Using RNA interference targeting a nicotinic acetylcholine receptor subunit to counteract insecticide accommodation mechanisms: example of the ß1 subunit in the imidacloprid-accommodated American cockroach, Periplaneta americana.

Insecticide accommodation and resistance are limiting factors to the much-needed increase in agricultural production. Various physiological and cellular modifications, such as the changes of insecticide molecular targets, have been linked to these events. Thus, a previous study demonstrated that the imidacloprid accommodation set up by the cockroach Periplaneta americana after an exposure to a sublethal dose of this insecticide involves functional alterations of two nicotinic acetylcholine receptor (nAChR) subtypes. As RNA interference (RNAi) is one of the most promising strategies for controlling pest insects, we evaluated, in this study, the use of RNAi that targets the ß1 nAChR subunit to counteract the imidacloprid accommodation phenomenon in cockroaches. Interestingly, we showed that ingestion of dsRNA-ß1 increased the sensitivity to imidacloprid of accommodated cockroaches. Thus, we have demonstrated for the first time that RNAi that targets an nAChR subunit can counteract the accommodation mechanism to insecticide targeting nAChRs set up by an insect.

Use of double-stranded RNA targeting ß2 divergent nicotinic acetylcholine receptor subunit to control pea aphid Acyrthosiphon pisum at larval and adult stages.

BACKGROUND: In recent years, the use of the RNA interference technology (RNAi) has emerged as one of the new strategies for species-specific control of insect pests. Its specificity depends on the distinctiveness of the target gene sequence for a given species. In this work, we assessed in the pea aphid Acyrthosiphon pisum (A. pisum) the use of a double-stranded RNA (dsRNA) that targets the ß2 divergent nicotinic acetylcholine receptor (nAChR) subunit (dsRNA-ß2), which shares low sequence identity with other subunits, to control populations of this pest at different developmental stages. Because nAChRs are targeted by neonicotinoid insecticides such as imidacloprid, we also assessed the effect of dsRNA-ß2 coupled to this insecticide on aphid survival. Finally, because the effect of a control agent on beneficial insect must be considered before any use of new pest management strategies, the acute toxicity of dsRNA-ß2 combined with imidacloprid was evaluated on honeybee Apis mellifera. RESULTS: In this work, we demonstrated that dsRNA-ß2 alone has an insecticidal effect on aphid larvae and adults. Moreover, dsRNA-ß2 and imidacloprid effects on aphid larvae and adults were additive, meaning that dsRNA-ß2 did not alter the efficacy of imidacloprid on these two developmental stages. Also, no obvious acute toxicity on Apis mellifera was reported. CONCLUSION: Using RNAi that targets ß2 divergent nAChR subunit is effective alone or combined with imidacloprid to control A. pisum at larval and adult stages. Because no obvious Apis mellifera mortality has been reported, this RNAi-based pest management strategy should be considered to control insect pest. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Phase II trial of concurrent sunitinib, temozolomide, and radiotherapy with adjuvant temozolomide for newly diagnosed MGMT unmethylated glioblastoma.

Background: The overall prognosis of glioblastoma (GBM) remains dismal, particularly for patients with unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In this phase II trial, we tested the combination of the antiangiogenic agent sunitinib with radiotherapy and temozolomide (TMZ) for newly diagnosed unmethylated MGMT GBM patients. Methods: We enrolled 37 patients with unmethylated MGMT promoter GBM, age 18-70, and KPS ≥70. Patients received 12.5 mg of daily sunitinib for 7 days, followed by concurrent chemoradiation plus 12.5 mg sunitinib, then adjuvant TMZ. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), safety, and neutrophil-to-lymphocyte ratio (NLR) biomarker. Results: At a median follow-up time of 15.3 months (range: 3.1-71.3 months), the median PFS was 7.15 months (95% CI: 5.4-10.5) and the 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8-19.4) and 2-year OS rate was 17.1%. Patients receiving >3 cycles of adjuvant TMZ, undergoing surgery at progression, and presenting a post-concurrent NLR ≤6 experienced a significant improved OS with hazard ratios of 0.197 (P = .001), 0.46 (P = .049), and 0.38 (P = .021), respectively, on multivariable analysis. Age >65 years predicted for worse OS with hazard ratio of 3.92 (P = .037). Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20%, and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events. Conclusion: Our findings suggest a potential benefit of combining sunitinib with chemoradiation in newly diagnosed GBM patients with unmethylated MGMT status and provide a strong rationale to test this combination in future studies.

