Human papillomavirus genotype distribution in head and neck cancer: Informing developing strategies for cancer prevention, diagnosis, treatment and surveillance.

Current clinical practice algorithms for HPV testing make no effort to discern the impact of genotypes for patients with head and neck squamous cell carcinoma (HNSC). Data was collected for all patients with HNSCs that had undergone HPV testing at an academic hospital as part of clinical care (2012-2019). Screening was performed using real-time PCR targeting L1 of low and high-risk HPV types, followed by genotyping of positive cases. Genotype status was correlated with age, site and histologic parameters. Of the 964 patients tested, 68% had HPV-positive cancers. Most arose from the oropharynx (OP) (89%) and sinonasal tract (5%). The most frequent genotype was 16 (84.4%) followed by 35 (5.6%), 33 (4.1%), 18 (2.7%), 45 (1.1%), 69 (0.8%) and others (1.3%). There was an association between genotype (16 vs non-16) and tumor origin (OP vs non-OP) (p < 0.0001). HPV18 was associated with transformation to an aggressive small cell phenotype, but HPV16 was not (22% vs 0%, p < 0.0001). Patients with HPV-non-16 OP carcinomas were older than patients with HPV16 OP carcinomas, but the difference was not significant. HPV genotypes are variable and unevenly distributed across anatomic sites of the head and neck. The association of HPV18 with small cell transformation suggests that variants can track with certain phenotypes in ways that may account for differences in clinical behavior. This study challenges the prevailing assumption of HPV equivalency across all high-risk genotypes in ways that may inform preventive, diagnostic, therapeutic and surveillance strategies.

Standard of care vs reduced-dose chemoradiation after induction chemotherapy in HPV+ oropharyngeal carcinoma patients: The Quarterback trial.

BACKGROUND: Human Papillomavirus oropharyngeal carcinoma (HPVOPC) has better progression free (PFS) and overall survival (OS) than non-HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant acute toxicity and late morbidity. We hypothesized that after induction chemotherapy (IC), reduced dose chemoradiation (rdCRT) would result in equivalent PFS and OS compared to sdCRT plus IC in HPVOPC and would reduce toxicity. METHODS: Patients with p16+, previously untreated, locally advanced HPVOPC and ≤20 pack years smoking history received 3 cycles of IC with docetaxel, cisplatin and fluorouracil (TPF). Clinical responders who were HPV positive by type-specific PCR were randomized 1:2 to sdCRT (7000 cGy) or rdCRT (5600 cGy) with weekly carboplatin. The endpoints of the study were 3 year PFS and OS. RESULTS: 23 patients were enrolled, 22 were evaluable for TPF toxicity and 20 were randomized, 8 to sdCRT and 12 to rdCRT. Sixteen (80%) were HPV 16+ and 4 (20%) were other high risk (HR) variants. Fourteen (70%) had high risk features: T4, N2c, or N3. Median follow up was 56 months (range 42-70). Three-year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures are locoregional within 4 months of completion of CRT; 2 were in HR variants (50%). CONCLUSIONS: rdCRT after IC resulted in similar PFS/OS compared sdCRT. These data support Phase 3 clinical trials of radiation dose reduction after IC as a treatment strategy in HPVOPC. Molecular HPV with variant testing and smoking history are necessary for de-escalation trials.

Real-time PCR HPV genotyping in fine needle aspirations of metastatic head and neck squamous cell carcinoma: Exposing the limitations of conventional p16 immunostaining.

BACKGROUND: Given the propensity for HPV-positive head and neck squamous cell carcinoma (HPV-HNSCC) to metastasize to cervical lymph nodes, fine needle aspiration (FNA) plays an important diagnostic role in their initial detection. Indeed, there is now an unwavering commitment to HPV testing of FNAs even in the absence of clear methodologic guidelines and threshold criteria. A particular difficulty pertains to the interpretation of p16 staining. DESIGN: Data was collected for 210 patients with suspected regionally metastatic HNSCC that had undergone FNA as part of standard clinical care. Initial HPV screening was performed on cell blocks with real-time PCR using primers targeting L1 of high-risk HPV types. Additional genotyping was performed on HPV-positive cases. The results were compared to p16 staining and subsequent excisions when available. RESULTS: Of the 207 samples with sufficient DNA, 175 (85%) were HPV positive. HPV-16 was the most commonly detected genotype (90%). Of the HPV-positive cases, the primary site was the oropharynx (n = 154, 88.0%), supraglottic larynx (n = 2, 1.1%), nasal cavity (n = 1, 0.6%), hypopharynx (n = 1, 0.6%) or unknown (n = 17, 9.7%). On comparison with 31 paired surgical excisions, HPV status was concordant in all cases (100% correlation). Of 142 HPV-positive cases with matching p16 stains, p16 staining was reported as positive (n = 85, 60%), focal (n = 27, 19%), negative (n = 24, 17%) or non-contributory (n = 6, 4%); and only 33% reached the standard threshold limit (i.e. 70%) for HPV positivity. CONCLUSION: For patients with metastatic HNSCC, real-time PCR of FNAs reliably reflects HPV status, and is superior to conventional p16 immunostaining.

