Citations

AbstractObjectivesWe investigated how tonsillectomy during childhood may influence the distribution of human papillomavirus (HPV) positive cancer of the tonsils in adult life using p16 as a surrogate marker for HPV infection.Study DesignRetrospective observational study.MethodsA total of 280 patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC) and known p16 status were eligible for this study. Each participant was called to obtain the childhood tonsillectomy history. Respondents were subgrouped by p16 status and the primary tumor location. Patient demographic and clinical information was analyzed for association with Fisher's exact and Wilcoxon rank sum tests. Location of tumor was modeled using univariate (UVA) and multivariate (MVA) logistic regression with associated odds ratios (OR) and 95% confidence intervals.ResultsOf the 280 patients, 115 (41%) were respondents: 104 (90.4%) were p16 positive and 11 (9.6%) were p16 negative. For p16 positive patients, we observed a majority (93%) of intact tonsils in those with tonsil cancer, compared to 45% of intact tonsils in patients with p16 positive cancer elsewhere in the oropharynx (P < .001). MVA logistic regression showed that female gender (OR = 4.16, P = .0675), prior smoking history (OR = 2.6, P = .0367), and intact tonsils (OR = 15.2, P < .0001) were associated with tonsillar OPSCC.ConclusionWe found that patients with p16 positive OPSCC at a non‐tonsil site were much more likely to have had prior tonsillectomy vs those with p16 positive OPSCC arising within the tonsil. Nevertheless, we do not advocate tonsillectomies as a public health policy to reduce HPV‐related OPSCC.Level of Evidence6

Abstract: Knee pain is among the most common problems in active patients, with common causes of medial knee pain including meniscal injury, osteoarthritis, medial collateral ligament (MCL) injury, and pes anserine bursopathy/distal hamstring tendinopathy. Some cases of medial knee pain are refractory to standard treatment options and may be caused by rare pathology. We present a case of medial knee pain secondary to medial tibial crest friction syndrome (MTCFS) in a 22-year-old male training for a sprint triathlon after rapidly increasing his training program. Magnetic resonance imaging revealed bone marrow and soft-tissue edema about the MTC deep to the MCL consistent with MTCFS. The patient failed a period of relative rest and activity modification, but improved with corticosteroid injection deep to the MCL in the location of his symptoms. This case highlights a potential management option for MTCFS, a disorder previously described only in radiologic literature.

