Human papillomavirus–related oropharyngeal cancer: HPV and p16 status in the recurrent versus parent tumor

Background Although typically associated with a favorable prognosis, a minority of human papillomavirus (HPV)‐related (+) oropharyngeal cancers recur after chemoradiation. We postulated that a minor HPV‐negative tumor subfraction may be responsible for recurrences of HPV+ oropharyngeal cancer. Methods Paired untreated primary and recurrent tumor specimens were identified for 37 patients with oropharyngeal cancer who received definitive chemoradiotherapy at our institution. Concordance in HPV/p16 expression between primary and recurrent tumors was assessed. Results Among 31 patients with HPV+/p16+ primary tumors, 30 (97%) retained evidence of both HPV and p16 expression at recurrence (27 HPV+/p16+; 3 HPV+/p16‐partial). One (3%) initially HPV+/p16+ patient developed an HPV‐negative/p16‐negative lung squamous cell carcinoma (SCC), representing either a discordant oropharyngeal cancer metastasis or second primary tumor. Conclusion HPV‐related oropharyngeal cancers retain HPV+/p16+ expression at recurrence. Our results fail to provide evidence that a minor HPV‐negative tumor subfraction is responsible for biologically aggressive behavior of HPV+ oropharyngeal cancer that recurs after chemoradiation. © 2014 Wiley Periodicals, Inc. Head Neck 37 : 8–11, 2015Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109811/1/hed23548.pd

Characterization of Human Immunodeficiency Virus Type 1 Monomeric and Trimeric gp120 Glycoproteins Stabilized in the CD4-Bound State: Antigenicity, Biophysics, and Immunogenicity

The human immunodeficiency virus type 1 exterior gp120 envelope glycoprotein is highly flexible, and this flexibility may contribute to the inability of monomeric gp120 immunogens to elicit broadly neutralizing antibodies. We previously showed that an S375W modification of a critical interfacial cavity central to the primary receptor binding site, the Phe43 cavity, stabilizes gp120 into the CD4-bound state. However, the immunological effects of this cavity-altering replacement were never tested. Subsequently, we screened other mutations that, along with the S375W alteration, might further stabilize the CD4-bound state. Here, we define a selected second cavity-altering replacement, T257S, and analyze the double mutations in several gp120 envelope glycoprotein contexts. The gp120 glycoproteins with the T257S-plus-S375W double mutation (T257S+S375W) have a superior antigenic profile compared to the originally identified single S375W replacement in terms of enhanced recognition by the broadly neutralizing CD4 binding-site antibody b12. Isothermal titration calorimetry measuring the entropy of the gp120 interaction with CD4 indicated that the double mutant was also stabilized into the CD4-bound state, with increasing relative fixation between core, full-length monomeric, and full-length trimeric versions of gp120. A significant increase in gp120 affinity for CD4 was also observed for the cavity-filling mutants relative to wild-type gp120. The most conformationally constrained T257S+S375W trimeric gp120 proteins were selected for immunogenicity analysis in rabbits and displayed a trend of improvement relative to their wild-type counterparts in terms of eliciting neutralizing antibodies. Together, the results suggest that conformational stabilization may improve the ability of gp120 to elicit neutralizing antibodies

Randomized phase II trial of urethral sparing intensity modulated radiation therapy in low-risk prostate cancer: implications for focal therapy

Abstract Background Low-risk prostate cancer (PCa) patients have excellent outcomes, with treatment modality often selected by perceived effects on quality of life. Acute urinary symptoms are common during external beam radiotherapy (EBRT), while chronic symptoms have been linked to urethral dose. Since most low-risk PCa occurs in the peripheral zone (PZ), we hypothesized that EBRT using urethral sparing intensity modulated radiation therapy (US-IMRT) could improve urinary health-related quality of life (HRQOL) while maintaining high rates of PCa control. Methods Patients with National Comprehensive Cancer Network (NCCN) defined low-risk PCa with no visible lesion within 5 mm of the prostatic urethra on MRI were randomized to US-IMRT or standard (S-) IMRT. Prescription dose was 75.6 Gy in 41 fractions to the PZ + 3–5 mm for US-IMRT and to the prostate + 3 mm for S-IMRT. For US-IMRT, mean proximal and distal urethral doses were limited to 65 Gy and 74 Gy, respectively. HRQOL was assessed using the Expanded Prostate Cancer Index (EPIC) Quality of Life questionnaire. The primary endpoint was change in urinary HRQOL at 3 months. Results From June 2004 to November 2006, 16 patients were randomized, after which a futility analysis concluded that continued accrual was unlikely to demonstrate a difference in the primary endpoint. Mean change in EPIC urinary HRQOL at 3 months was −0.5 ± 11.2 in the US-IMRT arm and +3.9 ± 15.3 in the S-IMRT arm (p = 0.52). Median PSA nadir was higher in the US-IMRT arm (1.46 vs. 0.78, p = 0.05). At 4.7 years median follow-up, three US-IMRT and no S-IMRT patients experienced PSA failure (p = 0.06; HR 8.8, 95% CI 0.9–86). Two out of 3 patients with PSA failure had biopsy-proven local failure, both located contralateral to the original site of disease. Conclusions Compared with S-IMRT, US-IMRT failed to improve urinary HRQOL and resulted in higher PSA nadir and inferior biochemical control. The high rate of PSA failure and contralateral local failures in US-IMRT patients, despite careful selection of MRI-screened low-risk patients, serve as a cautionary tale for focal PCa treatments.</p

