Citations

PURPOSE CALGB 40603 ( NCT00861705 ), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points. PATIENTS AND METHODS The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing. RESULTS Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS. CONCLUSION Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.

Abstract Purpose: HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor–positive (ER+) breast cancer. Patients and Methods: In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER−)/HER2mut MBC received neratinib monotherapy in an exploratory ER− cohort (n = 5). Results: The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%–62%), 30% (7%–65%), and 25% (1%–81%) in the fulvestrant-treated, fulvestrant-naïve, and ER− cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression. Conclusions: Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.

Objective: In a randomized trial, we aimed to evaluate the efficacy of cosyntropin injectable suspension, 1 mg/mL, compared to vigabatrin for infantile spasms syndrome. An additional arm was included to assess the efficacy of combination therapy (cosyntropin and vigabatrin) compared with cosyntropin monotherapy. Methods: Children (2 months to 2 years) with new-onset infantile spasms syndrome and hypsarhythmia were randomized into 3 arms: cosyntropin, vigabatrin, and cosyntropin and vigabatrin combined. Daily seizures and adverse events were recorded, and EEG was repeated at day 14 to assess for resolution of hypsarhythmia. The primary outcome measure was the composite of resolution of hypsarhythmia and absence of clinical spasms at day 14. Fisher exact test was used to compare outcomes. Results: 37 children were enrolled and 34 were included in the final efficacy analysis (1 withdrew prior to treatment and 2 did not return seizure diaries). Resolution of both hypsarhythmia and clinical spasms was achieved in in 9 of 12 participants (75%) treated with cosyntropin, 1/9 (11%) vigabatrin, and 5/13 (38%) cosyntropin and vigabatrin combined. The primary comparison of cosyntropin versus vigabatrin was significant (64% [95% confidence interval 21, 82], P < .01). Adverse events were reported in all 3 treatment arms: 31 (86%) had an adverse event, 7 (19%) had a serious adverse event, and 15 (42%) had an adverse event of special interest with no difference between treatment arms. Significance: This randomized trial was underpowered because of incomplete enrollment, yet it demonstrated that cosyntropin was more effective for short-term outcomes than vigabatrin as initial treatment for infantile spasms.

Objective To comprehensively assess multimorbidity burden in patients with rheumatoid arthritis (RA) in order to unify the multimorbidity definition for RA research and clinical practice. Methods In this population-based study, residents of eight Minnesota counties with prevalent RA on 1 January 2015 were identified. Age, sex and county-matched non-RA comparators were selected from the same population. Diagnostic codes were retrieved for 5 years before 1 January 2015. Using two codes ≥30 days apart, 44 previously defined morbidities and 78 non-overlapping chronic disease categories based on Clinical Classification Software were defined. Prevalence of each morbidity in the RA versus non-RA cohorts was compared using false discovery rate to adjust for multiple comparisons. Morbidities more common in RA than non-RA and those with prevalence ≥5% were retained. Results 1643 patients with RA and 1643 non-RA subjects (72% women; mean age 63.1 years) were studied. Using the 44 morbidities, multimorbidity (defined as 2+ morbidities) was present in 1411 (86%) of RA and 1164 (71%) of non-RA subjects (p<0.001) with 5+ morbidities present in 907 (55%) of RA and 619 (38%) of non-RA (p<0.001). Patients with RA had significantly higher prevalence of 24 of the 44 morbidities compared with non-RA, especially interstitial lung disease, fibromyalgia, osteoarthritis and osteoporosis. Among the additional 78 categories, 7 were significantly higher in RA than non-RA, including organic sleep disorders, vitamin D deficiency and foot ulcers. Conclusion Patients with RA have a higher prevalence of multimorbidity compared with non-RA subjects. These results confirm the list of 44 morbidities and add several other morbidities of interest in RA.

