Leprosy is a chronic infectious and neurological disease that is caused by infection of Mycobacterium leprae (M. leprae). A recent genome-wide association study indicated a suggestive association of LRRK2 genetic variant rs1873613 with leprosy in Chinese population. To validate this association and further identify potential causal variants of LRRK2 with leprosy, we genotyped 13 LRRK2 variants in 548 leprosy patients and 1078 healthy individuals from Yunnan Province and (re-)analyzed 3225 Han Chinese across China. Variants rs1427267, rs3761863, rs1873613, rs732374 and rs7298930 were significantly associated with leprosy per se and/or paucibacillary leprosy (PB). Haplotype A-G-A-C-A was significantly associated with leprosy per se (P=0.018) and PB (P=0.020). Overexpression of the protective allele (Thr2397) of rs3761863 in HEK293 cells led to a significantly increased nuclear factor of activated T-cells' activity compared with allele Met2397 after lipopolysaccharides stimulation. Allele Thr2397 could attenuate 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced autophagic activity in U251 cells. These data suggest that the protective effect of LRRK2 variant p.M2397T on leprosy might be mediated by increasing immune response and decreasing neurotoxicity after M. leprae loading. Our findings confirm that LRRK2 is a susceptible gene to leprosy in Han Chinese population.

Helical tomotherapy with prone breast positioning can simultaneously cover the breast and regional nodes with acceptable uniformity and can provide reduced mean dose to proximal organs at risk compared with tomotherapy with supine position. The similarity of plan quality to existing data for conventional breast radiotherapy indicates that this planning approach is appropriate, and that the risk of secondary tumour formation should not be significantly greater.

This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PPAx nodes that are pathologically negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC PPAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts may receive appropriate adjuvant systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1,636 pts are to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 6-21-18 is 967 (59.11%). Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. NCT01872975 Support: U10 CA-2166; -180868, -180822; 189867; Elekta Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Curran WJ, Wolmark N. Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC): NRG Oncology/NSABP B-51/RTOG 1304 [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 OT2-04-01.

Background: This phase III post-NC trial will evaluate if CWRNRT post Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the invasive breast cancer recurrence-free interval (IBC-RFI) rate in pts presenting with positive Ax nodes that are negative after NC. Secondary aims are OS, LRRFI, DRFI, DFS-DCIS, and second primary cancer as well as comparing RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease pts, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC pts with positive Ax nodes (FNA or core needle biopsy) complete ≥12 wks of NC (anthracycline and/or taxane). HER2-positive pts receive anti-HER2 therapy (tx). After NC BCS or Mx is performed with a sentinel node biopsy (≥3 nodes) and/or Ax dissection with histologically negative nodes. ER/PR and HER-2 neu status before NC is required. Pts receive required systemic tx. Radiation credentialing with a facility questionnaire and a case benchmark is required. Randomization for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI RNRT. Statistics: 1,636 pts to be enrolled over 5 yrs with definitive analysis at 7.5 yrs. Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction in the 5-yr cumulative rate of 4.6%. Intent-to-treat analysis with 3 interim analyses at 43, 86, and 129 events, with a 4th/final analysis at 172 events will occur. Accrual as of 6/4/15 is 143. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before randomization and at 3, 6, 12, and 24 months. Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. Support: U10 CA-2166; -180868, -180822; -189867; Elekta. Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Costantino JP, Curran Jr WJ, Wolmark N. NRG Oncology/NSABP B-51/RTOG 1304: A phase III clinical trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) will reduce invasive cancer events in patients (pts) with positive axillary (Ax) nodes who are ypN0 after neoadjuvant chemotherapy (NC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-02-02.

BackgroundAccurate delineation of the gross tumor volumes (GTV) is a prerequisite for precise radiotherapy planning and delivery. Different MRI sequences have different advantages and limitations in their ability to discriminate primary cervical tumor from normal tissue. The purpose of this work is to determine appropriate MRI techniques for GTV delineation for external-beam radiation therapy of locally advanced cervical cancer (LACC).Materials and MethodsGTVs were delineated on the MRI, CT, and PET images acquired for 23 LACC patients in treatment positions to obtain GTVs on CT (GTV-CT), on various MRI sequences including T1 (GTV-T1), T2 (GTV-T2), T1 with fat suppression and contrast (GTV-T1F+), DWI-ADC (GTV-ADC) and on PET were generated using the threshold of 40% of maximum SUV (GTV-SUV40%) as well as SUV of 2.5 (GTV-SUV2.5). MRI, CT and PET were registered for comparison. The GTVs defined by MRI were compared using the overlap ratio (OR) and relative volume ratio (RVR). The union of GTV-T2 and GTV-ADC was generated to represent the MRI-based GTV (GTV-MRI).ResultsThe differences between GTV-T2 and other MRI GTVs are significant (P < 0.05). The average ORs for GTV-T1, GTV-T1F+, and GTV-ADC related to GTV-T2 were 86.3%, 81.6%, and 61.6% with the corresponding average RVRs 113.8%, 112.3% and 77.2%, respectively. There is no significant difference between GTV-T1 and GTV-T1F+. GTV-ADC was generally smaller than GTV-T2, however, encompassed suspicious regions that are uncovered in GTV-T2 (up to 16% of GTV-T2) because of different imaging mechanisms. There was significant difference between GTV-MRI, GTV-SUV2.5, GTV-SUV40%, and GTV-CT. On average, GTV-MRI is 18.4% smaller than GTV-CT.ConclusionsMRI provides improved visualization of disease over CT or PET for cervical cancer. The GTV from the union of GTV-T2 and GTV-ADC provides a reasonable GTV including tumor region defined anatomically and functionally with MRI and substantially reduces the conventional GTV defined on CT.