Citations

Abstract Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response (DDR) could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here, we performed genetic or pharmacologic manipulation of key DDR elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double-strand breaks (DSB) induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ataxia-telangiectasia mutated (ATM) inhibitor, AZD0156, but not an inhibitor of ATM and Rad3-related, rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more DSBs to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor coadministration showed enhanced efficacy in HR-proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR-proficient tumors selectively enhances the relative biological effectiveness of proton Bragg peak irradiation. Significance: Coadministration of an ATM inhibitor rewires DNA repair machinery to render cancer cells uniquely hypersensitive to DNA damage induced by the proton Bragg peak, which is characterized by higher density ionization. See related commentary by Nickoloff, p. 3156

AbstractPurposeSevere adverse events (AEs), such as Guillain‐Barré syndrome (GBS) occur rarely after influenza vaccination. We identify highly associated AEs with GBS and develop prediction models for GBS using the US Vaccine Adverse Event Reporting System (VAERS) reports following trivalent influenza vaccination (FLU3).MethodsThis study analyzed 80 059 reports from the US VAERS between 1990 and 2017. Several AEs were identified as highly associated with GBS and were used to develop the prediction model. Some common and mild AEs that were suspected to be underreported when GBS occurred simultaneously were removed from the final model. The analyses were validated using European influenza vaccine AEs data from EudraVigilance.ResultsOf the 80 059 reports, 1185 (1.5%) were annotated as GBS related. Twenty‐four AEs were identified as having strong association with GBS. The full prediction model, using age, sex, and all 24 AEs achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 85.4% (90% CI: [83.8%, 86.9%]). After excluding the nine (e.g., pruritus, rash, injection site pain) likely underreported AEs, the final AUC became 77.5% (90% CI: [75.5%, 79.6%]). Two hundred and one (0.25%) reports were predicted as of high risk of GBS (predicted probability >25%) and 84 actually developed GBS.ConclusionThe prediction performance demonstrated the potential of developing risk‐prediction models utilizing the VAERS cohort. Excluding the likely underreported AEs sacrificed some prediction power but made the model more interpretable and feasible. The high absolute risk of even a small number of AE combinations suggests the promise of GBS prediction within the VAERS dataset.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.

Objective: The aim of this work is to formulate recommendations based on global expert consensus to guide the surgical community on the safe resumption of surgical and endoscopic activities. Background: The COVID-19 pandemic has caused marked disruptions in the delivery of surgical care worldwide. A thoughtful, structured approach to resuming surgical services is necessary as the impact of COVID-19 becomes better controlled. The Coronavirus Global Surgical Collaborative sought to formulate, through rigorous scientific methodology, consensus-based recommendations in collaboration with a multidisciplinary group of international experts and policymakers. Methods: Recommendations were developed following a Delphi process. Domain topics were formulated and subsequently subdivided into questions pertinent to different aspects of surgical care in the COVID-19 crisis. Forty-four experts from 15 countries across 4 continents drafted statements based on the specific questions. Anonymous Delphi voting on the statements was performed in 2 rounds, as well as in a telepresence meeting. Results: One hundred statements were formulated across 10 domains. The statements addressed terminology, impact on procedural services, patient/staff safety, managing a backlog of surgeries, methods to restart and sustain surgical services, education, and research. Eighty-three of the statements were approved during the first round of Delphi voting, and 11 during the second round. A final telepresence meeting and discussion yielded acceptance of 5 other statements. Conclusions: The Delphi process resulted in 99 recommendations. These consensus statements provide expert guidance, based on scientific methodology, for the safe resumption of surgical activities during the COVID-19 pandemic.

