Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis.

PURPOSE: A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival. PATIENTS AND METHODS: A total of 460 OPC tumor specimens from two large United States medical centers (1980-2017) underwent HPV16 whole-genome sequencing. Site-specific variable positions [single nucleotide polymorphisms (SNPs)] across the HPV16 genome were identified. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival. RESULTS: A total of 384 OPC tumor specimens (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. Some 284 HPV16 SNPs with a minor allele frequency ≥1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate correction (individual prevalence: 1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 [HR for overall survival (HRos): 3.75, 95% CI 1.77-7.95; Pfdr = 0.0099]; L2 gene positions 4410 (HRos: 5.32, 95% CI 1.91-14.81; Pfdr = 0.0120), 4539 (HRos: 6.54, 95% CI 2.03-21.08; Pfdr = 0.0117); 5050 (HRos: 6.53, 95% CI 2.34-18.24; Pfdr = 0.0030), and 5254 (HRos: 7.76, 95% CI 2.41-24.98; Pfdr = 0.0030); and L1 gene positions 5962 (HRos: 4.40, 95% CI 1.88-10.31; Pfdr = 0.0110) and 6025 (HRos: 5.71, 95% CI 2.43-13.41; Pfdr = 0.0008) and position 7173 within the upstream regulatory region (HRos: 9.90, 95% CI 3.05-32.12; Pfdr = 0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared with 18.67 years for patients without a high-risk SNP; log-rank test P < 0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment); increase in C-index was 0.069 (95% CI 0.019-0.119, P < 0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95% CI 0.015-0.111, P = 0.008). CONCLUSIONS: HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.

Tendinopathic supraspinatus tenocytes may have a neuroendocrine-like function, secreting CGRP, SP and VEGF: a pilot immunohistochemistry study.

We wanted to observe and compare the appearance of neurovascular tissue from tendon ex vivo, in patients with and without painful rotator cuff tendinopathy. Supraspinatus tendons were biopsied from 5 participants with painful tendinopathy and normal tendon from a young male. Slides were stained with haematoxylin and eosin and toluidine blue for histological assessment. Immunohistochemical markers for general nerves (protein gene-product 9.5 and synaptophysin), sensory nerves (calcitonin gene-related peptide; substance-P) and vascularisation (vascular endothelial growth factor) were used. PGP9.5 and CGRP-immunoreactive fibres were associated with vessels in cases and control. Synaptophysinlabelled fibres were observed in close relation to vessels in tendinopathy. PGP9.5, CGRP, SP and VEGF-immunoreaction also labelled tenocyte-like cells in degenerative areas and fibres in regions of fat and collagen. Sensory innervation and vascularity are increased in tendinopathy. The evidence for innervation and vascularity of symptomatic rotator cuff tendon may aid the development of novel investigations and therapies in the management of patients with this ailment.

A Case of HPV-Associated Oropharyngeal Squamous Cell Carcinoma with Block-Like, Partial Loss of p16 Expression.

BACKGROUND: Oropharyngeal squamous cell carcinoma is frequently associated with high-risk HPV infection, which confers a good prognosis. Immunohistochemistry for p16 is used as a surrogate for HPV status, but discrepant results are occasionally seen. Here, we report a case with a unique pattern of partial loss of p16. METHODS: A 63 year old male presented with a base of tongue nonkeratinizing squamous cell carcinoma and a large metastatic neck mass. The primary lesion and multiple regions of the metastatic mass were assessed with p16 immunohistochemistry, RNA in situ hybridization for high-risk HPV, and HPV16 genome sequencing. RESULTS: The primary lesion was p16 negative, and the metastatic neck mass had large, confluent regions that were either strongly p16 positive or entirely p16 negative. All of these regions were positive for high-risk HPV with identical HPV16 genomes. CONCLUSION: This unusual case illustrates a potential diagnostic pitfall, and it raises important questions regarding molecular mechanisms and prognostic implications of p16 staining in oropharyngeal squamous cell carcinoma.

Acute joint pathology and synovial inflammation is associated with increased intra-articular fracture severity in the mouse knee.

