Dual control of dopamine in Drosophila myeloid-like progenitor cell proliferation and regulation of lymph gland growth.

In Drosophila, definitive haematopoiesis takes place in a specialized organ termed "lymph gland". It harbours multi-potent stem-like blood progenitor cells whose development controls overall growth of this haematopoietic tissue and formation of mature blood cells. With respect to its development, neurotransmitters have emerged as potent regulators of blood-progenitor cell development and function. In this study, we extend our understanding of neurotransmitters and show that progenitors are self-sufficient with regard to synthesizing dopamine, a well-established neurotransmitter. These cells also have modules for dopamine sensing through the receptor and transporter. We found that modulating expression of these components in progenitor cells affected lymph gland growth, which suggested growth-promoting function of dopamine in blood-progenitor cells. Cell-cycle analysis of developing lymph glands revealed an unexpected requirement for intracellular dopamine in moderating the progression of early progenitor cells from S to G2 phase of the cell cycle, while activation of dopamine receptor signalling later in development regulated their progression from G2 and entry into mitosis. The dual capacity in which dopamine operated, first intracellularly to coordinate S/G2 transition and later extracellularly in G2/M transition, was critical for the growth of the lymph gland. Overall, the data presented highlight a novel non-canonical use of dopamine in the myeloid system that reveals an uncharacterized function of intracellular dopamine in cell-cycle phasing with outcomes on haematopoietic growth and immunity as well.

Lack of racial differences in clinical outcomes of breast cancer patients receiving neoadjuvant chemotherapy: a single academic center study.

PURPOSE: To examine the association between race and clinical outcomes (pathological complete response [pCR]; recurrence-free survival [RFS], and overall survival [OS]) in patients diagnosed with triple-negative (TNBC) or HER2-positive breast cancer treated with neoadjuvant chemotherapy (NAC). METHODS: Patients who self-identified as non-Hispanic white (NHW) or non-Hispanic Black (NHB) and were diagnosed with Stage I-III TNBC (n = 171 including 124 NHW and 47 NHB) and HER2-positive (n = 161 including 136 NHW and 25 NHB) breast cancer who received NAC from 2000 to 2018 at Roswell Park Comprehensive Cancer Center were included. Associations of race with pCR and survival outcomes were evaluated using logistic and Cox regression models, respectively. RESULTS: There was no statistically significant difference in pCR between NHB and NHW patients with TNBC (31.9 vs 29.8%; OR: 1.11, 95% CI 0.54-2.29) or HER2-positive breast cancer (36.0 vs 39.7%; OR: 0.87, 95% CI 0.36-3.11). After controlling for potential confounders, including age, stage, treatment regimens, insurance status, and comorbidities, no statistically significant difference in OS or RFS was observed between NHB and NHW patients within either subtype. CONCLUSION: TNBC or HER2-positive breast cancer patients treated at a single academic center in Buffalo, NY, showed similar outcomes independent of patients' race. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography, and clinical outcomes are warranted.

New Insights into Mechanisms of Immune Checkpoint Inhibitor-Induced Cardiovascular Toxicity.

PURPOSE OF REVIEW: The review aims to summarize the present knowledge about cardiovascular toxicities associated with immune checkpoint inhibitors (ICI) and dissect underlying mechanism associated with individual cardiovascular toxicity. RECENT FINDINGS: Widespread use of ICI therapy has allowed for increasing recognition of a wide spectrum of immune-related adverse events that leave all organ systems vulnerable. Immune-mediated cardiovascular toxicities, initially thought to be rare, are more often being reported and present considerable challenges due to their non-specific clinical presentation, potential to have a fulminant progression, and overlap with other cardiovascular and general medical illnesses. Myocarditis is the most common manifestation of ICI-associated cardiovascular toxicity. Pericardial diseases, vasculitis, Takotsubo syndrome, conduction abnormalities, and destabilization of atherosclerotic lesions constitute other significant adverse events. At this stage, mechanisms underlying fundamental biology of cardiac toxicity have not been studied comprehensively and there remain gaps of knowledge in the current literature concerning the underlying pathomechanisms. It is hypothesized that immune-mediated myocarditis is a result of an exaggerated adaptive immune response against shared epitopes in the myocardium and tumor cells. Further, underlying mechanism of other cardiovascular toxicities is still unclear, further compounded by sparsity of epidemiological data. It is paramount to understand the mechanisms behind ICI-induced cardiovascular toxicities to develop appropriate treatment and prevention strategies and minimize the morbidity and mortality of cancer patients undergoing ICI therapy.