Pain is a major public health problem, causing heavy social and economic burdens to patients and society while consuming tremendous medical resources at the same time. Thus, there is a critical need to find low-cost, efficacious, and therapeutic approaches to help manage pain. While acupuncture is increasingly recognized as a promising pain-relieving method, less is known about a specific form of auricular acupuncture known as Battlefield Acupuncture (BFA). The BFA technique involves the sequential placement of semi-permanent, single-use, French ASP[Formula: see text] golden needles to five specific acupoints in one or both ears, where they are left in place for 3–4 days or longer [Niemtzow, R.C., Battlefield acupuncture. Med. Acupunct. 19: 225–228, 2007]. The BFA needles (more accurately described as tiny conical darts) pierce the ear in designated locations in a particular order [Levy, C.E., N. Casler and D.B. FitzGerald. Battlefield acupuncture: an emerging method for easing pain. Am. J. Phys. Med. Rehabil. 97: e18–e19, 2018.]. (Figs. 4 and 5) It was developed by Dr. Richard C. Niemtzow in 2001, as a subgroup form of an auricular acupuncture technique based on the somatotopic arrangement of an inverted fetus pattern on the external ear [Romoli, M. Ear acupuncture: historical abstract–differences of ear cartography between the east and the west. Dtsch. Z. Akupunkt. 53: 24–33, 2010.]. Currently, BFA is widely used in the US military, but to our knowledge, there is no review which comprehensively synthesizes the current publications surrounding pain management. This review aims to investigate the effects and safety of BFA in adults with pain. Electronic databases were searched for randomized controlled trials (RCTs) published in English evaluating efficacy and safety of BFA in adults with pain, from database inception to September 6, 2019. The primary outcome was pain intensity change, and the secondary outcome was safety. Nine RCTs were included in this review, and five trials involving 344 participants were analyzed quantitatively. Compared with no intervention, usual care, sham BFA, and delayed BFA interventions, BFA had no significant improvement in the pain intensity felt by adults suffering from pain. Few adverse effects (AEs) were reported with BFA therapy, but they were mild and transitory. BFA is a safe, rapid, and easily learned acupuncture technique, mainly used in acute pain management, but no significant efficacy was found in adult individuals with pain, compared with the control groups. Given the poor methodological quality of the included studies, high-quality RCTs with rigorous evaluation methods are needed in the future.

Abstract OBJECTIVES Neuroendocrine thymic tumours (NETTs) are a distinct subgroup of rare malignancies. An international, multicentre retrospective analysis was used to study the clinicopathological features, current pattern of diagnosis, treatment and outcomes of patients with NETT. METHODS One hundred and forty-six NETT treated from 1989 to 2016 at 21 centres in China, Europe and North America were retrospectively collected and reclassified according to the World Health Organization histological type and International Thymic Malignancy Interest Group (ITMIG)/International Association for Studies in Lung Cancer (IASLC)/Union for International Cancer Control (UICC) staging. Clinicopathological features, diagnostic and therapeutic approaches and outcomes were investigated. Results in the earlier and latter halves of the study period were also compared. RESULTS The pretreatment work-up relied exclusively on computed tomography in 85.6% (125/146) of cases. Most patients had advanced disease, with 32.2% (47/146) having lymph node involvement. Higher-grade histological type was associated with more advanced disease (P &lt; 0.05). Induction therapies and surgical procedures were used more often in the latter half of the study. However, the complete resection rate remained unchanged, being 71.5% (98/137) in the whole group. Complete resection was associated with significantly longer 5-year overall survival (77.2% vs 51.2%; P &lt; 0.001) than incomplete or no resection. Significant survival differences were seen with the T, N and M categories of ITMIG/IASLC/UICC staging. Poorly differentiated carcinoma, ITMIG/IASLC/UICC stage IIIa or above and incomplete or no resection were independent risk factors for worse survival. No survival difference was noted between the earlier and the latter halves of the study (58.2% vs 71.9%; P = 0.299). CONCLUSIONS Current management similar to that for thymomas is unsatisfactory in providing disease control or long-term survival for patients with NETT. Specific diagnostic tools and novel therapeutic agents are needed to improve management outcomes of this disease.