Targeted Intraoperative Radiation Therapy during Breast-Conserving Surgery for Patients with Early Stage Breast Cancer: A Phase II Single Center Prospective Trial.

Purpose: Patients with early stage breast cancer (ESBC) are conventionally treated with breast-conserving surgery (BCS) followed by whole-breast external beam radiation therapy (EBRT). The emergence of targeted intraoperative radiation therapy (TARGIT) with Intrabeam has been used as a therapeutic alternative for patients with risk-adapted ESBC. Here we present our radiation therapy toxicities (RTT), postoperative complications (PC), and short-term outcomes of the prospective phase II trial at the McGill University Health Center. Methods and Materials: Patients aged ≥50 years with biopsy-proven hormone receptor-positive, grade 1 or 2, invasive ductal carcinoma of the breast, cT1N0, were eligible for the study. Enrolled patients underwent BCS followed by immediate TARGIT of 20 Gy in 1 fraction. Upon final pathology, patients with low-risk breast cancer (LRBC) received no further EBRT, and those with high-risk breast cancer (HRBC) received further 15 to 16 fractions of whole breast EBRT. HRBC criteria included pathologic tumor size >2 cm, grade 3, positive lympho-vascular invasion, multifocal disease, close margins (<2 mm), or positive nodal disease. Results: A total of 61 patients with ESBC were enrolled in the study; upon final pathology, 40 (65.6%) had LRBC, and 21 (34.4%) had HRBC. The median follow-up was 3.9 years. The most common HRBC criteria were close margins in 66.6% (n = 14) and lymphovascular invasion in 28.6% (n = 6). No grade 4 RTT were observed in either group. The most common PC were seroma and cellulitis for both groups. The rate of locoregional recurrence was 0% in both groups. The overall survival in LRBC was 97.5% and in HRBC 95.2% with no significant differences. Deaths were nonbreast cancer related. Conclusions: In patients with ESBC undergoing BCS, the use of TARGIT shows low rates of RTT and PC complications. Moreover, our short-term outcomes show no significant difference at 3.9 years median follow-up for locoregional recurrence or overall survival between groups of patients receiving TARGIT alone or TARGIT followed by EBRT. Of all patients, 34.4% required further EBRT, most commonly due to close margins.

Metabolomics-Guided Identification of a Distinctive Hepatocellular Carcinoma Signature.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to cancer-related morbidity and mortality burdens globally. Given the fundamental metabolic activity of hepatocytes within the liver, hepatocarcinogenesis is bound to be characterized by alterations in metabolite profiles as a manifestation of metabolic reprogramming. METHODS: HCC and adjacent non-tumoral liver specimens were obtained from patients after HCC resection. Global patterns in tissue metabolites were identified using non-targeted 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy whereas specific metabolites were quantified using targeted liquid chromatography-mass spectrometry (LC/MS). RESULTS: Principal component analysis (PCA) within our 1H-NMR dataset identified a principal component (PC) one of 53.3%, along which the two sample groups were distinctively clustered. Univariate analysis of tissue specimens identified more than 150 metabolites significantly altered in HCC compared to non-tumoral liver. For LC/MS, PCA identified a PC1 of 45.2%, along which samples from HCC tissues and non-tumoral tissues were clearly separated. Supervised analysis (PLS-DA) identified decreases in tissue glutathione, succinate, glycerol-3-phosphate, alanine, malate, and AMP as the most important contributors to the metabolomic signature of HCC by LC/MS. CONCLUSIONS: Together, 1H-NMR and LC/MS metabolomics have the capacity to distinguish HCC from non-tumoral liver. The characterization of such distinct profiles of metabolite abundances underscores the major metabolic alterations that result from hepatocarcinogenesis.

Evaluation of Dosimetry Formalisms in Intraoperative Radiation Therapy of Glioblastoma.