Outcomes of De Novo Oligometastatic Breast Cancer Treated With Surgery of Primary and Metastasis Directed Radiotherapy.

OBJECTIVES: With sensitive imaging for breast cancer, the question arises whether present-day oncologists treat dOMBC with palliative systemic therapy (ST), which, a few years earlier, would have been treated with curative intent. We retrospectively analyzed outcomes of dOMBC treated with curative intent using a combination of surgery, metastasis-directed radiotherapy (RT), and adjuvant/neoadjuvant ST and have also explored the possible role of total lesional glycolysis of metastases and p53 immunohistochemistry in predicting outcomes. METHODS: Data were collected from a prospectively maintained database using electronic medical records and Radiation Oncology Information System. In the study, dOMBC was defined as up to 3 metastatic sites, all amenable to treatment with ablative RT and primary and axillary disease amenable to curative surgery. Patients were treated with surgery, ST, and RT. RESULTS: Patients underwent either breast conservation surgery or modified radical mastectomy. Patients were treated with 6 to 8 cycles of chemotherapy in the neoadjuvant and/or adjuvant setting. Hormone receptor-positive patients received either tamoxifen or aromatase inhibitors. Trastuzumab was offered to Her-2-neu receptor-positive patients. RT included locoregional RT and metastases-directed ablative body RT. The median progression-free survival was 39 months (95% CI: -28.7 to 50.1 mo). Two and 3 year estimated disease-free survival (DFS) was 79% and 60.5%, respectively. The median overall survival was not reached. The estimated 3-year overall survival was 87.3%. Total lesional glycolysis of metastases score and p53 status did not affect DFS. CONCLUSION: Combination treatment of surgery, metastases-directed ablative RT, and ST may provide prolonged DFS in dOMBC.

Comparison of smear layer removing efficacy of Cold Atmospheric Pressure (CAP) Plasma Jet with different chelating agents. An ex-vivo study.

The present study aimed to assess the effectiveness of different final irrigation regimens (Cold Atmospheric Pressure Plasma Jet, MTAD, and EDTA) in removing the smear layer from intra-radicular dentin using a Scanning Electron Microscope (SEM). Eighty-four mandibular premolars were prepared with ProTaper Universal hand files and were equally divided into four groups i.e. Normal saline (control), EDTA, MTAD and CAP Plasma Jet. Prepared samples in the control, EDTA and MTAD groups were irrigated with 5 milliliters of the irrigant, and it was retained for 2 min. In the CAP Plasma Jet group, the plasma plume was directed towards the canal lumen for 2 min. The smear layer removal of all the groups was evaluated at the coronal, middle and apical thirds. Statistical analysis was performed using Kruskal-Wallis test followed by Dunn's test. Evaluation by SEM showed that the smear layer removal ability of MTAD and EDTA were significantly better than CAP Plasma Jet (p < 0.05). While CAP Plasma Jet showed results comparable to EDTA in the coronal third. In the middle and apical third of the canal, its effect was comparable to the control group (p > 0.05). MTAD and EDTA aided in better smear layer removal than the CAP Plasma Jet in the coronal, middle, and apical third of the test samples. CAP Plasma jet performed better in the coronal third.

Pediatric extremity rhabdomyosarcoma treated with re-brachytherapy in recurrent setting.

Rhabdomyosarcomas (RMS) are pediatric soft-tissue sarcomas arising from immature mesenchymal cells that are intended to form striated skeletal muscles. Brachytherapy delivers high-dose of precised radiation to the target tissue with high conformity, sparing the nearby normal tissues, hence allowing dose escalation and reducing the likelihood of normal tissue toxicity. There is a scarcity of reports on the use of brachytherapy for extremity RMS. We report the case of pediatric extremity RMS treated with re-brachytherapy in recurrent setting. A 4-year-old boy diagnosed with RMS of right upper arm underwent local excision of the lesion. Postoperative magnetic resonance imaging showed suspicious residual lesion. Revision surgery followed by brachytherapy with 30 Gy in 10 fractions twice a day over 5 days was delivered. The child developed local recurrence after 12 months. Reexcision and re-irradiation with brachytherapy were done delivering 27 Gy in 9 fractions twice a day over 5 days. The child is disease-free 18 months posttreatment with no significant disparity in limb length suggestive of successful preservation of growth epiphysis. Re-irradiation with interstitial brachytherapy can be considered as an option for the treatment of recurrent pediatric extremity rhabdomyosarcoma, in conjunction with surgery and chemotherapy, despite treated previously with brachytherapy.