OBJECTIVE: Post-traumatic arthritis is a frequent cause of disability and occurs most commonly and predictably after articular fracture. The objective of this investigation was to examine the effect of fracture severity on acute joint pathology in a novel murine model of intra-articular fracture. DESIGN: Low and high energy articular fractures (n=25 per group) of the tibial plateau were created in adult male C57BL/6 mice. The acute effect of articular fracture severity on synovial inflammation, bone morphology, liberated fracture area, cartilage pathology, chondrocyte viability, and systemic cytokines and biomarkers levels was assessed at 0, 1, 3, 5, and 7 days post-fracture. RESULTS: Increasing intra-articular fracture severity was associated with greater acute pathology in the synovium and bone compared to control limbs, including increased global synovitis and reduced periarticular bone density and thickness. Applied fracture energy was significantly correlated with degree of liberated cortical bone surface area, indicating greater comminution. Serum concentrations of hyaluronic acid (HA) were significantly increased 1 day post-fracture. While articular fracture significantly reduced chondrocyte viability, there was no relationship between fracture severity and chondrocyte viability, cartilage degeneration, or systemic levels of cytokines and biomarkers. CONCLUSIONS: This study demonstrates that articular fracture is associated with a loss of chondrocyte viability and increased levels of systemic biomarkers, and that increased intra-articular fracture severity is associated with increased acute joint pathology in a variety of joint tissues, including synovial inflammation, cortical comminution, and bone morphology. Further characterization of the early events following articular fracture could aid in the treatment of post-traumatic arthritis.

Disseminated Burkholderia gladioli infection in a lung transplant recipient with underlying hypocomplementemic urticarial vasculitis.

Burkholderia gladioli is difficult to definitively identify within the laboratory using phenotypic testing alone. We describe a case of recurrent B. gladioli infection in a lung transplant recipient with underlying hypocomplementemic urticarial vasculitis syndrome, discuss the difficulties encountered with laboratory identification, provide a review of the methodology required for definitive identification, and discuss potential pathophysiologic mechanisms in this patient responsible for the difficulty in treatment.

Ex vivo sentinel lymph node mapping in laparoscopic resection of colon cancer.

AIM: The study examined the feasibility and potential benefit of ex vivo sentinel lymph node (SLN) mapping, including multilevel sectioning (MLS) and immunohistochemistry (IHC) in colon cancer patients undergoing laparoscopic colectomy. The secondary goals were (i) to identify patient and tumour characteristics that might influence the success of the SLN technique, (ii) to investigate the extent of lymphadenectomy required to encompass tumour-positive nonsentinel lymph nodes (NSLN) and (iii) to ascertain the association of SLN status with oncological outcomes. METHOD: SLN mapping was performed after specimen extraction using 1% Isosulfan blue. The SLNs were analysed with H&E staining after MLS, and if negative, IHC was performed. NSLNs were grouped by distance either greater than or less than 4 cm from the tumour. RESULTS: Seventy-one patients completed the study between 2003 and 2007. Using H&E with MLS, the accuracy of SLN mapping was 76%, sensitivity was 52% and the false-negative rate was 48%. Excluding patients with clinically positive lymph nodes resulted in a significant improvement in accuracy to 81% and decreased the false-negative rate to 30%. Furthermore, as the only positive NSLN > 4 cm from the tumour was grossly positive, SLN mapping with a 4-cm mesenteric cuff would have given 100% sensitivity in patients without macroscopically involved nodes. CONCLUSIONS: SLN mapping may be of value in selected patients. It may be possible to accurately stage patients with a 4-cm cuff of mesentery, although further validation of this proposal is required.

Lightning on jupiter: rate, energetics, and effects.

Voyager data on the optical and radio-frequency detection of lightning discharges in the atmosphere of Jupiter suggest a stroke rate significantly lower than on the earth. The efficiency of conversion of atmospheric convective energy flux into lightning is almost certainly less than on the earth, probably near 10(-7) rather than the terrestrial value of 10(-4). At this level the rate of production of complex organic molecules by lightning and by thunder shock waves is negligible compared to the rates of known photochemical processes for forming colored inorganic solids.

The temperature gradient in the solar nebula.

