disease, including lesions with both low and high risk of progression to invasive cancer and recurrence. Over the past decade, research on the topic of DCIS has focused on the possibility of tailoring treatment for patients according to their risk for progression and recurrence, which is based on clinicopathologic, biomolecular and genetic factors. These efforts are ongoing, with recently completed and continuing clinical trials spanning the continuum of cancer care. We conducted a review to identify recent advances on the topic of diagnosis, risk stratification and management of DCIS. While novel imaging techniques have increased the rate of DCIS diagnosis, questions persist regarding the optimal management of lesions that would not be identified with conventional methods. Additionally, among trials investigating the potential for omission of surgery and use of active surveillance, 2 trials have completed accrual and 2 clinical trials are continuing to enroll patients. Identification of novel genetic patterns is expanding our potential for risk stratification and aiding our ability to de-escalate radiation and systemic therapies for DCIS. These advances provide hope for tailoring of DCIS treatment in the near future.

Real-world survival outcomes of immunotherapy for advanced non-small cell lung cancer: A single-center retrospective review.

BACKGROUND: Non-small cell lung cancer (NSCLC) is often diagnosed at an advanced stage. Clinical trials have demonstrated that first-line immunotherapy alone or in combination with chemotherapy improves overall survival. However, reports of survival outcomes in real-world settings are limited. We assessed survival in advanced NSCLC patients treated with immunotherapy alone or in combination with chemotherapy in first- or second-line at the Windsor Regional Cancer Program (WRCP) and compared it to existing literature. METHODS: We included patients diagnosed with stage IV NSCLC from January 2015 to December 2020 and treated with first-line chemoimmunotherapy (ChemoImmuno1), chemotherapy followed by immunotherapy (Chemo1), or immunotherapy followed by chemotherapy (Immno1) in our survival analysis. Patients with oncogene-addicted mutations were excluded. RESULTS: There were 160 patients of which 41.5% were female. Mean age was 68 years. Median overall survival from time of diagnosis was 474 days (95% CI: 249, 949) with an estimated 5-year survival of 11.1% (95% CI: 4.5, 21.3). Median OS in ChemoImmuno1 was 9.6 months, in Chemo1 was 19.2 months from time of diagnosis and 10.5 months from time of initiation of immunotherapy, and in Immuno1 was 18.4 months, respectively. Estimated survival at three years from time of diagnosis for ChemoImmuno1 was 17.6% and for Immuno1 was 17.9%. For Chemo1, from diagnosis it was 20.1% and from second-line therapy it was 15.4%. Survival outcomes were comparable to clinical trials and other studies. CONCLUSION: Real-world survival outcomes of immunotherapy for advanced NSCLC are comparable to the existing literature in this single center study.

Autoimmune anti-D in an RhD-positive young infant: Learning from a rare case.

BACKGROUND AND OBJECTIVES: Anti-D is usually immune in nature and is formed in individuals lacking D antigen or having variants/altered D phenotypes. In the Indian population, 93.8% are RhD positive, and R1 R1 is the commonest Rh phenotype. Here we report a rare and interesting case of autoimmune anti-D in an RhD-positive 3-month-old infant leading to warm autoimmune haemolytic anaemia. STUDY DESIGN AND METHODS: Auto-anti-D was detected serologically by immunohaematological techniques such as direct antiglobulin test, antibody detection and identification, dithiothreitol, enzyme treatment, antibody titration and elution. Molecular studies were performed to rule out genetic variants of RhD. RESULTS: Anti-D was confirmed in eluate and blood group post elution was B RhD positive. On genotyping using the Indian-specific RHD genotyping assay, the sample was found to be negative for the RHD*01W.150 (most common RhD variant in Indians) but positive for RHD exon 5 and RHD exon 10 along with glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The sample was further sequenced for RHD exons 1-10 by Sanger sequencing and found to be a wild type, thus, ruling out the presence of an RhD variant. CONCLUSION: This case is of interest because of the rare occurrence of autoimmune anti-D in an RhD-positive patient of such a young age (3 months). To the best of our knowledge, only two case reports have been published on autoimmune anti-D in infancy (in 1961 and 1964).

Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline.

PURPOSE: To provide evidence-based recommendations to practicing clinicians on the management of patients with small-cell lung cancer. METHODS: An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2022. Outcomes of interest included response rates, overall survival, disease-free survival or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 95 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Evidence-based recommendations were developed to address systemic therapy options, timing of therapy, treatment in patients who are older or with poor performance status, role of biomarkers, and use of myeloid-supporting agents in patients with small-cell lung cancer.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

NCCN Guidelines® Insights: Breast Cancer Screening and Diagnosis, Version 1.2023.

