Objective: The aim of this study was to analyze the wound complication (WC) rate and to determine the risk factors for WC in patients with soft tissue sarcoma treated with preoperative radiotherapy followed by surgical resection.Methods: Using the database of Oxford University Hospital (OUH) we retrospectively studied 126 cases of soft tissue sarcomas treated with preoperative radiotherapy and surgery between 2007 and 2021. WC were defined as minor wound complication (MiWC) not requiring surgical intervention or major wound complication (MaWC) if they received a secondary surgical intervention. Univariate and multiple regression analyses were performed using frequency of WC and MaWC as a dependent variable.Results: The incidence of WC and MaWC was 43.7% (55/126) and 19% (24/126). Age (OR:1.03, 95%CI: 1.00-1.06, p = 0.016), tumor size (OR:1.11, 95%CI:1.01-1.21, p = 0.027) and tumor site namely proximal lower limb vs upper limb (OR:10.87, 95%CI 1.15-103.03, p = 0.038) were risk factors on multivariate analysis. In nested case control analysis, the incidence of MaWC was 43.6% (24/55), the mean recovery time is 143 days in patients with MaWC. Smoking increases the risk for MaWC (OR:8.32, 95%CI:1.36-49.99, p = 0.022). The time interval between surgery and wound complication reduces the risk for MaWC (OR:0.91, 95%CI:0.84-0.99, p = 0.028) in multivariate analysis.Conclusions: Age, tumor site and size are risk factors for WC requiring preoperative radiotherapy. Smoking and the time interval between surgery and wound complication are risk factors for MaWC as compared with MiWC. MaWC rate (19%) are comparable to those in postoperative radiotherapy and surgery alone.

Background: The chronology of thymoma and associated paraneoplastic syndromes can be complex and unpredictable, with previous non-malignant thymic histology not precluding thymoma developing later. We present a case that demonstrates a complex history of myasthenia gravis (MG), thymoma and pure red cell aplasia (PRCA). Case Description: A 31-year-old female of Japanese descent presented with extraocular, bulbar and limb weakness 2 months post-partum, and was subsequently diagnosed with acetylcholine receptor antibody (AChR) positive MG. Following an initial response to prednisolone and pyridostigmine she underwent a thymectomy in Japan and was found to have a hyperplastic thymus. She subsequently improved but remained symptomatic, steroid dependent, and intermittently requiring intravenous immunoglobulin (IVIg). She was unable to tolerate azathioprine and was reluctant to try alternative steroid-sparing immunosuppression. Seven years post thymectomy, she experienced worsening symptoms requiring multiple admissions for supportive care, IVIg and plasma exchange. A CT thorax was performed which identified a thoracic inlet mass abutting the right brachiocephalic and left common carotid artery. A subsequent ultrasound guided biopsy confirmed a thymoma and this was resected. The histology was confirmed as B2, stage 2, R1. No adjuvant therapy was required. Following this, the patient’s MG markedly improved though she remained mildly symptomatic and dependent on low dose prednisolone. Five years later, she became increasingly fatigued in the absence of evidence of worsening MG and was found to have a slowly progressive anaemia. This culminated in an admission with an Hb of 40 g/L, elevated reticulocytes, macrocytosis, but normal haematinics. A subsequent bone marrow biopsy confirmed the diagnosis of PRCA. She remains dependent on transfusions and is due to start immunosuppression with ciclosporin. Conclusions: Thymoma can develop many years after a normal thymectomy for MG, with new paraneoplastic syndromes also developing later still. It is important to consider these possibilities if a patient’s MG deteriorates or new symptoms develop.