The available compositional data on planets and satellites can be used to place stringent limits on the thermal environment in the solar nebula. The densities of the terrestrial planets, Ceres and Vesta, the Galilean satellites, and Titan; the atmospheric compositions of several of these bodies; and geochemical and geophysical data on the earth combine to define a strong dependence of formation temperature on heliocentric distance. The pressure and temperature dependences of the condensation process are separable in the sense that the variation of the deduced formation temperatures with heliocentric distance is insensitive to even very diverse assumptions regarding the pressure profile in the nebula. It is impossible to reconcile the available compositional data with any model in which the formation temperatures of these bodies are determined by radiative equilibrium with the sun, regardless of the sun's luminosity. Rather, the data support Cameron's hypothesis of a dense, convective solar nebula, opaque to solar radiation, with an adiabatic temperature-pressure profile.

Satellites of the outer planets: thermal models.

Steady-state thermal models for the large satellites of the outer planets strongly indicate that their interiors are currently maintained at temperatures well above the ice-ammonia eutectic temperature by the decay of long-lived radioisotopes of potassium, uranium, and thorium. The present-day steady-state thermal structure of a representative satellite, J IV (Callisto), is shown to be characterized by the presence of a thin icy crust over a deep liquid mantle, with a dense core of hydrous silicates and iron oxides. Some dynamical consequences of this model are briefly discussed.

Venus: chemical weathering of igneous rocks and buffering of atmospheric composition.

Data from the Pioneer Venus radar mapper, combined with measurements of wind velocity and atmospheric composition, suggest that surface erosion on Venus varies with altitude. Calcium- and magnesium-rich weathering products are produced at high altitudes by gas-solid reactions with igneous minerals, then removed into the hotter lowlands by surface winds. These fine-grained weathering products may then rereact with the lower atmosphere and buffer the composition of the observed gases carbon dioxide, water vapor, sulfur dioxide, and hydrogen fluoride in some regions of the surface. This process is a plausible mechanism for the establishment in the lowlands of a calcium-rich mineral assemblage, which had previously been found necessary for the buffering of these species.

Venus: halide cloud condensation and volatile element inventories.

Several recently suggested Venus cloud condensates, including aluminum chloride and halides, oxides, and sulfides of arsenic and antimony, are assessed for their thermodynamic and geochemical plausibility. Aluminum chloride can confidently be ruled out, and condensation of arsenic sulfides on the surface will cause arsenic compounds to be too rare to produce the observed clouds. Antimony may be sufficiently volatile, but the expected molecular form is gaseous antimony sulfide, not the chloride. Arsenic and antimony compounds in the atmosphere will be regulated at very low levels by sulfide precipitation, irrespective of the planetary inventory of arsenic and antimony. Thus arguments for a volatile-deficient origin for Venus based on depletion of water and mercury (relative to the earth) cannot be tested by a search for atmospheric arsenic or antimony.

Vertical distribution of water in the atmosphere of venus: a simple thermochemical explanation.

Several lines of evidence concerning the vertical abundance profile of water in the atmosphere of Venus lead to strikingly unusual distributions (the water vapor abundance decreases sharply in the immediately vicinity of the surface) or to serious conflicts in the profiles (different infrared bands suggest water abundances that are discrepant by a factor of 2.5 to 10). These data sets can be reconciled if (i) water molecules associate with carbon dioxide and sulfur trioxide to make gaseous carbonic acid and sulfuric acid in the lower atmosphere, and (ii) the discrepant 0.94-micrometer water measurements are due to gaseous sulfuric acid, requiring it to be a somewhat stronger absorber than water vapor inthis wavelength region. A mean total water abundance of 50 +/- 20 parts per million and a near-surface free water vapor abundance of 10 +/- 4 parts per million are derived.

Jupiter's Clouds: Structure and Composition.

Recent infrared radiometric observations of Jupiter have disclosed local temperatures in the North Equatorial Belt far in excess of those at the level of the solid ammonia clouds, and visual observations reveal an orange-brown coloration within this belt. We suggest that, in a multilayer cloud model, solar ultraviolet photolysis of hydrogen sulfide in regions where ammonia clouds are sparse or absent should lead to the production of substantial quantities of inorganic chromophores.

Rotator cuff tendinopathy/subacromial impingement syndrome: is it time for a new method of assessment?