A randomized study for dosimetric assessment and clinical impact of bone marrow sparing intensity-modulated radiation therapy versus 3-dimensional conformal radiation therapy on hematological and gastrointestinal toxicities in cervical cancer.

Background: Cervical cancer requires multimodality therapy, resulting in acute toxicities. Intensity-modulated radiation therapy (IMRT) is postulated to spare bone marrow (BM) and bowel to reduce acute hematological and gastrointestinal (GI) toxicities of chemoradiotherapy. Patients and Methods: This is a prospective randomized phase III study enrolling patients with Stage IB to IVA cervical carcinoma in two arms receiving either three-dimensional conformal radiotherapy (3DCRT) or IMRT from December 2017 to December 2019. The primary objective was to compare the hematologic toxicities (Grade 2 or more neutropenia as the primary factor) and the secondary objectives were to compare GI toxicities, and dosimetric analysis for volumes of BM, and bowel irradiated. SPSS version 20 was used for all statistical calculations. Results: Eighty patients with histopathologically confirmed cervical cancer were randomized to receive IMRT or 3DCRT (40 in each arm). The median age of the patients was 56.5 (36-67) and 59.5 (37-68) years, respectively, in IMRT and 3DCRT arms. The median dose of external radiation was 50 Gy in 25 fractions, and of brachytherapy was 24 Gy in 3 fractions in both the arms. The incidence of grade ≥2 neutropenia was 42.5% and 15% in the 3DCRT and IMRT arms, respectively (P < 0.001). All patients received concurrent chemotherapy with cisplatin, with the median number of cycles being 5 (range 3-5) in both the arms. All five cycles of concurrent chemotherapy could be completed in 25 (62.5%) patients in the IMRT arm and 24 (60%) patients in the 3DCRT arm. Conclusions: IMRT significantly reduces acute hematologic and GI toxicities compared with 3DCRT with a better dosimetry profile.

Gender Differences in International Cardiology Guideline Authorship: A Comparison of the US, Canadian, and European Cardiology Guidelines From 2006 to 2020.

Background Women continue to be underrepresented in cardiology and even more so in leadership positions. We evaluated the trends and gender differences in the guideline writing groups of the American College of Cardiology/American Heart Association (ACC/AHA), Canadian Cardiovascular Society (CCS), and European Society of Cardiology (ESC) guidelines from 2006 to 2020. Methods and Results We extracted all guidelines authors from 2006 to 2020, assessed their gender from publicly available profiles, and compared differences based on subspecialties and specific societies. Stratified and trend analyses were performed using χ2 and average annual percentage change/average 5 year percentage change. A total of 80 ACC/AHA (1288 authors [28% women]), 64 CCS (988 authors [26% women]), and 59 ESC (1157 authors [16% women]) guidelines were analyzed. A significant increase in inclusion of women was seen in ACC/AHA (12.6% [2006] to 42.6% [2020]; average annual percentage change, 6.6% [2.3% to 11.1%]; P=0.005) and ESC (7.1% [2006] to 25.8% [2020]; average annual percentage change, 6.6% [0.2% to 13.5%]; P=0.04), but the trend remained similar in CCS (20.6% [2006] to 36.3% [2020]; average annual percentage change, -0.1% (-3.7% to 3.5%); P=0.94), guideline authors. More women were coauthors in the ACC/AHA and ESC guidelines when women were chairs of guidelines. There was a persistent disparity of women among guideline authors for general cardiology and all subspecialties, except for pediatric cardiology and heart failure guidelines. The appointment of women authors as a chair was significantly low in all societies (22.4% [ACC/AHA], 16.9% [CCS], and 7.2% [ESC]; P=0.008). Conclusions There is a significant disparity in the inclusion of women on all national guideline committees, in addition to serving as a chair of cardiology guidelines. Further advocacy is required to promote equity, diversity, and inclusion in our cardiology guidelines globally.

Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs. METHODS: We retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors. RESULTS: Among patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes. CONCLUSIONS: Routine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.