Head and neck cancer prevention: from primary prevention to impact of clinicians on reducing burden.

Survival from head and neck cancers (HNCs) of the lip, oral cavity, pharynx, and larynx has increased by 10% over the past few decades. Little over half of patients who develop HNCs will survive beyond 5 years. Survival is lower for individuals in many countries where traditional risk factors such as tobacco smoking, alcohol drinking, and betel quid chewing are highly prevalent but tertiary health care center access is limited or unavailable. Early diagnosis of HNC is the most important prognostic factor for each tumor site. Molecular-based research on HNC tumors holds promise for early stage detection, screening, vaccination, disease follow-up, and progression. Future investments for HNC control must consider both effectiveness and sustainability for both high- and low-resource countries alike, with priority toward risk factor prevention and earlier diagnosis.

Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions.

Background: The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet cisplatin and fluorouracil. We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens. Design: We nonsystematically reviewed published phase III clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017. Results: TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (i.e. cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further. Conclusions: TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

The Incremental Cost of Incompatible Living Donor Kidney Transplantation: A National Cohort Analysis.

Incompatible living donor kidney transplantation (ILDKT) has been established as an effective option for end-stage renal disease patients with willing but HLA-incompatible living donors, reducing mortality and improving quality of life. Depending on antibody titer, ILDKT can require highly resource-intensive procedures, including intravenous immunoglobulin, plasma exchange, and/or cell-depleting antibody treatment, as well as protocol biopsies and donor-specific antibody testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT (n = 926) with varying antibody titers to matched compatible transplants (n = 2762) performed between 2002 and 2011. Data were assembled from a national cohort study of ILDKT and a unique data set linking hospital cost accounting data and Medicare claims. ILDKT was more expensive than matched compatible transplantation, ranging from 20% higher adjusted costs for positive on Luminex assay but negative flow cytometric crossmatch, 26% higher for positive flow cytometric crossmatch but negative cytotoxic crossmatch, and 39% higher for positive cytotoxic crossmatch (p < 0.0001 for all). ILDKT was associated with longer median length of stay (12.9 vs. 7.8 days), higher Medicare payments ($91 330 vs. $63 782 p < 0.0001), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplantation.

Extremes of body mass index and postoperative complications after esophagectomy.

Obesity has been variously associated with reduced or similar rates of postoperative complications compared to normal weight patients undergoing esophagectomy for cancer. In contrast, little is known about esophagectomy risks in the underweight population. The relationship between the extremes of body mass index (BMI) and postoperative complications after esophagectomy was evaluated. Consecutive esophagectomy patients (2000-2013) were reviewed. The patients were stratified based on BMI at the time of diagnosis: underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), obese I (30-34.9), and obese II or III (≥35). Hospital length of stay as well as postoperative complications and their accordion severity grading were evaluated according to the BMI category. Of 388 patients, 78.6% were male with a median age of 62 years at the time of operation. Pathologic cancer stage was 0 to I in 53%. BMI distribution was as follows: 5.6% underweight, 28.7% normal, 31.4% overweight, 22.8% obese I, and 11.5% obese II or III. Performance status was 0 or 1 in 99.2%. Compared to normal BMI patients, underweight patients had increased pulmonary complications (odds ratio (OR) 3.32, P = 0.014) and increased other postoperative complications (OR 3.00, P = 0.043). Patients who were overweight did not have increased complications compared to normal BMI patients. BMI groups did not differ in mortality rates or complication accordion severity grading. Hospital length of stay trended toward a longer duration in the underweight population (P = 0.06). Underweight patients are at increased risk for postoperative pulmonary and other complications. Underweight patients may benefit from preoperative nutritional repletion and mitigation for sarcopenia. Aggressive postoperative pulmonary care may help reduce complications in these patients. In contrast, the operative risk in overweight and obese patients is similar to normal BMI patients.

Basal Tumor Cell Isolation and Patient-Derived Xenograft Engraftment Identify High-Risk Clinical Bladder Cancers.