The NCCN Guidelines for Breast Cancer Screening and Diagnosis provide health care providers with a practical, consistent framework for screening and evaluating a spectrum of clinical presentations and breast lesions. The NCCN Breast Cancer Screening and Diagnosis Panel is composed of a multidisciplinary team of experts in the field, including representation from medical oncology, gynecologic oncology, surgical oncology, internal medicine, family practice, preventive medicine, pathology, diagnostic and interventional radiology, as well as patient advocacy. The NCCN Breast Cancer Screening and Diagnosis Panel meets at least annually to review emerging data and comments from reviewers within their institutions to guide updates to existing recommendations. These NCCN Guidelines Insights summarize the panel's decision-making and discussion surrounding the most recent updates to the guideline's screening recommendations.

Challenges in the transfusion management of a 15-month-old pediatric patient with Bombay blood group phenotype.

Bombay blood group phenotype is often mistyped as O group which can lead to hemolytic transfusion reactions. There are a very few case reports of Bombay blood group phenotype in pediatric age group. Herein, we report an interesting case of Bombay blood group phenotype in a fifteen-month-old pediatric patient who presented with features of raised intracranial pressure and required an emergency surgery. The Bombay blood group was detected on detailed immunohematology work up which was further confirmed by molecular genotyping. The challenges faced in developing countries for transfusion management of such a case have been discussed.

Selective surgical excision of high-risk lesions.

Intraductal papilloma, flat epithelial atypia, radial scar, atypical lobular hyperplasia, and lobular carcinoma in situ have historically been referred to as high-risk lesions and managed with routine surgical excision after diagnosis on core needle biopsy. The misnomer high-risk stems from high rates of upgrade to malignancy reported in historic literature. However, recent studies have found much lower upgrade rates, <2%, than previously thought. These findings are explained by advances in imaging technology, larger-bore biopsy needles, and emphasis on radiology-pathology concordance. Concordant lesions have a low upgrade risk and can be managed with radiographic and clinical surveillance instead of surgical excision. Surgical de-escalation is feasible for many of these lesions with careful multidisciplinary review and a detailed risk-benefit discussion with patients.

Phenotyping and Genotyping of HNA: Prevalence, Risk of Alloimmunization, and HNA Incompatibilities in Indians.

Background: Antibodies to human neutrophil alloantigens (HNA) are involved in the pathophysiology of several clinical conditions including transfusion-related acute lung injury (TRALI), alloimmune and autoimmune neutropenia, and febrile nonhemolytic transfusion reactions leading to neutropenia. The cognate antigens are polymorphic structures expressed on several glycoproteins on the neutrophils, i.e., antigens HNA-1a, -1b, -1c, and -1d on Fc-γ-receptor IIIb; HNA-2 on CD177; HNA-3a and -3b on choline transporter-like protein 2; HNA-4a and -4b on CD11b/αM subunit of the αMß2-integrin (CD11b/CD18, Mac-1, CR3); and HNA-5a and -5b on αL-subunit (CD11a) of the αLß2 integrin (CD11a/CD18), leukocyte function associated molecule (LFA)-1. Currently, there is a lacuna of diagnostic methods for detection of HNA in India. This study aimed to determine the HNA frequencies in Indians, estimate the risk of alloimmunization, and prepare typed neutrophil panels, which can be used to detect HNA antibodies in neutropenia cases. Material and Methods: EDTA blood samples were collected from random 1,054 blood donors. HNA-2 was phenotyped on fresh EDTA samples using FITC labelled monoclonal anti-CD177 by flowcytometry. HNA-1 (FCGR3B) genotyping was carried out by DNA sequencing and PCR-RFLP. Antigens of HNA-3 (SLC44A2) and HNA-5 (ITGAL) were genotyped by PCR-RFLP using TaqαI and Bsp1286I restriction enzymes, respectively, while HNA-4 (ITGAM) was genotyped by PCR-SSP. Results: Allele frequencies of FCGR3B*01, FCGR3B*02, and FCGR3B*03 were found to be 0.433, 0.444, and 0.087, respectively. FCGR3B*01+*02+*03- was the most common genotype (33.78%). Ten individuals showed deficiency of FCGR3B individuals, while 23 showed hyperexpression, i.e., FCGR3B*01+*02+*03+. FCGR3B*04and *05 occurred with a frequency of 0.002 and 0.024. HNA-2 was found to be a high frequency antigen occurring in 98.8% population. Four percent individuals showed atypical expression of CD177 on their neutrophils. Allele frequencies of SLC44A2*01 and SLC44A2*02were 0.812 and 0.188, respectively, and that of ITGAM*01, ITGAM*02, ITGAL*01, and ITGAL*02 were 0.9546, 0.0454, 0.2372, and 0.7628, respectively. Conclusion: This is the first study in India to report the frequencies of HNA among blood donors. Typed neutrophil panels identified in the present study will enable us to investigate suspected cases of immune neutropenia in future.

