Citations

Abstract Calmodulin‐binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long‐term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals ( n = 26) with 23 novel CAMTA1 variants (frameshift‐7, nonsense‐6, splicing‐1, initiation codon‐1, missense‐5, and intragenic deletions‐3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under‐reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals.

Abstract Background Nontuberculous mycobacterial pulmonary disease (NTMPD) is a chronic lung infection that is challenging to treat, especially refractory NTMPD. Data are limited on the natural history, risk profile, and burden of refractory NTMPD. The objective of this study was to evaluate the burden of illness (BOI) among patients with NTMPD who later develop refractory NTMPD vs those who do not. Methods This was a retrospective analysis using BRR data. Patients treated for NTMPD were included and stratified as refractory (received oral clofazimine/bedaquiline or inhaled amikacin/ALIS, or remained sputum culture positive despite ≥ 6 months of treatment) or nonrefractory. Modified bronchiectasis severity index (mBSI) at baseline visit and BOI including comorbid conditions and surgeries at the treatment visit were compared by cross-sectional analysis between the two groups. Longitudinal analysis of BOI focused on exacerbations and hospitalizations in the refractory group at their pre-refractory visit and refractory visit (first visit meeting the refractory definition). Results A total of 1,064 patients treated for NTMPD were included: 462 (43.4%) refractory and 602 (56.6%) nonrefractory. During the baseline period, the refractory group had more severe bronchiectasis (Table 1, mBSI, mean [SD], 7.3 [3.4] vs 6.7 [3.4]). At the time of treatment, bronchiectasis was more common in the refractory than nonrefractory (96.2% vs 89.7%) group, as were hemoptysis (26.6% vs 16.3%) and GERD (50.5% vs 39.9%). Except BMI, there were no statistically significant differences between the pre-refractory and nonrefractory treatment visits (Table 2). In the refractory group, exacerbations and hospitalizations remained high from the pre-refractory to refractory visit (45.6% vs 39.4% and 13.3% vs 12.8%, respectively). Oxygen and bronchial hygiene use increased from the pre-refractory to the refractory visit (5.2% vs 9.3% and 54.5% vs 61.7%, respectively) consistent with increased management of respiratory conditions when not responding to treatment (Table 2). Conclusion Refractory NTMPD imposes a high disease burden on patients in the BRR. This high burden was present at pre-refractory visits and through the development of refractory status. Disclosures Timothy R. Aksamit, MD, AstraZeneca: Advisor/Consultant|Baxter International, Hill-Rom: Advisor/Consultant|Insmed Incorporated: Advisor/Consultant|Johnson & Johnson: Advisor/Consultant|Redhill Biopharma: Advisor/Consultant|RespirTech: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Zambon: Advisor/Consultant David M. Mannino, MD, AstraZeneca: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Up to Date: Advisor/Consultant Ping Wang, PhD, Insmed Incorporated: Salary|Insmed Incorporated: Stocks/Bonds Mariam Hassan, PhD, B. Pharm, Insmed Incorporated: Salary|Insmed Incorporated: Stocks/Bonds

Pontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, a subunit of the FAM91A1 complex, have been found in patients with PCH-like symptoms; however, definitive evidence that the mutations are causal is still lacking. Here, we show that depletion of FAM91A1 results in developmental defects in zebrafish similar to that of TBC1D23, an established PCH gene. FAM91A1 and TBC1D23 directly interact with each other and cooperate to regulate endosome-to-Golgi trafficking of KIAA0319L, a protein known to regulate axonal growth. Crystal structure of the FAM91A1–TBC1D23 complex reveals that TBC1D23 binds to a conserved surface on FAM91A1 by assuming a Z-shaped conformation. More importantly, the interaction between FAM91A1 and TBC1D23 can be used to predict the risk of certain TBC1D23-associated mutations to PCH. Collectively, our study provides a molecular basis for the interaction between TBC1D23 and FAM91A1 and suggests that disrupted endosomal trafficking underlies multiple PCH subtypes.