Strategies to identify tumors at highest risk for treatment failure are currently under investigation for patients with bladder cancer. We demonstrate that flow cytometric detection of poorly differentiated basal tumor cells (BTCs), as defined by the co-expression of CD90, CD44 and CD49f, directly from patients with early stage tumors (T1-T2 and N0) and patient-derived xenograft (PDX) engraftment in locally advanced tumors (T3-T4 or N+) predict poor prognosis in patients with bladder cancer. Comparative transcriptomic analysis of bladder tumor cells isolated from PDXs indicates unique patterns of gene expression during bladder tumor cell differentiation. We found cell division cycle 25C (CDC25C) overexpression in poorly differentiated BTCs and determined that CDC25C expression predicts adverse survival independent of standard clinical and pathologic features in bladder cancer patients. Taken together, our findings support the utility of BTCs and bladder cancer PDX models in the discovery of novel molecular targets and predictive biomarkers for personalizing oncology care for patients.

Consensus Conference on North American Training in Hepatopancreaticobiliary Surgery: A Review of the Conference and Presentation of Consensus Statements.

The findings and recommendations of the North American consensus conference on training in hepatopancreaticobiliary (HPB) surgery held in October 2014 are presented. The conference was hosted by the Society for Surgical Oncology (SSO), the Americas Hepato-Pancreatico-Biliary Association (AHPBA), and the American Society of Transplant Surgeons (ASTS). The current state of training in HPB surgery in North America was defined through three pathways-HPB, surgical oncology, and solid organ transplant fellowships. Consensus regarding programmatic requirements included establishment of minimum case volumes and inclusion of quality metrics. Formative assessment, using milestones as a framework and inclusive of both operative and nonoperative skills, must be present. Specific core HPB cases should be defined and used for evaluation of operative skills. The conference concluded with a focus on the optimal means to perform summative assessment to evaluate the individual fellow completing a fellowship in HPB surgery. Presentations from the hospital perspective and the American Board of Surgery led to consensus that summative assessment was desired by the public and the hospital systems and should occur in a uniform but possibly modular manner for all HPB fellowship pathways. A task force composed of representatives of the SSO, AHPBA, and ASTS are charged with implementation of the consensus statements emanating from this consensus conference.

Development and usability testing of a web-based self-management intervention for oral cancer survivors and their family caregivers.

Oral cancer (OC) survivors experience debilitating side effects that affect their quality of life (QOL) and that of their caregivers. This study aimed to develop and evaluate a dyadic, web-based intervention to improve survivor self-management and survivor/caregiver QOL. A qualitative needs assessment (semi-structured interviews) with 13 OC survivors and 12 caregivers was conducted to discern information and support needs as well as preferences regarding website features and tools. Results using Grounded Theory analysis showed that OC survivors and caregivers: (1) want and need practical advice about managing side effects; (2) want to reach out to other survivors/caregivers for information and support; and (3) have both overlapping and unique needs and preferences regarding website features. Usability testing (N = 6 survivors; 5 caregivers) uncovered problems with the intuitiveness, navigation and design of the website that were subsequently addressed. Users rated the website favourably on the dimensions of attractiveness, controllability, efficiency, intuitiveness and learnability, and gave it a total usability score of 80/100. Overall, this study demonstrates that OC survivors and caregivers are interested in using an online programme to improve QOL, and that providing tailored website content and features based on the person's role as survivor or caregiver is important in this population.

Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome.

BACKGROUND: The CXCL10/CXCR3 signalling mediates paracrine interactions between tumour and stromal cells that govern leukocyte trafficking and angiogenesis. Emerging data implicate noncanonical CXCL10/CXCR3 signalling in tumourigenesis and metastasis. However, little is known regarding the role for autocrine CXCL10/CXCR3 signalling in regulating the metastatic potential of individual tumour clones. METHODS: We performed transcriptomic and cytokine profiling to characterise the functions of CXCL10 and CXCR3 in tumour cells with different metastatic abilities. We modulated the expression of the CXCL10/CXCR3 pathway using shRNA-mediated silencing in both in vitro and in vivo models of B16F1 melanoma. In addition, we examined the expression of CXCL10 and CXCR3 and their associations with clinical outcomes in clinical data sets derived from over 670 patients with melanoma and colon and renal cell carcinomas. RESULTS: We identified a critical role for autocrine CXCL10/CXCR3 signalling in promoting tumour cell growth, motility and metastasis. Analysis of publicly available clinical data sets demonstrated that coexpression of CXCL10 and CXCR3 predicted an increased metastatic potential and was associated with early metastatic disease progression and poor overall survival. CONCLUSION: These findings support the potential for CXCL10/CXCR3 coexpression as a predictor of metastatic recurrence and point towards a role for targeting of this oncogenic axis in the treatment of metastatic disease.

Safe Conversion From Tacrolimus to Belatacept in High Immunologic Risk Kidney Transplant Recipients With Allograft Dysfunction.