Longitudinal Sedentary Time and Symptoms in Breast Cancer Patients during Chemotherapy Using Ecological Momentary Assessment.

PURPOSE: To examine the relationship between daily fluctuations in symptoms and sedentary behavior (SB) during chemotherapy (CT) for breast cancer. METHODS: Breast cancer patients ( N = 68, M age = 48.5 ± 10.4 yr) undergoing CT wore an activity monitor on their hip to assess daily SB and completed prompts assessing symptoms (affect, anxiety, depression, fatigue, pain, and physical and cognitive functioning) for 10 consecutive days (3 d pre-CT, day of, and 6 d post-CT) at the beginning, middle and end cycles of CT. Mixed models assessed the bidirectional between-person (BP) and within-person (WP) associations of current day symptoms with minutes of SB measured on 1) the same day and 2) the next day, controlling for relevant covariates. RESULTS: Within person same-day results revealed a significant association between affect, anxiety, fatigue, physical functioning, pain, and cognitive functioning and same-day SB. Worse than average symptom ratings on a given day were associated with more SB that day. There was a significant WP relationship between previous-day anxiety, depression, and physical function and next-day SB (i.e., worse than average symptom ratings the previous day were associated with more SB the next day). Within person same-day results revealed a significant association between same-day SB and affect, anxiety, fatigue, pain, physical functioning, and cognitive functioning. The WP relationships were significant for previous-day SB and next-day affect and pain (i.e., higher than average SB associated with lower ratings). Relationships persisted when controlling for moderate-to-vigorous physical activity. There were no significant BP results. CONCLUSIONS: Higher symptom ratings were associated with increased SB and higher SB was associated with worse symptoms. Future work should identify SB reduction intervention approaches tailoring to daily symptom burden during CT for breast cancer.

Ergonomics Workshop Improves Musculoskeletal Symptoms in General Surgery Residents.

INTRODUCTION: Poor operative ergonomics can lead to muscle fatigue and injury. However, formal ergonomics education is uncommon in surgical residencies. Our study examines the prevalence of musculoskeletal (MSK) symptoms, baseline ergonomics knowledge, and the impact of an ergonomics workshop in general surgery residents. METHODS: An anonymous voluntary presurvey and postsurvey was distributed to all general surgery residents at a single academic residency, assessing resident characteristics, MSK symptoms, and ergonomic knowledge before and after an ergonomics workshop. The workshop consisted of a lecture and a personalized posture coaching session with a physiatrist. RESULTS: The presurvey received 33/35 (94%) responses. Of respondents, 100% reported some degree of MSK pain. Prevalence of muscle stiffness and fatigue decreased with increasing height. Females reported higher frequencies of MSK pain (P = 0.01) and more muscle fatigue than males (100% versus 73%, P = 0.03). All residents reported little to no ergonomics knowledge with 68% reporting that ergonomics was rarely discussed in the operating room. The postsurvey received 26/35 (74%) responses. Of respondents, 100% reported the workshop was an effective method of ergonomics education. MSK symptom severity improved in 82% of residents. Reports that ergonomics was rarely discussed in the operating room significantly decreased to 22.8% of residents (P < 0.01). CONCLUSIONS: Surgical resident ergonomics knowledge is poor and MSK symptoms are common. Resident characteristics are associated with different MSK symptoms. Didactic teaching and personalized posture coaching improve ergonomics knowledge and reduce MSK symptom severity. Surgical residencies should consider implementing similar interventions to improve resident wellbeing.

Impairing proliferation of glioblastoma multiforme with CD44+ selective conjugated polymer nanoparticles.