Background: Standard first-line treatment for patients diagnosed with diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen. Despite numerous efforts to improve on this regimen, in all comers and specifically in those with activated B-cell (ABC)-type DLBCL, results from large randomized studies have failed to show a significant clinical advantage above this standard. Recently, 2 large clinical trials in previously untreated DLBCL evaluated the combination of lenalidomide/R-CHOP (R2-CHOP) vs standard R-CHOP and demonstrated discordant results. We analyzed data from these trials to identify differences that may have impacted the disparate trial outcomes while identifying patient characteristics associated with benefit from the addition of lenalidomide across the trials. Methods: The 2 trials included in this evaluation are ROBUST, an international, randomized, double-blinded, placebo-controlled, phase III study of R2-CHOP vs placebo/R-CHOP, and the Intergroup ECOG-ACRIN 1412 (E1412) trial, a US-only, randomized, open-label, phase II study of R2-CHOP vs R-CHOP. Additional key study design differences included dosing, and subtype timing and inclusion (both studies used gene expression profiling [GEP] by NanoString). R-CHOP dosing differed only for prednisone, which was a flat 100 mg dose, d1-5 in ROBUST and 100 mg/m2, d1-5 in E1412. The lenalidomide dose and schedule varied between studies: 15 mg/d, d1-14/21 for ROBUST (210 mg/cycle) and 25 mg/d, d1-10/21 (250 mg/cycle) for E1412. ROBUST enrolled only patients prospectively identified with the ABC subtype, whereas E1412 enrolled all otherwise eligible patients and retrospectively evaluated for ABC-type with prespecified ABC-type accrual and power parameters. Both studies enrolled patients with IPI status ≥ 2, ECOG PS 0-2, and Ann Arbor stage II-IV (E1412 stage II with mass > 10 cm). The primary endpoint in both was progression-free survival (PFS; central review for ROBUST and investigator-assessed for E1412). Secondary endpoints included event-free survival (EFS; key for ROBUST), overall and complete response rates, overall survival (OS), and safety. Results: ROBUST enrolled 570 ABC patients and E1412 enrolled 280 GCB, ABC, and unclassified DLBCL patients. Patient profiles in both studies (ROBUST [ABC]/E1412 [all COO]) were similar in terms of median ages (65 y/66 y), male sex (58%/61%), and ECOG PS 1-2 (55%/63%). Patients in E1412 were more high risk: IPI 2 (42% ROBUST/34% E1412), IPI ≥ 3 (58%/66%), and Ann Arbor stage III/IV disease (87%/97%). Importantly, there was a notable difference in the time from patient diagnosis to treatment: median 31 days for ROBUST and 21 days (22% > 31 d) for E1412. Only 6% of patients in ROBUST were treated within 2 weeks of diagnosis vs 30% in E1412. At a median follow-up of ~2.5 y for both studies, E1412 met its primary endpoint of improvement in PFS with 34% reduction in the risk of PD/death (2-y PFS: 76% vs 70%) for all patients, but did not reach statistical significance in ABC-DLBCL patients for 2-y PFS (71% vs 61%) or 2-y OS (88% vs 76%). ROBUST showed no significant improvement in the primary PFS endpoint (2-y PFS: 67% vs 64%) or 2-y OS (79% vs 80%) in ABC patients. Subgroup analyses of PFS comparing R2-CHOP vs R-CHOP control within each study suggested that certain baseline factors favor the R2-CHOP arm, including: female sex, high IPI score (≥ 3), non-bulky disease (< 7 cm), and high Ann Arbor stage IV disease. Conclusion: While the ROBUST study design integrated state-of-the-art, real-time GEP to prospectively identify ABC-DLBCL patients with rapid lab turnaround time, cases of logistical delays in tissue submission for central analysis and staging procedures may have resulted in accrual of patients with lower-risk DLBCL and prolonged time from diagnosis to treatment. In contrast, E1412 retrospectively stratified patients by COO through GEP and was able to accrue higher-risk patients irrespective of COO within a shorter time from diagnosis to treatment, which among other differences (eg, smaller population size, study phase), could contribute to the improvement over R-CHOP control. Our comparative findings have significant implications for the design of future biomarker-driven trials and provide momentum for studies of novel combinations with R-CHOP in DLBCL. Further investigation into other factors, including dose intensity and their correlation with outcomes, will be presented. Disclosures Nowakowski: Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding. Chiappella:Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau. Hong:Dana Farber Cancer Institute: Employment; Merck: Consultancy. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Amengual:Appia Pharmaceuticals: Research Funding; Epizyme: Speakers Bureau. Leonard:BeiGene: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Merck: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Bayer Corporation: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Jurczak:Morphosys: Research Funding; Bayer: Research Funding; Roche: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Celgene Corporation: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yamamoto:Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; ARIAD: Research Funding; MSD: Consultancy, Honoraria; Gilead Sciences: Research Funding; Ono: Consultancy, Honoraria, Research Funding; SymBio: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Solasia Pharma: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Czuczman:Celgene Corporation: Employment, Equity Ownership. Russo:Celgene Corporation: Employment, Equity Ownership. Hudak:Celgene Corporation: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Wade:Celgene: Employment, Equity Ownership. Kahl:ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Yes, these trials discuss off-label clinical trial investigation of lenalidomide plus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma.

Abstract: Chronic exertional compartment syndrome (CECS) is characterized by an excessive increase in intracompartmental muscle pressures after exercise. Athletes with CECS report pain, pressure, and occasionally neurologic symptoms in the affected compartment during exercise that abates with rest. Although many treatment options have been proposed, athletes often require a fasciotomy to return to unrestricted sports participation. Surgical success rates vary; complications are not uncommon; and after surgery, it usually takes athletes 6 or more weeks to return to unrestricted impact activities. This case report describes a new ultrasound-guided fasciotomy technique for the treatment of anterior leg compartment CECS. The procedure required a 3 mm incision, was performed in the office under local anesthesia, and allowed the athlete to resume running within 1 week of the procedure. Although the preliminary results of this study are promising, further translational research is required before the widespread adoption of this procedure is recommended.