Introduction: In 'IDEAL-60 patients (N = 78) treated for locally-advanced non-small-cell lung cancer using isotoxically dose-escalated radiotherapy, overall survival (OS) was associated more strongly with VLAwall-64-73-EQD2, the left atrial (LA) wall volume receiving 64-73 Gy equivalent dose in 2 Gy fractions (EQD2), than with whole-heart irradiation measures. Here we test this in an independent cohort 'OX-RT' (N = 64) treated routinely. Methods: Using Cox regression analysis we assessed how strongly OS was associated with VLAwall-64-73-EQD2, with whole-heart volumes receiving 64-73 Gy EQD2 or doses above 10-to-70 Gy thresholds, and with principal components of whole-heart dose-distributions. Additionally, we tested associations between OS and volumes of cardiac substructures receiving dose-ranges described by whole-heart principal components significantly associated with OS. Results: In univariable analyses of OX-RT, OS was associated more strongly with VLAwall-64-73-EQD2 than with whole-heart irradiation measures, but more strongly still with VAortV-29-38-EQD2, the volume of the aortic valve region receiving 29-38 Gy EQD2. The best multivariable OS model included LA wall and aortic valve region mean doses, and the aortic valve volume receiving >38 Gy EQD2, VAortV-38-EQD2. In a subsidiary analysis of IDEAL-6, the best multivariable model included VLAwall-64-73-EQD2, VAortV-29-38-EQD2, VAortV-38-EQD2 and mean aortic valve dose. Conclusion: We propose reducing heart mean doses to the lowest levels possible while meeting protocol dose-limits for lung, oesophagus, proximal bronchial tree, cord and brachial plexus. This in turn achieves large reductions in VAortV-29-38-EQD2 and VLAwall-64-73-EQD2, and we plan to closely monitor patients with values of these measures still >0% (their median value in OX-RT) following reduction. (C) 2021 Elsevier B.V. All rights reserved.

Méthodologie : À la suite de l'augmentation du nombre de cas de VHA chez les HARSAH signalés dans d'autres pays, tous les cas de VHA non liés aux voyages et signalés du 1er juin 2017 au 1er novembre 2018 ont fait l'objet d'une surveillance accrue, y compris une analyse rétrospective des cas signalés entre janvier 2017 et juin 2017. Une analyse descriptive et un séquençage viral ont été effectués pour décrire les modes de transmission de personne à personne et les interventions ciblées. Les stratégies de contrôle comprenaient des interventions visant à promouvoir le recours à la vaccination contre le VHA avant l'exposition, y compris des campagnes sur les réseaux sociaux destinées aux HARSAH, ainsi que des messages destinés aux professionnels de la santé et aux cliniques de vaccination.

BACKGROUND:In late 2016 and early 2017, a number of countries began reporting hepatitis A virus (HAV) outbreaks involving person-to-person transmission among men who have sex with men (MSM), people using illicit drugs and homeless or underhoused persons.OBJECTIVE:To describe the epidemiology and public health response to an outbreak of HAV disproportionately affecting MSM in Toronto, Canada from January 2017 to November 2018.METHODS:Following an increase in the number of cases of HAV in MSM being reported in other countries, enhanced surveillance was performed for all non-travel-related cases of HAV reported from June 1, 2017 to November 1, 2018, including a retrospective analysis of cases reported from January 2017 to June 2017. Descriptive analysis and viral sequencing were performed to describe person-to-person transmission patterns and target interventions. Control strategies included interventions to promote the uptake of preexposure HAV vaccination, including social media campaigns geared to MSM, messaging to healthcare providers and vaccine clinics.RESULTS:Based on the outbreak case definitions, 52 confirmed and probable cases of HAV were identified. Over 80% of outbreak cases were male (n=43/52) and, among those for whom data were available, 64% (n=25/39) reported an MSM exposure. Data on hospitalization was available for 51 cases; 56% of confirmed cases (n=23/41) and 40% of probable cases (n=4/10) required hospitalization. Of the cases with serum samples that had HAV sequencing, 83% (n=30/36) had one of the three strains seen circulating in outbreaks among MSM internationally; 72% (n=26/36) were VRD_521_2016, which had been detected in recently reported European outbreaks among MSM. Targeted promotion of publicly-funded vaccination using social media platforms popular with MSM and targeted vaccine clinics were developed to promote HAV awareness and vaccine uptake among MSM.CONCLUSION:Outbreaks of HAV, attributed to person-to-person transmission of strains of HAV that disproportionately affected MSM and were likely to have been imported from international MSM outbreaks, have now occurred in Canada. Genetic sequencing of HAV, risk factor analysis of cases, monitoring trends of vaccine coverage in high-risk groups and initiation of vaccination campaigns that address barriers to HAV preexposure vaccine coverage in the MSM population may prevent future outbreaks.