AbstractBackgroundRecent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk‐prediction model (called SPLC‐RAT) was developed and validated using data from population‐based epidemiological cohorts and clinical trials, but real‐world validation has been lacking. The predictive performance of SPLC‐RAT was evaluated in a hospital‐based cohort of lung cancer survivors.MethodsThe authors analyzed data from 8448 ever‐smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997–2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC‐RAT and further explored the potential of improving SPLC detection through risk model‐based surveillance using SPLC‐RAT versus existing clinical surveillance guidelines.ResultsOf 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person‐years. The application of SPLC‐RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10‐year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC‐RAT development cohort), the observed SPLC incidence was significantly elevated in the high‐risk versus low‐risk subgroup (13.1% vs. 1.1%, p < 1 × 10–6). The risk‐based surveillance through SPLC‐RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow‐ups needed to detect one SPLC (162 vs. 202).ConclusionIn a large, hospital‐based cohort, the authors validated the predictive performance of SPLC‐RAT in identifying high‐risk survivors of SPLC and showed its potential to improve SPLC detection through risk‐based surveillance.Plain Language Summary Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC). However, no evidence‐based guidelines for SPLC surveillance are available for lung cancer survivors. Recently, an SPLC risk‐prediction model was developed and validated using data from population‐based epidemiological cohorts and clinical trials, but real‐world validation has been lacking. Using a large, real‐world cohort of lung cancer survivors, we showed the high predictive accuracy and risk‐stratification ability of the SPLC risk‐prediction model. Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model‐based surveillance strategies compared to the existing consensus‐based clinical guidelines, including the National Comprehensive Cancer Network.

Abstract Introduction . Dispersion in an accelerator quantifies the deviation of the proton trajectory when there is a momentum deviation. We present for the first time a safe method of measuring dispersion in the clinic, using a scintillator detector and the momentum deviations within a spill. This is an important accelerator quantity as we found that this is the reason behind the large dose fluctuation in our absolute dosimetry measurement. Methods . Dispersions are measured for nine energies in a Hitachi ProBeat system at three locations (isocenter and at two profile monitors) and at two gantry angles (0 and 90 degrees) by first measuring the spot position and momentum drift within a spill. The spot position drift is measured by the XRV-4000 at the isocenter, and by the two profile monitors located at 0.57 and 2.27 m from the isocenter. The momentum drift is calculated from the intra-spill range drift which is measured using the Ranger accessory. The dispersion at isocenter and its gradient are calculated using the weighted least square regression on the measured dispersions at the three locations. A constraint is formulated on the dispersion and its gradient to ensure minimal intra-spill spot position deviation around the isocenter. Results . The measured intra-spill range and spot positional drift at isocenter are less than 0.25 mm and 0.7 mm respectively. The momentum spread calculated from the range drift are less than 0.08%. The dispersion at the isocenter ranged from 0.50 to 4.30 m and the zero-crossing happens upstream of isocenter for all energies. 2 of the 9 energies (168.0 and 187.5 MeV) violated the constraint and has an intra-spill spot positional deviation greater than 1.0 within 5 cm from the isocenter. Conclusion . This measurement is recommended as part of commissioning and annual quality assurance for accelerator monitoring and to ensure intra-spill spot deviations remain low.

Background: Due to lacking evidence on surveillance for gastric cancer (GC), this study aimed to determine the optimal postsurgical surveillance strategy for pathological stage (pStage) II/III GC patients and compare its cost-effectiveness with traditional surveillance strategies. Methods: Prospectively collected data from stage II/III GC patients (n=1661) who underwent upfront surgery at a large-volume tertiary cancer center in China (FJMUUH cohort) between January 2010 and October 2015. For external validation, two independent cohorts were included, which were composed of 380 stage II/III GC patients at an tertiary cancer center in U.S.A (Mayo cohort) between July 1991 and July 2012 and 270 stage II/III GC patients at another tertiary cancer center in China (QUAH cohort) between May 2010 and October 2014. Random forest models were used to predict dynamic recurrence hazards and to construct individual surveillance strategies for stage II/III GC. Cost-effectiveness was assessed by the Markov model. Results: The median follow-up period of the FJMUUH, the Mayo, and QUAH cohorts were 55, 158, and 70 months, respectively. In the FJMUUH cohort, the 5-year recurrence risk was higher in pStage III compared with pStage II GC patients (P<0.001). Our novel individual surveillance strategy achieved optimal cost-effectiveness for pStage II GC patients (ICER =$490/QALY). The most intensive NCCN surveillance guideline was more cost-effective (ICER =$983/QALY) for pStage III GC patients. The external validations confirmed our results. Conclusion: For patients with pStage II GC, individualized risk-based surveillance outperformed the JGCTG and NCCN surveillance guidelines. However, the NCCN surveillance guideline may be more suitable for patients with pStage III GC. Even though our results are limited by the retrospective study design, the authors believe that our findings should be considered when recommending postoperative surveillance for stage II/III GC with upfront surgery in the absence of a randomized clinical trial.