Citations

Abstract The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Abstract Background Hot flashes (HFs) negatively affect quality of life among perimenopausal and postmenopausal women. This study investigated the efficacy of oxybutynin vs placebo in decreasing HFs. Methods In this randomized, multicenter, double-blind study, women with and without breast cancer with 28 or more HFs per week, lasting longer than 30 days, who were not candidates for estrogen-based therapy, were assigned to oral oxybutynin (2.5 mg twice a day or 5 mg twice a day) or placebo for 6 weeks. The primary endpoint was the intrapatient change from baseline in weekly HF score between each oxybutynin dose and placebo using a repeated-measures mixed model. Secondary endpoints included changes in weekly HF frequency, HF-related daily interference scale questionnaires, and self-reported symptoms. Results We enrolled 150 women. Baseline characteristics were well balanced. Mean (SD) age was 57 (8.2) years. Two-thirds (65%) were taking tamoxifen or an aromatase inhibitor. Patients on both oxybutynin doses reported greater reductions in the weekly HF score (5 mg twice a day: −16.9 [SD 15.6], 2.5 mg twice a day: −10.6 [SD 7.7]), placebo −5.7 (SD 10.2); P < .005 for both oxybutynin doses vs placebo), HF frequency (5 mg twice a day: −7.5 [SD 6.6], 2.5 mg twice a day: −4.8 [SD 3.2], placebo: −2.6 [SD 4.3]; P < .003 for both oxybutynin doses vs placebo), and improvement in most HF-related daily interference scale measures and in overall quality of life. Patients on both oxybutynin arms reported more side effects than patients on placebo, particularly dry mouth, difficulty urinating, and abdominal pain. Most side effects were grade 1 or 2. There were no differences in study discontinuation because of adverse effects. Conclusion Oxybutynin is an effective and relatively well-tolerated treatment option for women with HFs.

Abstract BACKGROUND: Pomalidomide-dexamethasone (Pom-Dex) represents an important therapeutic advance for the treatment of patients with relapsed/refractory multiple myeloma (MM). Nonetheless, patients with lenalidomide (Len) and bortezomib (double) refractory disease have a median progression-free survival of only 3.7 months with the combination, thus highlighting the need for further progress. Ixazomib, a novel, oral proteasome inhibitor, has pharmacodynamic properties that may allow for improved proteasome inhibition at the tumoral level and has synergistic activity in combination with IMiDs in preclinical MM models. Clinical studies have demonstrated activity as a single agent in relapsed/refractory MM and in combination with Len-Dex in newly diagnosed patients. We therefore evaluated the safety and preliminary efficacy of the combination of Pom, ixazomib and Dex in patients with Len and proteasome inhibitor (PI) refractory MM in the phase I portion of Alliance study A061202. METHODS: Key eligibility criteria included: relapsed or relapsed/refractory disease; ≥2 prior lines of therapy; double refractory disease (progression on or ≤60 days from the last dose of a Len- and PI-based therapy); ECOG performance status (PS) ≤2; absolute neutrophil count ≥1.0 x 109/L, platelets ≥50 x 109/L, creatinine clearance ≥50 mL/min; and ≤grade 2 peripheral neuropathy. Patients were treated with escalating doses of Pom and ixazomib utilizing a standard 3 + 3 dose escalation design in combination with standard dose Dex (Table 1). Patients received 2 - 4 mg of Pom on days 1 - 21; ixazomib 3 - 4 mg on days 1, 8 and 15; and Dex 40 mg (20 mg for those >75 years of age) on days 1, 8, 15 and 22 of a 28-day cycle. Patients were treated until disease progression or the development of unacceptable toxicity. RESULTS: Out of 17 evaluable patients, the median age was 64 (range 47 - 77) and the median time from diagnosis 5.5 years (range 3.3 - 8.3). Sixty-five percent, 24% and 12% had ISS stage 1, 2 and 3 disease at the start of treatment, respectively, and 65% had high-risk cytogenetics (gain of 1q, del[17p] and/or high-risk IgH translocation). All patients had an ECOG PS of 0 or 1 (59% and 41%, respectively). Of 14 patients with complete prior treatment data available, 100% had received prior Len, bortezomib and Dex, 71% alkylating agents (cyclophosphamide or low dose melphalan), 71% autologous stem cell transplant and 29% carfilzomib. Eighty-two percent were refractory to sequential Len- and bortezomib regimens, whereas 6% were refractory to a prior Len/proteasome inhibitor combination (12% not reported). Two dose limiting toxicities have occurred to date, 1 each at dose levels 3 and 4 (Table 1). Grade 3 and 4 neutropenia, thrombocytopenia and lymphopenia attributable to protocol therapy have been seen in 29%/6%, 12%/6% and 29%/0% of patients, respectively. Twelve percent of patients have experienced grade 3 infection, regardless of attribution, but none have experienced ≥grade 4 infection. The incidence of therapy-related peripheral neuropathy was 24%, none of which was ≥grade 3 in severity. Other common, therapy-related adverse events have included fatigue (53%), nausea (24%), constipation (18%), diarrhea (29%), rash (18%), tremor (24%), anxiety (18%), insomnia (29%) and edema (24%), all of which were ≤grade 2 in severity. Fifty-three percent of patients had at least 1 of the 3 medications dose reduced, and 35% experienced dose delays. To date, 1 patient has discontinued therapy due to adverse events and 1 due to refusal of further therapy. Of 13 patients receiving >1 cycle of therapy, the best overall response rate was 62% (7 partial responses, 1 very good partial response). CONCLUSIONS: The Pom, ixazomib and Dex combination has demonstrated an acceptable toxicity profile thus far with encouraging preliminary efficacy. Updated results of the phase I portion of the study will be presented at the meeting, including the maximum tolerated dose that will be used in the randomized, phase II portion of the study, in which the 3-drug combination will be compared with Pom-Dex in double refractory MM patients. ClinicalTrials.gov Identifier: NCT02004275. Supported by U10CA180821, U10CA180882. Table 1. Dose Level Pomalidomide Dose (mg) Ixazomib Dose (mg) DLT Evaluable DLTs 1 2 3 3 None 2 3 3 3 None 3 4 3 6 1 febrile neutropenia 4‡ 4 4 4 1 grade 4 thrombocytopenia lasting 8 days ‡enrollment into dose level 4 is complete. Disclosures Voorhees: Janssen, Celgene, GlaxoSmithKline, Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: We will discuss the use of Ixazomib, an agent that is not FDA approved, in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma.. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