Abstract Background: CXCR4 is a chemokine receptor over-expressed on > 75% of cancers, including myeloid leukemia blasts. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal antibody which inhibits the binding of CXCR4 to CXCL12, resulting in the mobilization of leukocytes from the bone marrow to the peripheral blood. Ulocuplumab also induces apoptosis of CXCR4+ cells in clinicial samples (i.e., leukemia blasts) and in in vitro experiments (e.g. in Tregs). It is thus hypothesized that Ulocuplumab may induce the mobilization and apoptosis of myeloid blasts & immunosuppressive cells which could improve the overall response rate to chemotherapy Objective: To conduct a first-in-man phase I dose escalation/ expansion trial to determine the safety, pharmacology, and clinical benefit of Ulocuplumab in relapsed/refractory AML Results: Seventy three subjects (median age, 58 yrs; range, 21-79 y) with relapsed/refractory AML were treated with Ulocuplumab and MEC [mitoxantrone, 8 mg/m2; etoposide , 100 mg/m2; and cytarabine, 1 g/ m2; i.v. d 1-5]. Thirty subjects in escalation received a single infusion of Ulocuplumab (doses of 0.3, 1, 3, or 10 mg/kg) one week prior to starting MEC and 3 additional weekly doses per MEC cycle thereafter (starting on Day 1). Ulocuplumab was escalated to a maximum of 10 mg/kg without any dose-limiting toxicity during monotherapy or in combination with MEC in the 1st cycle. In expansion phase, 43 patients were similarly treated with10 mg/kg Ulocuplumab and MEC. The overall complete remission and complete remission with incomplete blood count recovery rate (CR/CRi) was 51%. Subjects with first CR > 6 months had better ORR (16/23, 70%) than those with CR1 ≤6 months or primary induction failure (6/20, 30%). Of note, four subjects had CR/CRi after a single dose of Ulocuplumab monotherapy. Transient, mild/moderate thrombocytopenia was the only treatment-related AE documented with Ulocuplumab monotherapy. Only one subject presented a mild infusion reaction on Cycle 1 Day 1. The safety profile in combination with MEC was similar to MEC alone as was the 60 day all-cause mortality (16.3%). A median 2- and 5-fold mobilization of leukocytes and leukemic blasts into the peripheral circulation was reported at day 8, respectively. There was a trend demonstrating that higher CXCR4 expression on AML blasts correlated with a positive clinical response. Reversible and manageable hyperleukoctosis occurred in one subject. Conclusions: This study shows that the blockade of the CXCR4-CXCL12 axis with Ulocuplumab has antileukemic activity and safely improves the historic response rate achieved with MEC alone (i.e.,24-28%). Disclosures Becker: Bristol-Myers Squibb: Research Funding. Off Label Use: Etoposide is indicated in the management of refractory testicular tumors and small cell lung cancer. . Foran:Bristol-Myers Squibb: Research Funding. Altman:Bristol-Myers Squibb: Research Funding. Yacoub:Bristol-Myers Squibb: Research Funding. Castro:Bristol-Myers Squibb: Research Funding. Sabbatini:Bristol-Myers Squibb: Employment. Dilea:Bristol-Myers Squibb: Employment. Wade:Bristol-Myers Squibb: Employment. Xing:Bristol-Myers Squibb: Employment. Gutierrez:Bristol-Myers Squibb: Employment. Cohen:Bristol-Myers Squibb: Employment. Smith:Bristol-Myers Squibb: Research Funding.

Adherence to therapy for pulmonary arterial hypertension is essential to optimize patient outcomes, but data on real‐world adherence to different pulmonary arterial hypertension drug classes are limited. This retrospective database analysis evaluated relationships between adherence, hospitalization, and healthcare costs in pulmonary arterial hypertension patients treated with endothelin receptor antagonists or phosphodiesterase type‐5 inhibitors. From the IQVIA Adjudicated Health Plan Database, patients with pulmonary arterial hypertension were identified based on diagnostic codes and prescriptions for endothelin receptor antagonists (ambrisentan, bosentan, macitentan) or phosphodiesterase type‐5 inhibitors (sildenafil, tadalafil) approved for pulmonary arterial hypertension. Patients were assigned to the class of their most recently initiated (index) pulmonary arterial hypertension therapy between 1 January 2009 and 30 June 2015. Medication adherence was measured by proportion of days covered; patients with proportion of days covered ≥80% were considered adherent. The proportion of adherent patients was higher for endothelin receptor antagonists (571/755; 75.6%) than for phosphodiesterase type‐5 inhibitors (970/1578; 61.5%; P < 0.0001). In both groups, hospitalizations declined as proportion of days covered increased. Among adherent patients, those on endothelin receptor antagonists had a significantly lower hospitalization rate than those on phosphodiesterase type‐5 inhibitors (23.1% versus 28.5%, P = 0. 0218), fewer hospitalizations (mean (standard deviation) 0.4 (0.8) versus 0.5 (0.9); P = 0.02), and mean hospitalization costs during the six‐month post‐index ($9510 versus $15,726, P = 0.0318). Increasing adherence reduced hospitalization risk more for endothelin receptor antagonists than for phosphodiesterase type‐5 inhibitors (hazard ratio 0.176 versus 0.549, P = 0.001). Rates and numbers of rehospitalizations within 30 days post‐discharge were similar between groups. Mean total costs were higher with endothelin receptor antagonists than phosphodiesterase type‐5 inhibitors in all patients ($91,328 versus $72,401, P = 0.0003) and in adherent patients ($88,867 versus $56,300, P < 0.0001), driven by higher drug costs.