Background: The FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Gilt) improves survival compared with standard salvage chemotherapy in relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML); however, relapses are common and long-term survival remains poor. Combination therapies of FLT3 tyrosine kinase inhibitors (TKIs) with agents that induce apoptosis have demonstrated preclinical synthetic lethality and enhanced cytotoxicity against FLT3mut+ clones. This may delay or prevent drug resistance. We present updated data from the dose-escalation and expansion cohorts of an ongoing, multicenter, open-label, Phase 1b trial (NCT03625505) of Gilt in combination with B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Ven) in patients (pts) with R/R FLT3mut+ AML. Methods: Pts with R/R AML with ≥1 prior line of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible. The expansion cohort required FLT3mut+ R/R AML at enrollment. Pts received the recommended Phase 2 dose (RP2D) of Ven 400 mg in combination with Gilt 120 mg daily in 28-day cycles, following a 3-day ramp-up of Ven. Pts with prior Gilt were excluded from expansion, and none were enrolled in dose escalation; prior Ven or other FLT3 inhibitor was permitted. Concurrent use of moderate or strong CYP3A4 inhibitor was allowed. Interruptions of Ven or both drugs simultaneously were permitted for management of adverse events (AEs), and subsequent cycles could include dose adjustments to minimize myelosuppression or other drug-related AEs. The primary endpoint was modified composite complete remission (mCRc; complete response [CR] + CR with incomplete platelet recovery [CRp] + CR with incomplete blood count recovery [CRi]) + morphologic leukemia-free state (MLFS). Responses were graded by the International Working Group (IWG) for AML criteria (with adapted CRi criteria as presented in the ADMIRAL trial) for comparison with composite CR (CRc) used in Gilt development. All criteria for response used by IWG were maintained in these response definitions. Secondary endpoints included CR + CR with partial hematologic recovery (CRh) and duration of response (DOR) of mCRc. Results: At data cutoff, April 15, 2020, 39 R/R pts started therapy at the RP2D (internal tandem duplications [ITD] only [n=32]; tyrosine kinase domain [TKD] mutation only [n=5]; both TKD and ITD [n=2]). Median age was 63 years (range 23-85) and the majority had an ECOG status of 1-2 (87.2%). Most pts (n=29; 74.4%) had received ≥2 prior lines of therapy, including ≥1 FLT3 TKI (n=25, 64.1%; midostaurin, n=19; sorafenib, n=5; crenolanib, n=1). Twelve pts (30.8%) had prior stem-cell transplant (SCT); 3 (7.7%) had received prior Ven. Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 37 pts (94.9%), and 28 (71.8%) reported serious AEs. The only Grade 3/4 nonhematologic TEAE reported in &gt;20% of pts was febrile neutropenia (48.7%). Four pts (10.3%) experienced a fatal AE, including colitis, disease progression, multiple organ dysfunction syndrome, and bronchopulmonary aspergillosis (all n=1). AEs leading to Ven and Gilt interruptions occurred in 19 pts (48.7%) and 18 pts (46.2%), respectively, and AEs leading to dose reductions occurred in 2 pts (5.1%) for each treatment. Six pts (15.4 %) and 5 pts (12.8%) discontinued Ven and Gilt, respectively, owing to AEs. mCRc was achieved by 83.8% of pts (n=31/37; Table). With median duration of follow-up of 2.9 (range 0.8−11.0) months in all pts, median event-free survival was 5.1 (95% confidence interval: 2.8, 8.3) months but administrative censoring after short follow-up for a large number of recently enrolled patients limits interpretation; median DOR has not been reached. Eight pts (21.6%), all ITD only, proceeded to SCT. CR + CRh was achieved by 7 pts (18.9%). Conclusions: Ven plus Gilt achieved a very high overall rate of marrow and blood blast elimination and mCRc rate (84%) in this expansion cohort of heavily pretreated FLT3mut+ pts, the majority of whom had prior FLT3 TKI exposure. Using similar response assessment criteria, the high mCRc rate here suggests substantially greater antileukemic activity from Ven plus Gilt compared with single-agent Gilt. Cytopenias were prominent but manageable with dose interruption/modification on subsequent cycles. Nonhematologic toxicities were modest, and the combination was well tolerated. Disclosures Daver: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Altman:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Agios, Theradex, Abbvie: Other: Advisory Board; Astellas, Agios: Honoraria, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Patents & Royalties: Scientific Advisory Board - no payment accepted; Biosight: Other: No payment but was reimbursed for travel . Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Ritchie:Abbvie: Honoraria; Sierra Oncology: Honoraria; Incyte: Speakers Bureau; Novartis: Honoraria; Jazz pharmaceuticals: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. McCloskey:Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Smith:Abbvie: Other: Research Support, Research Funding; Sanofi: Honoraria; Astellas Pharma: Honoraria, Other: Research Support, Research Funding; FujiFilm: Other: Research support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria. Schiller:Johnson & Johnson: Current equity holder in publicly-traded company; Novartis: Consultancy, Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Genentech-Roche: Research Funding; Geron: Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Celator: Research Funding; FujiFilm: Research Funding; Ariad: Research Funding; Constellation: Research Funding; Cyclacel: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Astellas Pharma: Honoraria, Research Funding; Actinium: Research Funding; Gamida: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Daiichi Sankyo: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Forma: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Sanofi: Speakers Bureau. Bradley:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Qin:AbbVie: Current Employment, Other: may hold stock or other options. Dilley:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Perl:Leukemia & Lymphoma Society.: Other; AbbVie Inc, Astellas, Actinium, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo Inc, FUJIFILM Pharmaceuticals USA Inc: Research Funding; AbbVie Inc, Actinium Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc, FORMA Therapeutics, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, NewLink Genetics: Other; AbbVie Inc, Arog Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc: Consultancy; Astellas, AbbVie Inc, Daiichi Sankyo, Actinium, Forma, Syndax, Loxo: Consultancy, Honoraria. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test.