Prior research explored reasons for tobacco use among pregnant Alaska Native (AN) women but did not address the postpartum period. This study followed up with AN women one to three years postpartum who had participated in a prenatal smoking cessation intervention study (Motivate Alaska Women (MAW) Phase 3) and had consented to be re-contacted for future studies. Of 47 eligible women, 32 (68%) participated. A semi-structured phone interview was conducted a mean of 2.0 years after delivery (range 1.6–2.8). Measures assessed self-reported tobacco use status in the 12 months after delivery, at 12 months postpartum, and at the time of the interview; reasons for maintaining abstinence, continued use, or relapse; and included the Perceived Stress Scale (PSS) and Negative Affect (NA) scale. Content analysis was used to generate themes from open-ended response items. Tobacco use was reported by 23 women (72%) at delivery, 30 (94%) within the 12 months after delivery, 27 (84%) at 12 months postpartum, and 29 (91%) at the time of the interview. Among nine women not using tobacco at delivery, seven (78%) relapsed during the 12 months after delivery. Of the 29 current tobacco users, 28 (97%) smoked cigarettes. Twenty-seven participants (84%) reported stress and 15 (52%) indicated addiction as reasons for continuing, starting, or resuming tobacco use. Types of stressors were related to parenting and traumatic experiences. Among current tobacco users, mean NA score (18.7) was significantly higher (p = 0.01) than the normative mean (14.8), but no differences were detected for PSS score. In this sample of AN women, postpartum tobacco use was highly prevalent, and stress was a primary reason that women endorsed for using tobacco. These preliminary results have several practice and research implications for exploring ways to support non-tobacco use among postpartum AN women.