PURPOSE: The intraoperative radiotherapy in newly diagnosed glioblastoma multiforme (INTRAGO) clinical trial assesses survival in patients with glioblastoma treated with intraoperative radiation therapy (IORT) using the INTRABEAM. Treatment planning for INTRABEAM relies on vendor-provided in-water depth dose curves obtained according to the TARGeted Intraoperative radioTherapy (TARGIT) dosimetry protocol. However, recent studies have shown discrepancies between the estimated TARGIT and delivered doses. This work evaluates the effect of the choice of dosimetry formalism on organs at risk (OAR) doses. METHODS AND MATERIALS: A treatment planning framework for INTRABEAM was developed to retrospectively calculate the IORT dose in 8 INTRAGO patients. These patients received an IORT prescription dose of 20 to 30 Gy in addition to external beam radiation therapy. The IORT dose was obtained using (1) the TARGIT method; (2) the manufacturer's V4.0 method; (3) the CQ method, which uses an ionization chamber Monte Carlo (MC) calculated factor; (4) MC dose-to-water; and (5) MC dose-to-tissue. The IORT dose was converted to 2 Gy fractions equivalent dose. RESULTS: According to the TARGIT method, the OAR dose constraints were respected in all cases. However, the other formalisms estimated a higher mean dose to OARs and revealed 1 case where the constraint for the brain stem was exceeded. The addition of the external beam radiation therapy and TARGIT IORT doses resulted in 10 cases of OARs exceeding the dose constraints. The more accurate MC calculation of dose-to-tissue led to the highest dosimetric differences, with 3, 3, 2, and 2 cases (out of 8) exceeding the dose constraint to the brain stem, optic chiasm, optic nerves, and lenses, respectively. Moreover, the mean cumulative dose to brain stem exceeded its constraint of 66 Gy with the MC dose-to-tissue method, which was not evident with the current INTRAGO clinical practice. CONCLUSIONS: The current clinical approach of calculating the IORT dose with the TARGIT method may considerably underestimate doses to nearby OARs. In practice, OAR dose constraints may have been exceeded, as revealed by more accurate methods.

Radiation-Induced Sarcomas of the Breast: A Review of a 20-Year Single-Center Experience.

Background Radiation-induced sarcomas (RISs) are histologically proven sarcomas within or around a previously irradiated site, per Cahan's criteria. RIS incidence is higher in breast cancer compared to other solid cancers and the prognosis remains poor given limited treatment options. This study aimed to review 20-year experience with RISs at a large tertiary care center. Methodology Using our institutional cancer registry database, we included patients meeting Cahan's criteria diagnosed between 2000 and 2020. Patient demographics, oncologic treatment, and oncologic outcomes data were collected. Descriptive statistics were used to describe demographic data. Oncologic outcomes were assessed using the Kaplan-Meier method. Results A total of 19 patients were identified. The median age at RIS diagnosis was 72 years (range = 39-82 months), and the median latency period for the development of RIS was 112 months (range = 53-300 months). All patients underwent surgery, three patients received systemic therapy, and six patients received re-irradiation as salvage treatment. The median follow-up time was 31 months (range = 6-172 months) from the diagnosis of RIS. Overall, five patients had local recurrence, and one patient developed distant metastases. The median time to progression was seven months (range = 4-14 months). The progression-free survival (95% confidence interval (CI)) at two years was 56.1% (37.4-84.4%). At follow-up two years after the diagnosis of sarcoma, the overall survival (95% CI) was 88.9% (75.5-100%). Conclusions While breast RIS remains rare, when managed in a large tertiary care center, overall survival outcomes appear favorable. A significant proportion of patients recur locally after maximal treatment and require salvage therapy to improve outcomes. These patients should be managed in high-volume centers where multidisciplinary expertise is available.

Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Background: Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Methods: This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Results: Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). Conclusions: The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Management of Oligometastatic Breast Cancer: An Expert Committee's Opinion.

Patients with oligometastatic breast cancer (BC) are candidates of choice for metastasis-directed therapy (MDT). This paper summarizes the opinions of an expert committee about the management of oligometastatic BC. The experts could complete the questionnaire from 13 September 2021, to 10 October 2021, followed by a discussion. The experts were physicians working in the Province of Quebec (Canada) and specialized in BC care, including surgical oncologists, medical oncologists, and radiation oncologists. The experts provided their opinions about the context of the disease and therapeutic approach, local and systemic therapies, and the prognosis of oligometastatic BC. In addition to the expert panel's opinions about the management of oligometastatic disease per se, the experts stated that a prospective data registry should be implemented to collect data about oligometastatic BC to improve knowledge about oligometastatic BC and implement data-driven MDT. These data could also allow for the design of treatment algorithms. In conclusion, this paper presents the expert panel's opinions about the management of oligometastatic BC and highlights the needs to be met to improve the care of this condition.

Is Postoperative Radiotherapy Needed in the Management of Adult Craniopharyngiomas?