Background: Pre-clinically, phosphoinositide 3-kinase (PI3K) inhibition radiosen-sitises tumours by increasing intrinsic radiosensitivity and by reducing tumour hypoxia. We assessed whether buparlisib, a class 1 PI3K inhibitor, can be safely combined with radiotherapy in patients with non-small cell lung carcinoma (NSCLC) and investigated its effect on tumour hypoxia. Methods: This was a 3 thorn 3 dose escalation and dose expansion phase I trial in patients with advanced NSCLC. Buparlisib dose levels were 50 mg, 80 mg and 100 mg once daily orally for 2 weeks, with palliative thoracic radiotherapy (20 Gy in 5 fractions) delivered during week 2. Tumour hypoxic volume (HV) was measured using 18 F-fluoromisonidazole positron-emission tomographyecomputed tomography at baseline and following 1 week of buparlisib. Results: Twenty-one patients were recruited with 9 patients evaluable for maximum tolerated dose (MTD) analysis. No dose-limiting toxicity was reported; therefore, 100 mg was declared the MTD, and 10 patients received this dose in the expansion phase. Ninety-four percent of treatment-related adverse events were <= grade 2 with fatigue (67%), nausea (24%) and decreased appetite (19%) most common per patient. One serious adverse event (grade 3 hypoalbuminaemia) was possibly related to buparlisib. No unexpected radiotherapy toxicity was reported. Ten (67%) of 15 patients evaluable for imaging analysis were responders with 20% median reduction in HV at the MTD. Conclusion: This is the first clinical trial to combine a PI3K inhibitor with radiotherapy in NSCLC and investigate the effects of PI3K inhibition on tumour hypoxia. This combination was well tolerated and PI3K inhibition reduced hypoxia, warranting investigation into whether this novel class of radiosensitisers can improve radiotherapy outcomes. (C) 2019 The Author(s). Published by Elsevier Ltd.

Background: The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab-based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis. Aims: We present the 1-year follow up on safety and efficacy data for the 28 patients enrolled in the safety run-in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis. Methods: Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT-ProBNP ≤8,500 ng/L. In the safety run-in, patients received DARA (1,800 mg in 15 mL) co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m2 PO or IV, Bor 1.3 mg/m2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter. Results: Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow-up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (>6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow-up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1. Summary/Conclusion: DARA-CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well-tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.

BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). CONCLUSIONS Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.

