Tim Helliwell

Second primary tumors in patients with head and neck squamous cell carcinoma

Background. The concept that a patient could develop cancer twice was first put forward by Billroth. Second primary neoplasms are a particular feature of head and neck cancer.

Evaluation of Human Papilloma Virus Diagnostic Testing in Oropharyngeal Squamous Cell Carcinoma: Sensitivity, Specificity, and Prognostic Discrimination

Purpose: Human papillomavirus-16 (HPV16) is the causative agent in a biologically distinct subset of oropharyngeal squamous cell carcinoma (OPSCC) with highly favorable prognosis. In clinical trials, HPV16 status is an essential inclusion or stratification parameter, highlighting the importance of accurate testing. Experimental Design: Fixed and fresh-frozen tissue from 108 OPSCC cases were subject to eight possible assay/assay combinations: p16 immunohistochemistry (p16 IHC); in situ hybridization for high-risk HPV (HR HPV ISH); quantitative PCR (qPCR) for both viral E6 RNA (RNA qPCR) and DNA (DNA qPCR); and combinations of the above. Results: HPV16-positive OPSCC presented in younger patients (mean 7.5 years younger, P = 0.003) who smoked less than HPV-negative patients (P = 0.007). The proportion of HPV16-positive cases increased from 15% to 57% (P = 0.001) between 1988 and 2009. A combination of p16 IHC/DNA qPCR showed acceptable sensitivity (97%) and specificity (94%) compared with the RNA qPCR “gold standard”, as well as being the best discriminator of favorable outcome (overall survival P = 0.002). p16 IHC/HR HPV ISH also had acceptable specificity (90%) but the substantial reduction in its sensitivity (88%) impacted upon its prognostic value (P = 0.02). p16 IHC, HR HPV ISH, or DNA qPCR was not sufficiently specific to recommend in clinical trials when used in isolation. Conclusions: Caution must be exercised in applying HPV16 diagnostic tests because of significant disparities in accuracy and prognostic value in previously published techniques. Clin Cancer Res; 17(19); 6262–71. ©2011 AACR.

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP3) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.

Effect of Passive Stretching on the Wasting of Muscle in the Critically Ill

This study examine whether muscle wasting in critically ill patients can be prevented by passive stretching alone in the absence of contractile activity. Five critically ill patients who required a complete neuromuscular blockade for 7 days of ventilator support were studied. One leg of each patient was treated with continuous passive motion (CPM) for three 3-h periods daily while the other leg received only routine nursing care. Fiber atrophy was prevented in the more severely ill patients and there was a slight gain in fiber area (mean increase, +11%) in the CPM limb compared with the control leg, which decreased (mean decrease, -35%) over 7 days. Fiber area was preserved in both fiber types but was more pronounced in type I muscle fibers. Protein loss was significantly less in the CPM limb. There was a significantly greater increase in wet weight per mg DNA in the control limb. However, as an index of wasting, the ratio of protein to DNA decreased similarly in both limbs. Passive stretching can preserve the architecture of muscle fibers. Whether it can prevent muscle wasting remains uncertain.

Biomarkers in dysplasia of the oral cavity: A systematic review

Oral dysplasia is a potentially precancerous lesion diagnosed histologically. While the risk of progression is associated with histological grade, it is currently impossible to predict accurately which lesions will progress. More accurate markers predicting progression to cancer would enable the targeting of these lesions for more aggressive treatment and closer follow-up. We have performed a systematic review with pooling of data to assess the evidence for the use of biomarkers in predicting transformation of oral dysplasia into cancer. We systematically searched the Cochrane library, MEDLINE, EMBASE, AMED, Cinahl and the Kings Fund electronic databases using the terms: oral dysplasia, leukoplakia, erythroplakia, biomarkers and genetic markers. The following a priori selection criteria were used: longitudinal cohort or case-controlled studies of oral dysplasia that progressed to cancer. Cross-sectional studies and studies reporting only on leukoplakia were excluded. Data were extracted by two reviewers. Quality assessment was carried out using validated tools. We assessed the relative risk of progression form oral dysplasia to cancer and pooled data where possible. 2550 studies were identified, from which 288 were scrutinised in greater detail. Of these, 247 were excluded, mainly due to cross-sectional design. Of the 41 studies containing follow-up data, 28 were excluded, most commonly due to data only being available for lesions once they had progressed to cancer. A lack of clear histological definition of oral lesions was also a common finding. Data were extracted from 13 longitudinal studies. The evidence consists mainly of small, single centre, retrospective studies. In oral dysplasia, loss of heterozygosity (LOH), particularly at the 3p+/-9p loci, increases the risk of progression to cancer (RR 17.60 (2.77, 108.37) p<0.001), as does survivin (RR 30 (4.25, 197.73), p0.001), matrix metalloproteinase (MMP 9), (RR 19.00 (1.56, 209.38) p=0.02) and DNA content (RR 12.00 (1.17, 82.10) p=0.03). Other markers identified by this review including p53, p73, MMP 1 and 2 and cathepsin L mRNA, did not predict progression. LOH, survivin, MMP 9 and DNA content are potential markers for increased risk of progression from oral dysplasia to cancer. Many methodological limitations have been identified by this review, however, and we recommend these results are interpreted with caution. Research into this field should concentrate on longitudinal design, with pooling of data from multiple centres to achieve larger cohorts. We recommend standardisation of definitions to allow appropriate comparisons to be made.