Context.— Blood culture contamination is a common problem faced by medical centers and leads to significant cost. A possible method to reduce contamination is to discard the initial aliquot of blood, which contains skin and bacteria. Objective.— To determine whether the rate of contaminant blood cultures could be reduced by changing the order of draw to divert the first 7 mL to a gold- or green-top tube. Design.— A preintervention and postintervention study was conducted. During the 18-month intervention phase (September 2015–February 2017), all nurses in the emergency department and inpatient floor phlebotomists collected blood cultures by drawing the first 7 mL of blood into a gold- or green-top tube followed by drawing blood for blood culture bottles. The 18 months immediately preceding the study period (February 2014–July 2015) were used for comparison. Results.— There was an overall statistically significant decrease in contamination rate from 2.46% in the prediversion protocol group to 1.70% in the postdiversion protocol group (P < .001). Emergency department drawn cultures and inpatient cultures showed significant decrease in contamination rates between the preprotocol and postprotocol groups, 2.92% versus 1.95% (P < .001) for emergency department, and 1.82% versus 1.31% (P = .03) for inpatient. We noted less month-to-month variation during the study period compared with the preintervention period. Conclusions.— By using this simple diversion method, we were able to improve blood culture contamination rates for our emergency department and inpatients while incurring no added cost to the procedure.

Abstract Background: HF occur in about 75% of midlife women and are associated with quality of life disruption and premature endocrine therapy discontinuation among breast cancer survivors. Estrogen therapy, effective for HF, is contraindicated in hormone receptor-positive breast cancer (BC). Previous studies have suggested that Oxy could be effective in managing HF. Methods: This randomized, placebo (P)-controlled trial enrolled women who had experienced HF ≥28 times per week over >30 days and of sufficient severity to seek treatment. Patients (pts) were randomized to receive oral Oxy at two doses: 2.5mg BID for 6 weeks (Oxy2.5), 2.5mg BID for a week with subsequent increase to 5mg BID (Oxy5), or matching P, in equal ratios. Baseline and monthly questionnaires were administered including a HF diary, the HF related daily interference scale (HFRDIS) and a symptom experience questionnaire. The primary endpoint was intra-patient change in weekly HF score and frequency from baseline to end of study compared using Kruskal-Wallis tests. Results: 150 pts were accrued between 2/23/2017-3/5/2018. 4 pts cancelled before starting treatment and were excluded from analyses. This interim report includes the first 104 pts for which at least one post-baseline evaluation was available. Baseline characteristics were well-balanced between the arms. Sixty-two percent were on tamoxifen or an aromatase inhibitor for the duration of the study. Pts on both Oxy doses had a significantly greater reduction in HF score and frequency compared to P. Pts on Oxy2.5 had a mean change in HF score of -10 (SD 7.4) vs -5.1 (SD 9.7) with P, p=0.003; and a mean change in average weekly number of HF of -4.6 (SD 3.1) vs -2.3 (SD 3.9), p=0.002. Pts on Oxy5 had a mean change in HF score of -16.2 (SD 5.1) vs -5.1 (SD 9.7) with P, p<0.001; and a mean change in average weekly number of HF of -7.0 (SD 4.0) vs -2.3 (SD 3.9), p<0.001. Repeated measures mixed models confirmed that, after adjusting for baseline values, both Oxy arms had significantly lower HF scores and frequency compared to P (p<0.001). HFRDIS revealed that pts in both Oxy arms experienced improvement in the following HF interference measures: work, social activities, leisure activities, sleep, relations, life enjoyment, and overall quality of life. Pts on Oxy5 also had improvement in HF interference with mood. Pts on Oxy2.5 experienced more stomach pain (p=0.031), diarrhea (p=0.007), nausea (p=0.04), headaches (0.032), episodes of confusion (0.012), dry mouth (p=0.003) and dry eyes (0.027) compared to P. Pts on Oxy5 experienced more constipation (0.004), dry mouth (0.001) and difficulty urinating (0.004) compared to P. There were no differences in study discontinuation due to adverse effects between either Oxy arm and P (Oxy2.5 vs P, p=0.653; Oxy5 vs P, p=0.483). Conclusions: Oxy is superior to P for management of HF. Oxy2.5 and 5 were both associated with significant improvements in HF scores and frequency as well as improvement in HF interference with several quality of life measures. While pts on Oxy experienced more side effects than pts on P, rates of discontinuation due to adverse events were low. This study was supported by the Breast Cancer Research Foundation. Citation Format: Leon-Ferre RA, Novotny PJ, Faubion SS, Ruddy KJ, Flora D, Dakhil C, Rowland KM, Graham ML, Le-Lindqwister N, Loprinzi CL. A randomized, double-blind, placebo-controlled trial of oxybutynin (Oxy) for hot flashes (HF): ACCRU study SC-1603 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS6-02.

AbstractFemale Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.