Disorders of the shoulder are extremely common, with reports of prevalence ranging from 30% of people experiencing shoulder pain at some stage of their lives up to 50% of the population experiencing at least one episode of shoulder pain annually. In addition to the high incidence, shoulder dysfunction is often persistent and recurrent, with 54% of sufferers reporting ongoing symptoms after 3 years. To a large extent the substantial morbidity reflects (i) a current lack of understanding of the pathoaetiology, (ii) a lack of diagnostic accuracy in the assessment process, and (iii) inadequacies in current intervention techniques. Pathology of the rotator cuff and subacromial bursa is considered to be the principal cause of pain and symptoms arising from the shoulder. Generally these diagnostic labels relate more to a clinical hypothesis as to the underlying cause of the symptoms than to definitive evidence of the histological basis for the diagnosis or the correlation between structural failure and symptoms. Diagnosing rotator cuff tendinopathy or subacromial impingement syndrome currently involves performing a structured assessment that includes taking the patient's history in conjunction with performing clinical assessment procedures that generally involve tests used to implicate an isolated structure. Based on the response to the clinical tests, a diagnosis of rotator cuff tendinopathy or subacromial impingement syndrome is achieved. The clinical diagnosis is strengthened with the findings from supporting investigations such as blood tests, radiographs, ultrasound, magnetic resonance imaging (MRI), computed axial tomography (CT), radionucleotide isotope scan, single photon emission computed tomography, electromyography, nerve conduction and diagnostic analgesic injection. This process eventually results in the formation of a clinical hypothesis, and then, in conjunction with the patient, a management plan is decided upon and implemented. This paper focuses on the dilemmas associated with the current process, and an alternative method for the clinical examination of the shoulder for this group of patients is proposed.

Rotator cuff tendinopathy.

PURPOSE: A review was conducted to synthesise the available research literature on the pathogenesis of rotator cuff tendinopathy. RELEVANCE: Musculoskeletal disorders of the shoulder are extremely common, with reports of prevalence ranging from one in three people experiencing shoulder pain at some stage of their lives to approximately half the population experiencing at least one episode of shoulder pain annually. Pathology of the soft tissues of the shoulder, including the musculotendinous rotator cuff and subacromial bursa, is a principal cause of pain and suffering. CONCLUSIONS: The pathoaetiology of rotator cuff failure is multifactorial and results from a combination of intrinsic, extrinsic and environmental factors. The specialised morphology of the rotator cuff, together with the effects of stress shielding, may contribute to the development of rotator cuff tendinopathy. Profound changes within the subacromial bursa are strongly related to the pathology and resulting symptoms. A considerable body of research is necessary to more fully understand the aetiology and pathohistology of rotator cuff tendinopathy and its relationship with bursal pathology. Once this knowledge exists more effective management will become available.

The clinical significance of radiologically detected silent pulmonary nodules in early breast cancer.

BACKGROUND: Increasing numbers of patients with early cancer undergo routine staging using computerized tomography (CT). Those in whom indeterminate pulmonary nodules are visualized without the presence of other metastatic lesions represent a clinical dilemma regarding their management as early breast cancer or metastatic disease. PATIENTS AND METHODS: Medical records of breast cancer patients who underwent thoracic CT scans between the years 2002 and 2008 were analyzed. Those with obvious metastatic disease were excluded. Patients were identified via the radiology database by searching for the terms: 'suspicious lung metastases' and 'indeterminate nodules'. RESULTS: Out of 1578 new patients assessed from 2002 to 2008, we carried out 802 staging CT scans. Thirty-four cases (4.2%) with indeterminate pulmonary nodules were identified. We categorized cases by size and number of nodules. At a median follow-up of 18 months, there were no changes in lesion size in 86% of patients with a solitary nodule <1 cm and 89% with multiple subcentimeter nodules. In contrast, in 100% of cases with pulmonary nodules >1 cm, the nodules had progressed at follow-up (chi(2), P = 0.004). CONCLUSIONS: Breast cancer cases with subcentimeter indeterminate pulmonary lesions and no evidence of metastases elsewhere are unlikely to represent metastatic disease. Treatment with curative intent or entry into clinical trials should not be excluded.

Basaloid squamous cell carcinoma arising in [corrected] the renal pelvis.