Glioblastoma is one of the most aggressive types of cancer with success of therapy being hampered by the existence of treatment resistant populations of stem-like Tumour Initiating Cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole-based Conjugated Polymer Nanoparticles (CPNs) with an average diameter of 109 nm. CPNs were designed to include fluorescein-conjugated Hyaluronic Acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake of HA-CPNs in CD44 positive GBM-patient derived cultures. Interestingly, we found that uptake alone regulated the levels and signaling activity of the CD44 receptor, decreasing stemness, invasive properties and proliferation of the CD44-TIC populations in vitro and in a patient-derived xenograft zebrafish model. This work proposes a novel, CPN- based, and surface moiety-driven selective way of targeting of TIC populations in brain cancer.

Pattern of Treatment Initiation and Outcomes for Patients With Metastatic Non-small Cell Lung Cancer in Ontario.

INTRODUCTION: The impact of diagnosis and treatment delay on outcomes in advanced non-small cell lung carcinoma (NSCLC) is not well understood. In this study, we examined the effect of the length of time to the first chemotherapy treatment initiation and the other factors affecting overall survival. METHODS: This retrospective study used data from the Institute of Clinical Evaluative Sciences and identified 4520 patients in Ontario who were diagnosed with stage IV NSCLC between 2007 and 2016, treated using chemotherapy. We adjusted the analysis for location (rural vs urban), gender, distance from the nearest cancer center, first chemotherapy treatment used, income, and age.  Results: Type of the chemotherapy, length of time to the first treatment, and distance from the nearest cancer center had a statistically significant impact on survival. Paclitaxel was associated with decreased risk of death compared to vinorelbine (Hazard Ratio (HR)=0.835, 95%CI 0.753-0.925), gemcitabine (HR=0.916, 95%CI 0.998-0.826), and docetaxel (HR=0.771, 95%CI 0.994-0.513). Every additional 10 km distance from the nearest cancer center was associated with a 0.5% increased risk of death (HR=1.005, 95%CI 1.000-1.010). A longer time to the first treatment was associated with increased survival. In fact, every 10 days increase in wait time was associated with a 0.5% decrease in the risk of death (HR=0.995, 95%CI 0.993-0.998).  Conclusion: Chemotherapy treatment using paclitaxel and living closer to the cancer center is associated with better survival. A longer time between diagnosis and treatment leading to better survival could perhaps be explained by patients on the "sicker" end of the spectrum receiving treatment sooner.

Using ecological momentary assessment to understand associations between daily physical activity and symptoms in breast cancer patients undergoing chemotherapy.

PURPOSE: Understanding real-time relationships between physical activity (PA) and symptoms during chemotherapy (CT) could have important implications for intervention. This study used ecological momentary assessment to examine the relationship between objective PA and symptoms during CT. METHODS: Breast cancers patients (n = 67; Mage = 48.6 (SD = 10.3)) participated in data collection at three time points during CT: beginning, middle, and end. At each time point, participants answered four prompts assessing symptoms and wore an accelerometer for 10 days (3 days pre-CT, day of CT, and 6 days post-CT). Multilevel linear regression models examined the between- and within-person associations between moderate to vigorous (MVPA) and light-intensity physical activity (LPA) and same and next-day symptom ratings controlling for covariates. RESULTS: On days when individuals engaged in more LPA or MVPA, separately, they reported improved affect, anxiety, fatigue, physical functioning (walking and activities of daily living), pain, and cognition that day (p < 0.001 for all). Findings were consistent for next-day symptom ratings with the exception that only previous day LPA was related to next-day fatigue and neither LPA nor MVPA were related to next-day cognition (p < 0.001 for all). No between-person effects were found. CONCLUSIONS: Within person higher than usual PA on a given day, regardless of intensity, is associated with improved symptoms ratings on the current and next day. IMPLICATIONS FOR CANCER SURVIVORS: Encouraging breast cancer patients undergoing CT to engage in daily PA could help manage CT-associated symptoms.

Chemotherapy during the last 30 days of life and the role of palliative care referral, a single center experience.