BACKGROUND: The optimal treatment of adult craniopharyngioma (CP) remains controversial. Although benign, these tumors tend to recur locally. The choice between gross total resection (GTR) versus subtotal resection (STR) with adjuvant or delayed radiotherapy (RT) is debated. The objective of this study is to review our experience with adult CPs over a 20-year period and identify an optimal management strategy. METHODS: From 1999 to 2020, we reviewed all patients diagnosed with CP at our institution. We collected data regarding tumor characteristics, treatments, and toxicity. Disease progression was defined as growth on imaging. Descriptive statistics were used to assess patient characteristics. The Kaplan Meier method was used to assess progression-free survival (PFS) and corresponding 95% confidence intervals (CI) from the time since treatment initiation. RESULTS: Twenty-four patients with a median age of 50 were included in this study. The median follow-up was 85 months. Seven patients had initial GTR, 10 STR, and 7 STR + RT. The overall 5-year PFS was 56% (95% CI: 38-83%): 100% in the STR + RT group, 69% in the GTR group, and 18% in the STR group (p = 0.01). Of the 17 patients initially treated with surgery alone, 3 with GTR and 6 with STR required salvage RT at a median of 46 months, with no further progression after salvage RT. CONCLUSIONS: Our study underscores the importance of RT for local control and suggests that STR + RT should be considered a viable option in the management of these tumors as it may be associated with improved PFS compared to surgery alone.

Radiomics as an emerging tool in the management of brain metastases.

Brain metastases (BM) are associated with significant morbidity and mortality in patients with advanced cancer. Despite significant advances in surgical, radiation, and systemic therapy in recent years, the median overall survival of patients with BM is less than 1 year. The acquisition of medical images, such as computed tomography (CT) and magnetic resonance imaging (MRI), is critical for the diagnosis and stratification of patients to appropriate treatments. Radiomic analyses have the potential to improve the standard of care for patients with BM by applying artificial intelligence (AI) with already acquired medical images to predict clinical outcomes and direct the personalized care of BM patients. Herein, we outline the existing literature applying radiomics for the clinical management of BM. This includes predicting patient response to radiotherapy and identifying radiation necrosis, performing virtual biopsies to predict tumor mutation status, and determining the cancer of origin in brain tumors identified via imaging. With further development, radiomics has the potential to aid in BM patient stratification while circumventing the need for invasive tissue sampling, particularly for patients not eligible for surgical resection.

Pharmacological and molecular characterization of the A-type muscarinic acetylcholine receptor from Anopheles gambiae.

Muscarinic acetylcholine receptors (mAChRs) which are G protein-coupled receptors play key roles in insect physiology. Whereas vertebrate mAChRs are important targets for pharmaceutical drugs, insect mAChRs are under-exploited by the agro-chemical industry. Moreover, insect mAChRs have been less well studied than their vertebrate counterparts. Their critical functions mean that a better knowledge of the insect mAChRs is crucial for the effort to develop a new molecular-level strategy for insect pest management. Almost all insects possess three mAChRs named A, B and C which differ according to their coupling effector systems and their pharmacological profile. The aim of this study was to characterize the A-type mAChR (mAChR-A) from Anopheles gambiae which is the major vector of malaria in order to develop new strategies in pest management. In this paper, we reported that mAChR-A is more expressed in adult mosquitoes than in larvae. Furthermore, using calcium imaging recordings, we found that the An. gambiae mAChR-A expressed in Sf9 cells is activated by specific muscarinic agonists acetylcholine, muscarine and oxotremorine M and blocked by several mAChR antagonists. Moreover, using inhibitors of phosphoinositide pathway such as Gαq/11 protein blocker, we have shown that an increased intracellular calcium concentration elicited by the acetylcholine application was mediated by PLC/IP3R pathway. As a rise in intracellular calcium concentration could lead to an increase in the insecticide target sensitivity, these results suggest that An. gambiae mAChR-A should not be only considered as a potential target for new molecules but also as a key element to optimize the efficacy of insecticide in vector control.

Exposure to a sublethal dose of imidacloprid induces cellular and physiological changes in Periplaneta americana: Involvement of α2 nicotinic acetylcholine subunit in imidacloprid sensitivity.