Basaloid squamous cell carcinoma is an uncommon and highly aggressive variant that can occur anywhere squamous cancers occur. It is most often seen in the head and neck, the perianal region, and the female genital tract. It is extremely rare in the urinary system. In this article, we report the first known case of basaloid squamous cell carcinoma arising in the renal pelvis. Given the aggressive nature of this neoplasm, it should not be omitted from the differential diagnosis of neoplasms arising from the urothelium.

Squamous and Neuroendocrine Specific Immunohistochemical Markers in Head and Neck Squamous Cell Carcinoma: A Tissue Microarray Study.

The performance characteristics of neuroendocrine-specific and squamous-specific immunohistochemical markers in head and neck squamous cell carcinomas (SCC), in particular in oropharyngeal tumors in this era of human papillomavirus (HPV)-induced cases, are not well-established. The differential diagnosis for poorly differentiated SCCs, for nonkeratinizing oropharyngeal SCCs, and for other specific SCC variants such as basaloid SCC and undifferentiated (or lymphoepithelial-like) carcinomas includes neuroendocrine carcinomas. Given that neuroendocrine carcinomas of the head and neck are aggressive regardless of HPV status, separating them from SCC is critically important. In this study, we examined the neuroendocrine markers CD56, synaptophysin, and chromogranin-A along with the squamous markers p40 and cytokeratin 5/6 in a large tissue microarray cohort of oral, oropharyngeal, laryngeal, and hypopharyngeal SCCs with known HPV results by RNA in situ hybridization for the oropharyngeal tumors. Results were stratified by site and specific SCC variant. The neuroendocrine stains were rarely expressed in SCC (<1% overall) with CD56 the least, and chromogranin-A the most, specific markers. Further, p40 and cytokeratin 5/6 were very consistently expressed in all head and neck SCC (>98% overall), including very strong, consistent staining in oropharyngeal HPV-related nonkeratinizing SCC. Undifferentiated (or lymphoepithelial-like) carcinomas of the oropharynx are more frequently p40 or cytokeratin 5/6 negative or show only weak or focal expression. In summary, markers of neuroendocrine and squamous differentiation show very high specificity and sensitivity, respectively, across the different types of head and neck SCC.

The inverse electron-demand Diels-Alder reaction as a new methodology for the synthesis of 225Ac-labelled radioimmunoconjugates.

The inverse electron-demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO) facilitates the efficient radiosynthesis of 225Ac-labelled radioimmunoconjugates in a two-step method, outperforming conventional approaches based on isothiocyanate couplings.

Antibiotic cycling to decrease bacterial antibiotic resistance: a 5-year experience on a bone marrow transplant unit.

Multidrug-resistant pathogens have important effects on clinical outcomes. Antibiotic cycling is one approach to control anti-microbial resistance, but few studies have examined cycling in hematology-oncology units. Antibiotic cycling was implemented in January 1999 at our hematology-oncology unit, alternating piperacillin-tazobactam (pip-tazo) and cefepime in 3 months periods, until June 2004. Clinical isolates were compared in post- and pre-intervention periods and with the susceptibility among the solid organ transplant intensive care unit (TICU) isolates. The rate of Gram-negative isolates remained stable. Among Gram-negatives, susceptibility to cefepime and pip-tazo remained stable. There was an increase in Enterococcus spp. (P=0.007), and susceptibility to ampicillin and vancomycin decreased (odds ratio (OR): 0.04, 95% confidence interval (CI): 0.17-0.89 and OR: 0.23, 95% CI: 0.09-0.58). Compared with the TICU, there was increased susceptibility to pip-tazo and cefepime among enterics (OR: 7.32, 95% CI: 4.44-12.07 and OR: 8.82, 95% CI: 2.1-37.13) and Pseudomonas aeruginosa (OR: 4.27, 95% CI: 1.47-12.4 and OR: 4.61, 95% CI: 1.75-12.1) and decreased susceptibility to ampicillin and vancomycin among enterococci (OR: 0.44, 95% CI: 0.30-0.63 and OR: 0.38, 95% CI: 0.26-0.56). Cycling was associated with preserved antibiotic susceptibility among Gram-negatives, but with an increase in Enterococcus spp. and vancomycin and ampicillin resistance among enterococci.