Purpose or ObjectivePostmastectomy radiation therapy (PMRT) reduces locoregional recurrence of breast cancer and improves survival in patients with lymph node involvement.A SEER analysis demonstrated an intermediate prognosis for pN1mi patients between lymph node negative (pN0) and lymph node positive (pN1) patients.This study addresses whether the subset of patients with lymph node micrometastasis (pN1mi) benefit from PMRT. Material and MethodsWe queried the surveillance, epidemiology, and end results (SEER) cancer registry version for women older than 18 years, with a diagnosis of primary breast cancer based on International Classification of Diseases for Oncology codes, diagnosed between 1998 and 2013, with invasive ductal or invasive lobular carcinoma histology, pathologic T1 or T2 primaries, micrometastatic nodal disease, who underwent mastectomy.Patients with distant metastatic disease, multiple primary cancers, unknown grade or undifferentiated carcinomas, and those who received neo-adjuvant radiotherapy were excluded.Univariate survival analysis was performed using the Kaplan-Meier method.Multivariate analysis was performed using a Cox proportionate hazards model.Variables included in multivariate analysis included age (continuous), menopausal status (as determined by age <50 or ≥50), race, histology (invasive ductal, lobular, or mixed), tumor grade (low and intermediate vs. high), T stage (T1 vs. T2), estrogen receptor status, progesterone receptor status, type of surgery (simple or radical mastectomy), and use of post-mastectomy radiation.The primary endpoint was overall survival.We then defined a risk of women with at least two of three high risk features (age <50, grade 3, T2) and evaluated the effect of radiotherapy on this subset. ResultsThe analysis included 8,820 patients who met the inclusion and exclusion criteria as described above.The use of PMRT in pN1mi patients was associated with a higher risk of all cause mortality on multivariate analysis (HR 1.17, 95% CI 1.01 -1.35, p=0.04).Other factors of worse all cause mortality include African American race, older age, premenopausal status, high grade, lobular histology, ER/PR negativity, and simple mastectomy.The subset of women with at least two of three high risk features included 3,242 patients.For this subset, PMRT was not significantly associated with overall survival (HR 1.11, p=0.29). ConclusionThe use of PMRT in women with nodal micrometastasis without additional established indications for PMRT is associated with worse overall survival.For women with lymph node micrometastases and additional risk factors, PMRT is not associated with overall survival.Caution should be used in considering PMRT based on the finding of lymph node micrometastasis even in the setting of additional risk factors.

BACKGROUND:In 2017, a mumps outbreak was identified in a cohort of 18-34 year olds in Toronto, Canada.OBJECTIVE:To describe a large community mumps outbreak in an urban centre from January 2017 to February 2018 among young adults.METHODS:A broad range of interventions were implemented in an attempt to reach the target audience; including case and contact management, vaccination clinics at schools and clinicians' offices, school exclusions, bar inspections, traditional communication strategies (including health care provider updates and posters) and newer communication strategies (including three sequential social media campaigns).RESULTS:A total of 143 cases of mumps were identified. Although cases' ages ranged from three to 72 years, most (76%) were 18-34 year olds, many of whom had frequented bars and local food establishments in downtown Toronto. 84% (n=120) of the cases were community-acquired. Only 16% (n=23) of the cases reported exposures in schools and post-secondary school institutions. Of those, 39% (n=56) of cases had an unknown vaccination history; 34% (n=49) were either not vaccinated or partially vaccinated with one dose of measles-mumps-rubella vaccine; and 27% (n=38) had received the recommended two doses of mumps vaccine. Determining vaccination status was a challenge, in part due to the lack of a registry. Vaccination was recommended when subjects were known to have had fewer than two doses of vaccine or had an unknown vaccination status. A social media campaign, emphasizing the risk of social activities if not protected from the mumps, yielded over 500,000 impressions from Facebook and Twitter messages and ads and an impressive engagement rate of between 1% and 10x%.CONCLUSION:This was the largest mumps outbreak in Toronto in over 20 years. Among young adults, ongoing social media and traditional communication campaigns can contribute to the control of community mumps outbreaks. Encouraging vaccine uptake is desirable, but without a vaccine registry it is difficult to assess vaccination coverage among adults. Susceptible cohorts of young adults who were not adequately vaccinated pose a risk for future outbreaks. Given that almost 30% of the mumps cases were fully vaccinated with two doses of mumps-containing vaccine, even two doses may not provide complete protection.

Méthodologie : Une vaste gamme d’interventions ont été mises en place afin d’atteindre le public cible, dont la gestion des personnes atteintes et des contacts ; des cliniques de vaccination en milieu scolaire et au cabinet du médecin ; des exclusions scolaires ; l’inspection des bars ; des stratégies de communication traditionnelles (y compris l’avertissement des fournisseurs de soins de santé et des affiches) et de nouvelles stratégies de communication (dont trois campagnes séquentielles sur les réseaux sociaux).