A Rare Case of Missing Primary in Metastatic Renal Cell Carcinoma.

Renal cell carcinoma (RCC) can present with a myriad of clinical symptoms and signs. It is also notorious for its initial presentation with distant metastasis. We report a case of a 42-year-old male diagnosed with papillary RCC (PRCC) presenting with pleural and nodal metastases in the absence of a radiographically-detected tumor primary. PRCC was diagnosed on immunohistochemical analysis of the tissue from the pleura and mediastinal lymph nodes and confirmed by gene expression profiling studies. As per treatment guidelines for metastatic RCC, the patient was started on sunitinib with evidence of disease progression after two cycles and palliative care approach was recommended due to rapidly declining performance status. Prospective data on the optimal management of metastatic PRCC are lacking, but drugs used are similar to the treatment of clear cell carcinomas (vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors) and checkpoint inhibitors. Further molecular study of these rare tumors is warranted to detect drivers of oncogenesis and identify targets for therapeutic intervention.

Identification of Epidermal Growth Factor Receptor Tyrosine-Kinase Mutations in Non-small Cell Lung Cancer: Testing Platform Matters.

Personalized medicine using targeted therapies has revolutionized the management of non-small cell lung cancer (NSCLC) in the past decade. The discovery that sensitizing epidermal growth factor receptor (EGFR) mutations are predictive for therapeutic benefit from EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib marked the beginning of a new era in lung cancer therapeutics. Indeed, EGFR mutation testing is category A recommendation at the time of diagnosis for patients presenting with advanced-stage NSCLC. In our case, the original report of EGFR mutation testing using pyro-sequencing from the initial biopsy was reported out as wild-type/no mutation seen in the hot spots. However, the tumor had a long duration of response to erlotinib but later developed resistance, hence there was a high index of suspicion. Consequently, it was decided to retest the tumor with more sensitive technology. Next generation sequencing identified exon 19 deletion - a sensitizing mutation. This explained the excellent response on initiating erlotinib, however, exon 21 mutation was also reported which confers resistance to TKI. The case shows that test sensitivity can have a great impact on treatment decisions and if there is a high index of suspicion, initial testing and, or retesting using newer more sensitive technology should be considered.

Metabolic control of cellular immune-competency by odors in Drosophila.

Studies in different animal model systems have revealed the impact of odors on immune cells; however, any understanding on why and how odors control cellular immunity remained unclear. We find that Drosophila employ an olfactory-immune cross-talk to tune a specific cell type, the lamellocytes, from hematopoietic-progenitor cells. We show that neuronally released GABA derived upon olfactory stimulation is utilized by blood-progenitor cells as a metabolite and through its catabolism, these cells stabilize Sima/HIFα protein. Sima capacitates blood-progenitor cells with the ability to initiate lamellocyte differentiation. This systemic axis becomes relevant for larvae dwelling in wasp-infested environments where chances of infection are high. By co-opting the olfactory route, the preconditioned animals elevate their systemic GABA levels leading to the upregulation of blood-progenitor cell Sima expression. This elevates their immune-potential and primes them to respond rapidly when infected with parasitic wasps. The present work highlights the importance of the olfaction in immunity and shows how odor detection during animal development is utilized to establish a long-range axis in the control of blood-progenitor competency and immune-priming.

Suspected Metformin-induced Cobalamin Deficiency Mimicking Thrombotic Thrombocytopenic Purpura.

Thrombotic thrombocytopenic purpura (TTP) can often be life threatening and requires timely diagnosis and prompt initiation of plasmapharesis. Cobalamin deficiency can closely mimic TTP and distinguishing between the two diseases can prove to be a diagnostic challenge. Previously, cobalamin-related pseudo-TTP has been associated with pernicious anemia, dietary insufficiency and hereditary disorders of cobalamin activation. Here in, we discuss the first case of suspected metformin-induced cobalamin deficiency causing pseudo-TTP. Our patient was a 36-year-old female with type 2 diabetes mellitus on metformin for eight years who presented with hemolytic anemia, thrombocytopenia, schistocytes and mild acute renal failure. The initial impression was TTP; however, further workup revealed very low serum cobalamin levels and elevated methylmalonic acid levels. Apart from metformin use, no other cause of cobalamin deficiency was identified. We recommended upper gastrointestinal endoscopy to definitively rule out pernicious anemia.