Abstract PrimPol has been recently identified as a DNA damage tolerant polymerase that plays an important role in replication stress response. However, the regulatory mechanisms of PrimPol are not well defined. In this study, we identify that the deubiquitinase USP36 interferes with degradation of PrimPol to regulate the replication stress response. Mechanistically, USP36 is deubiquitinated following DNA replication stress, which in turn facilitates its upregulation and interaction with PrimPol. USP36 deubiquitinates K29-linked polyubiquitination of PrimPol and increases its protein stability. Depletion of USP36 results in replication stress-related defects and elevates cell sensitivity to DNA-damage agents, such as cisplatin and olaparib. Moreover, USP36 expression positively correlates with the level of PrimPol protein and poor prognosis in patient samples. These findings indicate that the regulation of PrimPol K29-linked ubiquitination by USP36 plays a critical role in DNA replication stress and chemotherapy response.

AbstractMolecular prognostic factors for individualized treatment of squamous cell carcinoma (SCC) are poorly defined. Our study developed and validated a novel molecular tools aid in preinguinal and postinguinal lymphadenectomy risk stratification in node‐positive penile SCC. Patients with node‐positive penile SCC who underwent inguinal or ilioinguinal lymphadenectomy were divided into three cohorts: a discovery set, a development set and a validation set. The local ethics committee approved the study. The primary endpoint was cancer‐specific survival (CSS). At the discovery stage, 17 CpG sites were significantly associated with CSS. In the development set, we constructed a 3‐CpG‐based prognostic score for survival prediction. The hazard ratio (HR) of the panel (dichotomized using the optimal cutoff) was 5.8 in the multivariate analyses (P < .001). The addition of the methylation score significantly improved the pN‐stage C‐index from 0.70 to 0.79 (incremental C = 0.09, P < .001). In the validation set, the methylation panel showed a HR of 9.9 in the multivariate analyses. The addition of the molecular marker improved the pN‐stage C‐index from 0.69 to 0.78 (incremental C = 0.09, P < .001). The methylation score remarkably separated survival curves in different pN stages, which indicate that the tool can be applied to tailor the treatment in both preinguinal and postinguinal lymphadenectomy settings. We developed and validated a prognostic methylation panel for node‐positive penile SCC. The tool may aid in the risk stratification of the population with heterogeneous outcomes and needs prospective validation. Patients in high‐risk group may benefit from more aggressive therapy or clinical trials.