AbstractPurposeTo demonstrate the feasibility of simultaneous dual‐contrast imaging in a large animal using a newly developed dual‐source energy‐integrating detector (EID)‐based multi‐energy computed tomography (MECT) system.MethodsTwo imaging tasks that may have potential clinical applications were investigated: head/neck (HN) CT angiography (CTA)/CT venography (CTV) with iodine and gadolinium, and small bowel imaging with iodine and bismuth in domestic swine. Dual‐source X‐ray beam configurations of 70 kV + Au120/Sn120 kV and 70 kV + Au140/Sn140 kV were used for the HN‐CTA/CTV and small bowel imaging studies, respectively. A test bolus scan was performed for each study. The regions of interest (ROIs) in the carotid artery and jugular vein for HN‐CTA/CTV imaging and abdominal aorta for small bowel imaging were used to determine the time‐attenuation curves, based on which the timing for contrast injection and the CT scan was determined. In the HN‐CTA/CTV study, an MECT scan was performed at the time point corresponding to the optimal arterial enhancement by iodine and the optimal venous enhancement by gadolinium. In the small bowel imaging study, an MECT scan was performed at the optimal time point to simultaneously capture the mesenteric arterial enhancement of iodine and the enteric enhancement of bismuth. Image‐based material decomposition was performed to decompose different materials for each study. To quantitatively characterize contrast material separation and misclassification, two ROIs on left common carotid artery and left internal jugular vein in HN‐CTA/CTV imaging and three ROIs on superior mesenteric artery, ileal lumen, and collapsed ileum (ileal wall) in small bowel imaging were placed to measure the mean concentration values and the standard deviations.ResultsIn the HN‐CTA/CTV study, common carotid arteries containing iodine and internal/external jugular veins containing gadolinium were clearly delineated from each other. Fine vessels such as cephalic veins and branches of external jugular veins were noticeable but clear visualization was hindered by image noise in gadolinium‐specific (CTV) images, as reviewed by a neuroradiologist. In the small bowel imaging study, the mesenteric arteries and collapsed bowel wall containing iodine and the small bowel loops containing bismuth were clearly distinctive from each other in the iodine‐ and bismuth‐specific images after material decomposition, as reviewed by an abdominal radiologist. Quantitative analyses showed that the misclassifications between the two contrast materials were less than 1.7 and 0.1 mg/ml for CTA/CTV and small bowel imaging studies, respectively.ConclusionsFeasibility of simultaneous CTA/CTV imaging in head and neck with iodine and gadolinium and simultaneous imaging of arterial and enteric phases of small bowel with iodine and bismuth, using a dual‐source EID‐MECT system, was demonstrated in a swine study. Compared to iodine and gadolinium in CTA/CTV, better delineation and classification of iodine and bismuth in small bowel imaging were achieved mainly due to wider separation between the corresponding two K‐edge energies.

ObjectiveTo identify the incidence, risk factors, and outcomes of rheumatoid arthritis–associated interstitial lung disease (RA‐ILD) and to assess time trends in the incidence and mortality in RA‐ILD.MethodsWe included adult residents of Olmsted County, Minnesota with incident RA between 1999 and 2014. Subjects were followed until death, emigration, or April 30, 2019. ILD was defined as the presence of a radiologist‐defined pattern consistent with ILD on chest computed tomography (CT). When chest CT was absent, the combination of chest radiograph abnormalities compatible with ILD and restrictive pattern on pulmonary function testing was considered consistent with ILD. Potential risk factors included age, sex, smoking, obesity, seropositivity, extraarticular manifestations (EAMs), and medications. For survival analysis, we matched RA‐ILD patients to RA–non‐ILD comparators. The frequency and mortality from clinician‐diagnosed RA‐ILD from 1999 to 2014 was compared against a cohort from 1955 to 1994.ResultsDuring the 1999–2014 time period, 645 individuals (70% women) had incident RA, were a median age of 55.3 years, and 53% never smoked. Twenty‐two patients had ILD before RA, and 51 (67% women) developed ILD during follow‐up. The 20‐year cumulative incidence of RA‐ILD was 15.3%. Ever‐smoking (hazard ratio [HR] 1.92), age at RA onset (HR 1.89 per 10‐year increase), and severe EAMs (HR 2.29) were associated with incident RA‐ILD. The RA‐ILD cases had higher mortality than their matched RA comparators (HR 2.42). Incidence of RA‐ILD was non‐significantly lower from 1999 to 2014 than from 1955 to1994, but mortality was improved.ConclusionsRA‐ILD occurs in nearly 1 in 6 patients with RA within 20 years and is associated with shorter survival. Lack of significant change in RA‐ILD incidence over 6 decades deserves further investigation.

Introduction Tourette’s syndrome (TS) affects approximately 1% of children. This study will determine the efficacy and safety of paired comprehensive behavioural intervention for tics (CBIT) plus repetitive transcranial magnetic stimulation (rTMS) treatment in children with Tourette’s syndrome. We hypothesise that CBIT and active rTMS to the supplementary motor area (SMA) will (1) decrease tic severity, and (2) be associated with changes indicative of enhanced neuroplasticity (eg, changes in in vivo metabolite concentrations and TMS neurophysiology measures). Methods and analysis This study will recruit 50 youth with TS, aged 6–18 for a phase II, double-blind, block randomised, sham-controlled trial comparing active rTMS plus CBIT to sham rTMS plus CBIT in a 1:1 ratio. The CBIT protocol is eight sessions over 10 weeks, once a week for 6 weeks and then biweekly. The rTMS protocol is 20 sessions of functional MRI-guided, low-frequency (1 Hz) rTMS targeted to the bilateral SMA over 5 weeks (weeks 2–6). MRI, clinical and motor assessments and neurophysiological evaluations including motor mapping will be performed 1 week before CBIT start, 1 week after rTMS treatment and 1 week after CBIT completion. The primary outcome measure is Tourette’s symptom change from baseline to post-CBIT treatment, as measured by the Yale Global Tic Severity Scale. Secondary outcomes include changes in imaging, neurophysiological and behavioural markers. Ethics and dissemination Ethical approval by the Conjoint Health Research Ethics Board (REB18-0220). The results of this study will be published in peer-reviewed scientific journals, on ClinicalTrials.gov and shared with the Tourette and OCD Alberta Network. The results will also be disseminated through the Alberta Addictions and Mental Health Research Hub. Trial registration NCT03844919 .