The Ras/PI3K/Akt pathway plays an important role in determining intrinsic and extrinsic tumour radiosensitivity. Buparlisib (BKM120) is a highly specific pan class-1 PI3K inhibitor. Pre-clinically, this class of agents radiosensitises tumours by direct effects on intrinsic radiosensitivity and by reducing tumour hypoxia. We therefore assessed the safety and determined the maximum tolerated dose (MTD) of buparlisib in combination with radiotherapy in patients with NSCLC and investigated its effect on tumour hypoxia. BKM120 was a single centre, open-label, dose-escalation and dose-expansion phase 1 trial. Patients with advanced stage NSCLC received 2 weeks of oral buparlisib. Palliative thoracic radiotherapy (20Gy in 5 fractions) was delivered during the second week of treatment. 18F-fluoromisonidazole (FMISO) PET scans were used to assess tumour hypoxic volume (HV) before and after 1 week of buparlisib treatment. HV was defined as the volume with a tumour-to-blood F-MISO uptake ratio ≥ 1.4. From June 2013 to August 2017, 21 patients were recruited. 11 patients were registered to the dose escalation phase with 9 evaluable for MTD analysis: 3 in Cohort 1 (50mg OD), 3 in Cohort 2 (80mg OD) and 3 in Cohort 3 (100mg OD). No DLT was reported therefore 100mg OD was declared the MTD and 10 patients received this dose in the expansion phase. Of all patients who received buparlisib (n=21), 1 SAE (Grade 3 hypoalbuminaemia) was possibly related to buparlisib (5%). The most common buparlisib-related AEs were fatigue (8.3%) and nausea (3.3%). 93.9% of all AEs with any relation to buparlisib were ≤ Grade 2. There was no reported radiotherapy associated toxicity. 15 patients were evaluable for tumour hypoxia imaging analysis. Median change in HV in Cohort 1 (n=3), Cohort 2 (n=3) and Cohort 3 combined with the expansion cohort (n=9) was 7%, -18% and -20%, respectively. This is the first clinical trial of a specific PI3K inhibitor with concurrent radiotherapy in NSCLC. This combination was found to be safe and well-tolerated. This study provides clinical evidence that PI3K inhibition rapidly reduces tumour hypoxia and therefore warrants further trials combining this class of agents with radiotherapy.

OBJECTIVES: Our aims were to assess risks of early rebleeding after successful endoscopic hemostasis for Forrest oozing (FIB) peptic ulcer bleeding (PUBs) compared with other stigmata of recent hemorrhage (SRH).METHODS: These were post hoc multivariable analyses of a large, international, double-blind study (NCT00251979) of patients randomized to high-dose intravenous (IV) esomeprazole (PPI) or placebo for 72 h. Rebleeding rates of patients with PUB SRH treated with either PPI or placebo after successful endoscopic hemostasis were also compared.RESULTS: For patients treated with placebo for 72 h after successful endoscopic hemostasis, rebleed rates by SRH were spurting arterial bleeding (FIA) 22.5%, adherent clot (FIIB) 17.6%, non-bleeding visible vessel (FIIA) 11.3%, and oozing bleeding (FIB) 4.9%. Compared with FIB patients, FIA, FIIB, and FIIA had significantly greater risks of rebleeding with odds ratios (95% CI's) from 2.61 (1.05, 6.52) for FIIA to 6.66 (2.19, 20.26) for FIA. After hemostasis, PUB rebleeding rates for FIB patients at 72 h were similar with esomeprazole (5.4%) and placebo (4.9%), whereas rebleed rates for all other major SRH (FIA, FIIA, FIIB) were lower for PPI than placebo, but the treatment by SRH interaction test was not statistically significant.CONCLUSIONS: After successful endoscopic hemostasis, FIB patients had very low PUB rebleeding rates irrespective of PPI or placebo treatment. This implies that after successful endoscopic hemostasis the prognostic classification of FIB ulcers as a high-risk SRH and the recommendation to treat these with high-dose IV PPI's should be re-evaluated.