BACKGROUND: Patients with cirrhosis are growing older and the overlap between hepatic encephalopathy (HE) & pre-dementia mild cognitive impairment (MCI) is unclear. HE affects visuospatial/psychomotor speed while MCI affects memory. Aim: Determine the performance of elderly cirrhotics on tests for HE and dementia and their impact on quality of life (QOL). METHODS: Outpatient cirrhotics and controls ages 65–95 years were recruited at 4 centers. Subjects had to have MMSE > 25, no current HE or dementia to be eligible. All subjects got tests for HE (psychometric hepatic encephalopathy score, PHES: 5 tests & low score = poor, EncephalApp, OffTime + OnTime, high score = poor) and QOL: Sickness Impact profile (SIP, high score = poor QOL). Cirrhotics also got tests for MCI; RBANS (tests immediate memory, delayed memory, language, visuo-spatial & attention). A neuro-psychologist evaluated results and divided cirrhotics into (A) unimpaired (B) MCI only (C) HE only & (D) (MCI/HE overlap). Demographics, MELD, alcohol etiology, and SIP were compared. Finally, age, gender and education-adjusted norms were created for PHES and EncephalApp based on the controls. Presence of MHE and sensitivity of EncephalApp for MHE diagnosis were evaluated. RESULTS: 109 cirrhotics and 100 non-cirrhotic subjects were included. Demographics/education levels were statistically similar between centers. Controls were older than cirrhotics (74.9 ± 6.6 vs 70.5 ± 4.4, P < 0.05) and had similar education/gender distribution. Despite this, controls performed better than cirrhotics on all tests (PHES 2.9 ± 12.4 vs −4.5 ± +4.5, P < 0.001, EncephalApp Off+On 181.4 ± +71.9 vs 218.2 ± +80.0, P = 0.03) and had a better QOL (SIP total 3.8 ± +7.1 vs 7.9 ± +9.5, Psych 3.3 ± +8.4 vs 7.2 ± +11.1, Phys 3.0 ± +6.2 vs 6.7 ± +9.5, all P < 0.001). Within cirrhosis subgroups (Table 1), demographics, MELD/alc & MMSE were similar. Pts with both MCI/HE had worse cognition on all tests, which translated into a worse QOL compared to other groups. Presence of HE, with/without MCI, contributed towards poor QOL. Norms for PHES/EncephalApp: Adjusting for age, gender & education, 17% (n = 17) patients were positive for MHE on PHES compared to controls. On EncephalApp, 49% (n = 47) patients were positive. AUC for EncephalApp using PHES as the gold standard was 0.86 (0.78-0.95 CI). CONCLUSIONS: In this multi-center study, adjusted norms defining the high sensitivity of EncephalApp to diagnose HE in older individuals were created. Presence of HE regardless of MCI contributed towards poor cognition and QOL in patients >65 years.

PURPOSE The volume treated with postoperative radiation therapy (PORT) is a mediator of toxicity, and reduced volumes result in improved quality of life (QOL). In this phase II trial, treatment volumes were reduced by omitting PORT to the pathologically negative (PN0) neck in patients with primary head and neck squamous cell carcinoma. METHODS Patients with head and neck squamous cell carcinoma who underwent surgical resection and neck dissection with a PN0 neck and high-risk features mandating PORT to the primary and/or involved neck were eligible. The primary end point was greater than 90% disease control in the unirradiated neck. QOL was evaluated using the MD Anderson Dysphagia Inventory and the University of Michigan patient-reported xerostomia questionnaire. RESULTS Seventy-three patients were enrolled, and 72 were evaluable. Median age was 56 years (range, 31 to 81 years); 58 patients were male, and 47 (65%) had a smoking history. Sites included oral cavity (n = 14), oropharynx (n = 37), hypopharynx (n = 4), larynx (n = 16), and unknown primary tumor (n = 1). According to the American Joint Committee on Cancer Staging Manual (7 th edition), 67 patients (93%) had stage III/IV disease, and 71% of tumors involved or crossed midline. No patient had contralateral neck PORT. In 17 patients (24%), only the primary site was treated. At a median follow-up of 53 months, two patients experienced treatment failure of the PN0 unirradiated neck; they also experienced treatment failure locally. Unirradiated neck control was 97% (95% CI, 93.4% to 100.0%). Five-year rates of local control, regional control, progression-free survival, and overall survival were 84%, 93%, 60%, and 64%, respectively. QOL measures were not significantly different from baseline at 12 and 24 months post-PORT ( P > .05). CONCLUSION Eliminating PORT to the PN0 neck resulted in excellent control rates in the unirradiated neck without long-term adverse effects on global QOL.