BACKGROUND: Chemotherapy use closer to the end of life is a marker of poor-quality care. There are now multiple studies and local reviews addressing this issue. Understanding the practice locally will give valuable insight and opportunity for improvement. METHODS: The study is a retrospective chart review of patients on chemotherapy at the Windsor Regional Cancer Center who died between April 1st, 2016 to December 31st, 2018. Information on demographics, type of cancer, type, intent and route of chemotherapy, line of chemotherapy, referral to hospice and palliative care services was collected. RESULTS: A total of 681 patients on chemotherapy died between April 1st, 2016 to Dec 13th, 2018. Of these, 119 (17.4 %) died within 30 days following chemotherapy. Chemotherapy was parenteral (Intravenous and Subcutaneous) for the majority (75.2%) of the patients. Most (66.4%) of the patients died of disease progression. Intent for chemotherapy was palliative in 85% of patients, adjuvant/neoadjuvant in 6.6% and curative in 8.4% of the patients. Chemotherapy was 1st, 2nd, 3rd line or more in 67.4%, 21.3% and 11.3% of the patients respectively. The type of chemotherapy was conventional in 74.3% of patients and targeted/immunotherapy in 25.7% of patients. Of the variables studied, lack of palliative referral and having lung cancer or melanoma were significantly associated with higher risk of getting chemotherapy within the last 30 days of life. The odds of getting chemotherapy within the last 30 days of life was 0.35, 95% CI (0.24-0.53), P <0.001 for those who were referred to palliative care. On the other hand, the odds of getting chemotherapy were 4.18, 95% CI (1.17-13.71), P = 0.037 and 2.21, 95% CI (1.24-4.01), P = 0.037 for those with melanoma and lung cancer respectively. In addition, those with early referral to palliative care (90 days or more prior to death) were least likely to receive chemotherapy within the last 30 days of life. CONCLUSION: Administration of chemotherapy within the last 30 days of life could cause unnecessary suffering to patients and cost to society. Early referral to palliative care was significantly associated with reduced risk of getting chemotherapy within the last 30 days of life in this study. Prospective study is recommended to further investigate the role of early palliative referral on use of chemotherapy during the last 30 days of life.

A prospective phase II clinical trial identifying the optimal regimen for carboplatin plus standard backbone of anthracycline and taxane-based chemotherapy in triple negative breast cancer.

Addition of platinums to combination chemotherapy for triple negative breast cancer (TNBC) has shown efficacy and is increasingly accepted in the clinic, yet optimal delivery is unknown. A prospective clinical trial with TNBC patients was conducted to determine the optimal chemotherapy regimen to deliver carboplatin with standard dose dense ACT. Tissue microarray was conducted to isolate markers indicative of response to treatment. 90 TNBC patients were enrolled onto our trial. The most successful version placed the carboplatin on the second and final paclitaxel treatment with liberal hematological parameters. Our final regimen had the lowest grade 3 or 4 toxicities, no delays, no dose reductions of carboplatin, and 32% reduction in paclitaxel doses. Stage I (AJCC7) patients did well with carboplatin-based chemotherapy with zero relapse rate. Reduction in protein levels of androgen receptor and PD-L1 were found to be potential indicators of patient relapse. We have optimized a protocol for the addition of carboplatin to standard of care chemotherapy in TNBC patients. Early data indicates reduced protein levels of androgen receptor and PD-L1 as indicators of response to treatment.Trial registration This trial was registered at Canadian Cancer Trials. http://www.canadiancancertrials.ca/.

Molecular characterization of rare D--/D-- variants in individuals of Indian origin.

BACKGROUND: Rh antigens are critical in haemolytic disease of the foetus and newborn (HDFN). The D-- phenotype is a rare blood group characterised by the lack of expression of C, c, E and e antigens at the surface of red blood cells because of mutations in both RHCE alleles inactivating the expression of a "normal" protein. The aim of the study was to determine the molecular basis of D-- individuals of Indian origin. MATERIALS AND METHODS: Ten Rh D-positive postnatal women who had produced antibodies against all Rh antigens, except D, leading to HDFN and foetal loss, were investigated. Extensive serological and molecular (polymerase chain reaction [PCR] using sequence-specific primers), quantitative multiplex PCR of short fluorescent fragments (QMPSF), and Sanger sequencing analyses were carried out. RESULTS: Serological testing with anti-C, anti-c, anti-E, and anti-e reagents showed absence of the four antigens in all ten index cases, as well as in three siblings. Flow cytometry indicated absence of these antigens with a typical exalted expression of the D antigen, thus confirming the rare D-- phenotype. Molecular analysis by QMPSF suggested homozygous CE-D hybrid alleles causing the D-- phenotype: RHCE-D(3-9)-CE (n = 11), RHCE-D(3-8)-CE (n=1), and RHCE-D(2-6)-CE (n=1). DISCUSSION: For the first time, we report the molecular basis of the D-- phenotype in the Indian population. Identification and characterisation of RHCE-null variants by molecular methods can help resolve transfusion-related problems in these individuals. Family studies of index cases helped to identify rare blood donors and offer counselling to females of child-bearing age on the complications involved in such pregnancies.