Neonicotinoids are the most important class of insecticides used as pest management tools during several decades. Exposition of insect to sublethal dose of insecticide induces physiological and cellular changes that could contribute to the adaptation of the insects in order to loss their sensitivity to insecticides. The aim of our study is to demonstrate that a subchronic exposure to a sublethal dose of a neonicotinoid imidacloprid is sufficient to induce molecular changes leading to a loss of imidacloprid sensitivity. We report that in the cockroach, Periplaneta americana, subchronic exposure to a sublethal dose of imidacloprid induced weak changes in detoxification enzyme activity and a significant decrease of the nicotinic acetylcholine α2 mRNA. This molecular effect is correlated to a decrease of imidacloprid sensitivity of cockroaches. Using RNA interference, we shown the key role of nicotinic acetylcholine α2 subunit in imidacloprid sensitivity. Thus, quantitative changes in insecticide targets lead to decreased sensitivity to insecticides. This parameter needs to be considered in order to develop sustainable insect resistance management strategies.

Independently validated sex-specific nomograms for predicting survival in patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825.

BACKGROUND/PURPOSE: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. METHODS: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. RESULTS: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. CONCLUSIONS: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ .

MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype.

Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. This review aims to offer a comprehensive overview and highlight the importance of the c-Myc transcription factor on the regulation of metabolic pathways, in particular that of glutamine and glutaminolysis. Glutamine can be extensively metabolized into a variety of substrates and be integrated in a complex metabolic network inside the cell, from energy metabolism to nucleotide and non-essential amino acid synthesis. Together, understanding metabolic reprogramming and its underlying genetic makeup, such as MYC activation, allows for a better understanding of the cancer cell phenotype and thus of the potential vulnerabilities of cancers from a metabolic standpoint.

Extreme weekly locoregional hypofractionated radiation in elderly women with non-metastatic breast cancer.

BACKGROUND AND PURPOSE: Breast cancer locoregional (LR) radiation in the elderly requires careful consideration between the benefits of aggressive treatment and its potential toll on these patients. Extreme weekly LR hypofractionated radiation (HFRT), delivering >5 Gy per fraction, may be better suited in such a population. It represents a good compromise between RT omission and exhaustive daily radiation. This study aims to report the local and LR control rate as well as the acute and long-term side effects of the elderly patients treated with HFRT in our institution, and to compare these results to those from the literature. MATERIALS AND METHODS: We conducted a retrospective study by reviewing medical records of elderly patients with breast cancer treated with adjuvant once-weekly LR HFRT between 2011 and 2020. Fifty patients presenting with primary non-metastatic node-positive breast tumors were included. Treatment outcomes including local/LR control and overall survival were reported. Early and late toxicity profiles were also assessed. RESULTS: After a median follow-up of 4.8 years, only one local recurrence in the chest wall occurred and there was no regional recurrence. The distant metastatic rate was 6%. The long-term recurrence-free survival rate was 80% at 5 years. The cause specific survival rate was 90% at 5 years. The overall survival rate was 69.4% and 55.5% at 3 and 5 years, respectively. There were 44 (88%) patients with Grade 1 or 2 early toxicity. There was no Grade 3 or higher acute toxicity registered. Late toxicity was mainly Grade 1 or 2 subcutaneous fibrosis, lymphoedema, and neuropathy except for one patient with Grade 3 fibrosis. CONCLUSION: Extreme LR HFRT is well tolerated with good outcomes and is a good alternative for elderly and frail patients. Our results confirm the efficacy and safety of such a regimen. Further randomized trials assessing both oncologic outcome and toxicity profile are justified.

Examination of the Dose-Effect Relationship of Radiation-Induced Hypopituitarism: Results of a Case-Control Study.

PURPOSE: Previous reports have documented a dose-effect relationship for radiation-induced hypopituitarism in patients receiving therapy near or at the base of the skull. We aimed to characterize this long-term endocrinopathy further by examining the effect of dose on both the incidence and severity of toxicity, as well as exploring a possible dose threshold for this effect. METHODS AND MATERIALS: Out of an initial 346 patients who had received radiation therapy to the base of the skull, 53 patients with adequate endocrine evaluation were found. Of these, 19 patients who subsequently developed at least 1 endocrinopathy (cases) as well as 17 patients who did not (controls) were identified, for a total of 36. Patients' charts were reviewed, and endocrinologic laboratory tests recorded. Treatment plans were reviewed and doses to the hypothalamus and pituitary gland were calculated. One-way analysis of variance was used to determine differences between cases and controls, and Pearson's correlation coefficient was used to relate mean pituitary dose to serum free thyroxine, insulin-like growth factor 1, prolactin, cortisol, and luteinizing hormone. RESULTS: There were 20 men and 16 women, with a median age of 58. Median follow-up was 32 months (range, 18- 85 months). Median total plan dose delivered was 54 Gy (range, 50.4-70 Gy). Independent sample t tests as well as univariate analysis showed a significantly greater dose to the hypothalamus and pituitary of the cases compared with the controls, while other factors were not significantly different between the 2 groups. There was a statistically significant negative correlation (Pearson's correlation coefficient = -0.65, P = .001) between the mean dose to the pituitary gland and the serum free thyroxine. No case of endocrine toxicity was observed at a mean dose to the pituitary below 30 Gy. CONCLUSIONS: Our results suggest that late endocrinopathy is a true deterministic effect, with a dose threshold, and with both the incidence and severity of toxicity being related to the dose.