Ultrasound‐guided fine needle aspiration cytology in the diagnosis and management of thyroid nodules

Objective:  To examine the accuracy of fine needle aspiration cytology (FNAC) in the diagnosis of thyroid nodules and compare the inadequacy rates for ultrasound‐guided and freehand FNAC.

Objective quantification of muscle and fat in human dystrophic muscle by magnetic resonance image analysis

Information about changes in muscle composition has to date been primarily restricted to histological examination of biopsy samples or qualitative assessment of images obtained using a variety of techniques (e.g., ultrasound, CT, and MRI). We describe the development of a quantitative method for the analysis of muscle composition using MR T2 relaxation time mapping and image analysis. This approach provides an objective means of studying muscle and, when used in conjunction with force production measurements, may provide an accurate measure of response to muscle therapy.

Alkaptonuria – a review of surgical and autopsy pathology

Alkaptonuria is a rare, inherited defect of homogentisic acid 1,2‐dioxygenase that leads to the widespread deposition of polymeric homogentisic acid, and clinical symptoms from degeneration of joints and the aortic valve. Pathological descriptions are few and mainly those of late‐stage changes related to joint or valve failure. In this review, the macroscopic and histopathological changes in the tissues in alkaptonuria are illustrated by the detailed autopsy study of a 74‐year‐old female who died from disseminated ovarian carcinoma. The pathology is discussed in the context of the literature and in relation to potential pathogenic mechanisms of tissue damage. This review highlights the heterogeneity of some of the manifestations. In symptomatic patients, degenerative changes in synovial and intervertebral joints are usually well advanced, while early changes include diffuse cartilage pigmentation and chondrocyte necrosis. The initial stage of pigment deposition in the cardiovascular system may be influenced by intravascular pressure and flow disturbances, whereas more intense pigmentation affects fibrolipid components of atheromatous plaques. Pigmentation of the aortic and mitral valve cusps and valve rings is a result of intracellular and extracellular pigment deposition and is associated with calcification and clinically significant aortic stenosis.

Occult node metastases in head and neck squamous carcinoma

SummaryThe present study examined the Liverpool database in an attempt to determine what proportion of N0 necks for various head and neck primary sites harbored subclinical squamous cell carcinoma and whether empiric treatment of occult disease improved survival over and above a “wait-and-watch policy” (treatment when metastasis becomes manifest). One hundred seventeen neck dissections were carried out for N0 necks, with 32% of specimens found to contain squamous cell carcinoma. The risk of carcinoma was highest in the hypopharynx, with 50% of specimens associated with a pyriform fossa primary cancer. Twenty-nine percent of neck dissection specimens for oral cavity cancer contained carcinoma and this was commonly associated with lateral border of tongue or anterior floor of mouth carcinomas. Twenty-five percent of specimens when primary tumor was in the oropharynx contained carcinoma and were due to tonsillar carcinoma. Twenty-one percent of laryngeal cancers produced histologically positive nodes and were mostly associated with posterior epiglottic tumors. Two hundred forty-six patients had a pyriform fossa cancer and of these only 37 had N0 disease and surgical treatment. Of these, 23 patients had radical neck dissections, whereas in 14 the necks were not treated. There was no difference in survival between the two groups (ξ12 = 0.787, P = NS). The Liverpool database also contained 1631 previously untreated patients with no clinical evidence of neck node metastases. Of these only 107 had a neck dissection. There was no difference in survival (ξ12 = 2.79, P = NS). When these data were analyzed by multivariate methods (Coxs proportional hazards model) prophylactic neck dissection was found to have no significant effect.

Investigation of Muscle Imbalance in the Leg in Symptomatic Forefoot Pes Cavus: A Multidisciplinary Study

The cross-sectional areas of the peroneal and anterior muscle compartments at the same level in the upper leg were measured using magnetic resonance imaging in 41 cases of forefoot pes cavus. The pes cavus group included idiopathic cases and pes cavus associated with Charcot-Marie-Tooth disease, Friedreichs ataxia, cerebral palsy, status postpoliomyelitis, nerve trauma, and spinal cord tethering. Thirty-nine of these cases were symptomatic. The results were compared with studies of 11 normal controls. It was found that in the majority of cases of forefoot cavus, the peroneal compartment was enlarged relative to the anterior compartment when compared with the normal controls. Biopsies of the tibialis anterior and peroneus longus muscles in 18 patients with forefoot pes cavus showed that any relative expansion of the peroneus longus was not due to pseudohypertrophy. Overaction of the peroneus longus in comparison to its antagonist the tibialis anterior is proposed as an important factor in the pathogenesis of the majority of symptomatic cases of forefoot pes cavus.