There is no literature on the use of belatacept for sensitized patients or regrafts in kidney transplantation. We present our initial experience in high immunologic risk kidney transplant recipients who were converted from tacrolimus to belatacept for presumed acute calcineurin inhibitor (CNI) toxicity and/or interstitial fibrosis/tubular atrophy. Six (mean age = 40 years) patients were switched from tacrolimus to belatacept at a median of 4 months posttransplant. Renal function improved significantly from a peak mean estimated glomerular filtration rate (eGFR) of 23.8 ± 12.9 mL/min/1.73 m(2) prior to the switch to an eGFR of 42 ± 12.5 mL/min/1.73 m(2) (p = 0.03) at a mean follow-up of 16.5 months postconversion. No new rejection episodes were diagnosed despite a prior history of rejection in 2/6 (33%) patients. Surveillance biopsies performed in 5/6 patients did not show subclinical rejection. No development of donor-specific antibodies (DSA) was noted. In this preliminary investigation, we report improved kidney function without a concurrent increase in risk of rejection and DSA in six sensitized patients converted from tacrolimus to belatacept. Improvement in renal function was noted even in patients with chronic allograft fibrosis without evidence of acute CNI toxicity. Further studies with protocol biopsies are needed to ensure safety and wider applicability of this approach.

Quantifying the risk of incompatible kidney transplantation: a multicenter study.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention.

Treatment of oropharyngeal squamous cell carcinoma with IMRT: patterns of failure after concurrent chemoradiotherapy and sequential therapy.

BACKGROUND: The optimal management of oropharyngeal squamous cell carcinoma (OPSCC) is controversial. Modern radiotherapy typically employs intensity-modulated radiation therapy (IMRT), and herein, we report the Dana-Farber Cancer Institute (DFCI) experience with IMRT-based treatment of OPSCC. DESIGN: Retrospective study of all patients treated at DFCI for OPSCC with definitive or adjuvant IMRT between 8/04 and 8/09. The primary end point was overall survival (OS); secondary end points were locoregional control (LRC) and freedom from distant metastases (FFDM). Propensity score matching was used to create concurrent chemoradiotherapy (CCRT) and sequential therapy (ST) cohorts equally balanced for patient and disease characteristics. RESULTS: One hundred and sixty-three patients were included with 75% presenting with stage IV disease. Fifty-six patients (34%) were treated with ST. The three-year actuarial OS, LRC, and FFDM rates for the entire cohort/ST subset were 86%/89%, 86%/87%, and 88%/93%, respectively. There were no differences in OS, LRC, or FFDM between CCRT and ST in the propensity-matched cohort. CONCLUSIONS: IMRT was associated with excellent OS, LRC, and FFDM. Although the results following ST were superb, there was no obvious benefit to ST after adjustment for selection bias. We recommend that ST be reserved for medically fit patients with a high risk of distant metastases.

Benign extraosseous cartilage tumours of the hand and wrist.

Benign extraosseous cartilage tumours of the hand and wrist comprise soft tissue chondromas, synovial chondromatosis and tenosynovial chrondromatosis. These tumours can significantly affect patients as they are often painful, functionally limiting and cosmetically displeasing. Although each tumour is generally considered to be a distinct entity, they share radiological and histopathological similarities. Occasionally, all three tumours may be seen in the same patient. This is an important consideration because of the risk of recurrence that may not necessarily occur at the same anatomical site but instead extend to different sites, such as a tendon sheath and/or joint.

MicroRNA profiles in allograft tissues and paired urines associate with chronic allograft dysfunction with IF/TA.

Despite the advances in immunosuppression, renal allograft attrition over time remains unabated due to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA). We aimed to evaluate microRNA (miRNA) signatures in CAD with IF/TA and appraise correlation with paired urine samples and potential utility in prospective evaluation of graft function. MiRNA signatures were established between CAD with IF/TA versus normal allografts by microarray. Validation of the microarray results and prospective evaluation of urine samples was performed using real-time quantitative-PCR (RT-qPCR). Fifty-six miRNAs were identified in samples with CAD-IF/TA. Five miRNAs were selected for further validation based on array fold change, p-value and in silico predicted mRNA targets. We confirmed the differential expression of these five miRNAs by RT-qPCR using an independent set of samples. Differential expression was detected for miR-142-3p, miR-204, miR-107 and miR-211 (p < 0.001) and miR-32 (p < 0.05). Furthermore, differential expression of miR-142-3p (p < 0.01), miR-204 (p < 0.01) and miR-211 (p < 0.05) was also observed between patient groups in urine samples. A characteristic miRNA signature for IF/TA that correlates with paired urine samples was identified. These results support the potential use of miRNAs as noninvasive markers of IF/TA and for monitoring graft function.