Impact of retropharyngeal adenopathy on distant control and survival in HPV-related oropharyngeal cancer treated with chemoradiotherapy

PURPOSE: Retropharyngeal adenopathy (RPA) is poor prognostic factor in head and neck (HN) cancer. However, the prognostic significance of RPA in Human Papillomavirus-related (HPV+) oropharyngeal cancer (OPC) is unknown. PATIENTS AND METHODS: 185 patients with HPV+ OPC were assessed. Pre-therapy images reviewed by a HN radiologist to determine presence of RPA. Doses to the RPAs were determined from treatment plans. Outcomes analyzed using Kaplan-Meier method, log-rank tests, and correlations determined using Spearman’s rank analyses. RESULTS: 29 (16%) of the HPV+ patients had RPA. At median follow-up 49 months, 5-year overall survival (OS), failure-free survival (FFS) and distant failure-free survival (DFFS) were 57% vs. 81% (P=0.02), 63% vs 80% (P=0.015) and 70% vs 91% (p=0.002) for patients with/without RPA, respectively. No differences observed in local/ regional control rates, exceeding 90% in both groups, and No RPA recurrences were observed. In multivariable analysis, stages T4 or N3, and RPA, were independently, statistically significantly associated with both OS and distant failure, while N2c, age, disease site, and smoking status, were not. CONCLUSION: RPA in HPV+ OPC is an independent prognostic factor for distant failure, translating into worse OS. Patients with RPA may not be suitable candidates for trials of systemic treatment de-escalation

Long‐term neck and shoulder function among survivors of oropharyngeal squamous cell carcinoma treated with chemoradiation as assessed with the neck dissection impairment index

BackgroundOf interest is the long‐term neck and shoulder impairment of patients treated with primary chemoradiotherapy (CRT). This is important for counseling patients regarding treatment decisions when discussing primary CRT.MethodsA cross‐sectional study to identify factors that contribute to neck and shoulder dysfunction in patients treated with primary CRT. We utilized the neck dissection impairment index (NDII). Eighty‐seven patients treated between 2003 and 2010, who were free of disease, responded; 24 of these 87 underwent post‐CRT neck dissection. Mean interval since completion of CRT was over 5 years (62.7 months). Mean age, 63.5 years, male:female 75:12.ResultsMean NDII score was 87.4 (SD 22.1, range 5–100). Multiple linear regression revealed worse NDII scores for patients with larger pre‐CRT gross tumor nodal volume (GTVnodal), controlled for age, sex, body mass index (BMI), and the presence of neck dissection (p = 0.02). There were significant associations with increasing GTVnodal and “low” scores for components of the NDII that assessed neck pain (p = 0.02), neck stiffness (p = 0.01), lifting heavy objects (p = 0.02), reaching overhead (p = 0.02), and ability to do work (p = 0.02). Physical therapy (PT) was evaluated as an “anchor” but it was prescribed “as needed.” Regression revealed participation in PT was associated with higher GTVnodal, lower BMI, presence of neck dissection, and female sex (p = 0.00007).ConclusionGTVnodal was an independent predictor of neck and shoulder impairment. High GTVnodal was associated with increased pain and stiffness, and increased difficulty lifting heavy objects, reaching overhead, overall ability to perform work‐related tasks and was associated with participation in post‐treatment PT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167456/1/hed26636.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167456/2/hed26636_am.pd