Combination of pembrolizumab and imatinib in a patient with double KIT mutant melanoma: A case report.

RATIONALE: The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations. PATIENT CONCERNS AND DIAGNOSIS: We report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I. INTERVENTIONS: She was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy. OUTCOMES: Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression. LESSONS: Treatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.

Clinical Outcomes after Transcatheter Aortic Valve Replacement in Cancer Survivors Treated with Ionizing Radiation.

BACKGROUND: Improved cancer survival in patients treated with thoracic ionizing radiation (XRT) has resulted in unanticipated surge of aortic stenosis. Transcatheter aortic valve replacement (TAVR) has revolutionized the management of severe aortic stenosis. However, long-term clinical outcomes in radiation-exposed cohorts undergoing TAVR are unknown. We compared the all-cause mortality and major adverse cardiac events (MACE) in patients with prior chest XRT (C-XRT) undergoing TAVR. METHODS: This is an observational cohort study in subjects who underwent TAVR for symptomatic severe aortic stenosis from 2012 to 2017 in a tertiary care referral center. We examined the all-cause mortality and MACE using cox proportional hazard analysis to identify the clinical predictors of survival in the cohort of patients who had a history of prior C-XRT for malignancy. RESULTS: Of the 610 patients who underwent TAVR for symptomatic severe aortic stenosis, 75 had prior C-XRT. The majority of C-XRT patients had prior breast cancer (44%) followed by Hodgkin's lymphoma (31%), with the median time from XRT to TAVR of 19.0 years. During a mean follow up of 17.1 months after TAVR, all-cause mortality was 17%. Those with prior C-XRT had higher all-cause mortality (XRT: 29%; non-XRT:15%, p<0.01) and MACE (XRT: 57%; non-XRT: 27%, p<0.001) after TAVR. Patients with prior XRT had a higher incidence of atrial fibrillation (XRT: 48 %; non-XRT: 2.4%, p<0.01) and high-grade heart block (XRT: 20%; non-XRT: 9.1%, p=0.007) requiring pacemaker implant after TAVR. On multivariate cox proportional hazard analysis, prior XRT (HR: 2.07, p=0.003), poor renal function (HR: 1.29, p<0.001) and post-operative anemia requiring transfusion (HR: 1.16, p:0.001) were the strongest predictors of reduced survival. CONCLUSIONS: Cancer survivors with prior C- XRT have higher incidence of all-cause mortality and MACE after TAVR. Careful patient selection and follow-up strategies are needed to improve outcomes.

High-dose-rate interstitial brachytherapy in recurrent head and neck cancer: an effective salvage option.

PURPOSE: High-dose-rate (HDR) interstitial brachytherapy has an established role in head and neck malignancies and offers good survival rates; however, there is scant data on improved local control (LC) and treatment-related complications in recurrent cases. We present our results in patients with recurrent head and neck cancers treated with HDR interstitial brachytherapy. MATERIAL AND METHODS: Twenty-five patients with recurrent head and neck cancers were treated with HDR interstitial brachytherapy using Iridium 192 between 2009 and 2016. Of these, 75% received radical brachytherapy, and 25% received external beam radiation therapy (EBRT) followed by brachytherapy boost. Treatment sites included oral cavity (15/25) and oropharynx (10/25). Median dose of 4.5 Gy was administered twice per day, with median total brachytherapy dose of 40.5 Gy in radical and 27 Gy for EBRT cases. RESULTS: With median follow-up of 25 months, 4 local recurrences were observed within first year of follow-up. Two-year local control and overall survival outcomes for the entire group were 75% and 68%, respectively. Local control rate with radical BRT vs. BRT as a boost following EBRT was found to be significant (2-year LCR 62% vs. 85%; p < 0.02). Dosimetric assessment revealed D90 - 4.08 Gy, V100 - 94.1%, V150 - 24.7%, and V200 - 10.1%. Xerostomia, altered taste, and dysphagia were the major complications commonly grade 1 and 2. Grade 3 toxicity was only 2%. Pre-treatment volume > 85 cc had a negative impact on overall survival (26 months vs. 12 months; p = 0.02), and interval time between primary and recurrence more than 15 months had an impact on the local control rate (p < 0.01). CONCLUSIONS: Results of HDR interstitial brachytherapy have shown acceptable local control and overall survival rates along with tolerable toxicities and morbidity in recurrent head and neck cancers.