The cys-loop ligand-gated ion channel gene superfamilies of the cockroaches Blattella germanica and Periplaneta americana.

BACKGROUND: Cockroaches are serious urban pests that can transfer disease-causing microorganisms as well as trigger allergic reactions and asthma. They are commonly managed by pesticides that act on cys-loop ligand-gated ion channels (cysLGIC). To provide further information that will enhance our understanding of how insecticides act on their molecular targets in cockroaches, we used genome and reverse transcriptase polymerase chain reaction (RT-PCR) data to characterize the cysLGIC gene superfamilies from Blattella germanica and Periplaneta americana. RESULTS: The B. germanica and P. americana cysLGIC superfamilies consist of 30 and 32 subunit-encoding genes, respectively, which are the largest insect cysLGIC superfamilies characterized to date. As with other insects, the cockroaches possess ion channels predicted to be gated by acetylcholine, γ-aminobutyric acid, glutamate and histamine, as well as orthologues of the drosophila pH-sensitive chloride channel (pHCl), CG8916 and CG12344. The large cysLGIC superfamilies of cockroaches are a result of an expanded number of divergent nicotinic acetylcholine receptor subunits, with B. germanica and P. americana, respectively, possessing eight and ten subunit genes. Diversity of the cockroach cysLGICs is also broadened by alternative splicing and RNA A-to-I editing. Unusually, both cockroach species possess a second glutamate-gated chloride channel as well as another CG8916 subunit. CONCLUSION: These findings on B. germanica and P. americana enhance our understanding of the evolution of the insect cysLGIC superfamily and provide a useful basis for the study of their function, the detection and management of insecticide resistance, and for the development of improved pesticides with greater specificity towards these major pests. © 2020 Society of Chemical Industry.

SARS-CoV-2 Fulminant Myocarditis.

An 18-year-old male without prior medical history developed fulminant myocarditis concomitant to severe COVID-19 pneumonia, which was confirmed using serial cardiac magnetic resonance. This may have important diagnostic, monitoring, and pathogenic implications. (Level of Difficulty: Intermediate.).

High-risk Meningioma: Initial Outcomes From NRG Oncology/RTOG 0539.

BACKGROUND: Phase 2 cooperative group meningioma trial assessing the safety and efficacy of risk-adaptive management strategies. This is the initial analysis of the high-risk cohort. METHODS AND MATERIALS: High-risk patients were those with a new or recurrent World Health Organization (WHO) grade III meningioma of any resection extent, recurrent WHO grade II of any resection extent, or new WHO grade II after subtotal resection. Patients received intensity-modulated radiotherapy (IMRT) using a simultaneous integrated boost technique (60 Gy high dose and 54 Gy low dose in 30 fractions). Three-year progression-free survival (PFS) was the primary endpoint. Adverse events (AEs) were scored per NCI Common Terminology Criteria for Adverse Events version 3. RESULTS: Of 57 enrolled patients, 53 received protocol treatment. Median follow-up was 4.0 years (4.8 years for living patients). Two patients withdrew without progression before year 3; for the remaining 51 patients, 3-year PFS was 58.8%. Among all 53 protocol-treated patients, 3-year PFS was 59.2%. Three-year local control was 68.9%, and overall survival was 78.6%. Of 51 patients, 1 patient (1.9%) experienced a late grade-5 necrosis-related AE. All other acute (23 of 53 patients) and late (21 of 51 patients) AEs were grades 1 to 3. CONCLUSIONS: Patients with high-risk meningioma treated with IMRT (60 Gy/30) experienced 3-year PFS of 58.8%. Combined acute and late AEs were limited to grades 1 to 3, except for a single necrosis-related grade 5 event. These results support postoperative IMRT for high-risk meningioma and invite ongoing investigations to improve outcomes further.