Quality of life, cognitive, physical and emotional function at diagnosis predicts head and neck cancer survival: analysis of cases from the Head and Neck 5000 study.

PURPOSE: The aim of this paper is to determine whether health-related quality of life (HRQOL) at diagnosis of head and neck cancer (HNC) is associated with overall survival following treatment with curative intent after adjusting for other factors. METHODS: Data were collected from 5511 participants of the Head and Neck 5000 study (HN5000). HRQOL was measured using the EORTC QLQ-C30. Questionnaire and covariate data were available from 2171 participants diagnosed as follows: oral cavity (655), oropharynx HPV+ (723) and HPV- (277), and larynx (516). On average, participants were followed up 3.2 years (SD 1.2) after diagnosis. Data were adjusted for age, gender, co-morbidity, intended treatment, education level, income from benefits, smoking status and alcohol consumption. RESULTS: There was a clinically meaningful difference between Global HRQOL scores at diagnosis and survival in an unadjusted and adjusted model: [HR = 0.86, CI 0.82-0.89, p < 0.001 (unadjusted) and HR = 0.90, CI 0.86-0.94, p < 0.001 (adjusted)]. In analyses stratified by tumour site and HPV status, this association was similarly noted before adjustment and persisted after. There were some tumour sub-site variations: improved survival for people with laryngeal cancer reporting higher levels of physical role or social functioning and people with oral cancer reporting higher levels of role or social functioning. CONCLUSION: As survival is the main priority for most people diagnosed with cancer, pre-treatment HRQOL is an additional factor to be included in risk stratification and case-mix adjustments. There is merit in incorporating HRQOL into routine clinical care as this is a useful facet in patient-clinician decision making, prognostication and recovery.

Assessing the validity of EQ-5D-5L in people with head & neck cancer: Does a generic quality of life measure perform as well as a disease-specific measure in a patient population?

BACKGROUND: Head and neck cancer (HNC) is an important cause of morbidity and mortality globally. Radical treatment methods may result in facial disfigurement and/or functional difficulties with subsequent adverse impacts on health-related quality of life (HRQoL). Guidelines suggest that HRQoL should be measured repeatedly throughout treatment to enable refined treatment protocols and tailored follow-up support but questionnaires are often long and burdensome. We compared condition-specific and generic metrics to assess HRQoL for people with this condition. METHODS: We used data from the prospective Head and Neck 5000 clinical cohort study - 5511 participants with a new diagnosis of HNC between 2011 and 2014. HRQoL data were collected at baseline from 2065 people who completed both the condition-specific EORTC-QLQ-C30 and the shorter, generic EQ-5D-5L questionnaires. RESULTS: There was strong evidence of association between comparable scales on each questionnaire at baseline: higher levels of functioning and lower levels of reported symptoms assessed with EQ-5D-5L were associated with lower EORTC-QLQ-C30 symptom scores. A moderate relationship (0.61) was found between overall QoL in the EQ-5D-5L index and self-perceived health (EQ VAS). CONCLUSIONS: HRQoL data collected from the generic EQ-5D-5L and cancer-specific EORTC-QLQ-C30 questionnaires are comparable at baseline for people diagnosed with HNC. This would allow a reduced burden of data collection but the EQ-5D-5L may not be sensitive to some condition-specific symptoms. Clinicians and researchers must clarify their aims and outcomes of interest before choosing their HRQoL measures. Further work is required to examine the ability to detect change in these measures over time.

Should paediatricians initiate orthopaedic hip dysplasia referrals for infants with isolated asymmetric skin folds?

PURPOSE: Asymmetric skin folds (ASFs) have been linked to developmental dysplasia of the hip (DDH) in select studies, leading to their inclusion in paediatric practice guidelines regarding orthopaedic referral for hip evaluation. The purpose of this study was to investigate the utility of isolated ASFs as a screening tool for DDH in a series of patient referrals evaluated at a single institution. METHODS: We performed a retrospective review of consecutive patients between 0 and 12 months of age referred to orthopaedic clinics for isolated ASFs. We recorded radiographic findings (acetabular inclination or alpha angle), diagnosis rendered and treatment administered. RESULTS: A total of 66 patients were included (mean age 6.4 months; 2.47 to 10.76). All patients received pelvic radiographs or ultrasound. In all, 36 patients (55%) were considered normal by their treating physician and 25 (38%) were considered dysplastic and underwent brace treatment. One hip with an isolated ASF was found to have a dislocated hip on radiograph prior to their initial orthopaedic visit. None of the patients in this study have required surgery to date. CONCLUSION: Using ASFs as a reason for referral led to increased diagnosis of mild dysplasia resulting in orthotic treatment. Thus, in our particular clinical environment, isolated ASFs can be an indicator of mild dysplasia and warrant further workup or referral. Because treatment philosophies regarding recognition and treatment of mild dysplasia vary amongst centres, the value of screening with ASFs likewise depends on the treating orthopaedic surgeon's threshold for treatment of mild dysplasia. LEVEL OF EVIDENCE: Level IV- Retrospective.

Mammary analogue secretory carcinoma of the salivary glands: a diagnostic dilemma.

Mammary analogue secretory carcinoma (MASC) is a recently identified salivary gland neoplasm that can mimic other salivary gland tumours such as acinic cell carcinoma and cystadenocarcinoma. It is distinguished from these by differences in immunohistochemical profile and the identification of an ETV6-NTRK3 translocation (12;15)(p13;q25), which is also found in secretory carcinomas of the breast. Previous publications have suggested that MASC tumours have similar biological behaviour to acinic cell carcinoma. We report two cases of MASC that affected the upper lip, and showed an infiltrative and locally aggressive growth pattern that required several operations to ensure clearance of microscopic tumour cells.

Co-overexpression of Bag-1 and heat shock protein 70 in human epidermal squamous cell carcinoma: Bag-1-mediated resistance to 5-fluorouracil-induced apoptosis.

BACKGROUND: The aim was to determine whether Bcl-2-associated athanogene-1 (Bag-1) and/or its binding protein heat shock protein-70 (Hsp70) exhibit deregulated expression in epidermal squamous cell carcinoma (SCC) and whether Bag-1 confers apoptosis resistance. METHOD: Immunohistochemistry for Bag-1 and Hsp70 was performed on 60 epidermal SCC and 10 normal skin samples. The epidermal SCC cell line SCC-13 was treated with 5-fluorouracil (5-FU) after Bag-1 knockdown to determine whether high Bag-1 levels contribute to growth and/or apoptosis resistance. RESULTS: Normal epithelium expressed primarily nuclear Bag-1. Most tumours showed reduced nuclear Bag-1 staining, but a subset exhibited strong Bag-1 staining, with cytoplasmic Bag-1 staining intensity correlating with cytoplasmic Hsp70 staining intensity (r(s)=0.462; P<0.001) and less differentiation (P<0.001). Bag-1 knockdown resulted in markedly reduced SCC-13 cell yield, increased spontaneous apoptosis and enhanced sensitivity to 5-FU-induced apoptosis. Apoptosis induced by 5-FU in the Bag-1-knockdown cells was significantly greater than the additive apoptotic effect of 5-FU or Bag-1 knockdown alone. CONCLUSIONS: Overexpression of Bag-1 and Hsp70 in poorly differentiated SCC may confer both enhanced tumour cell growth and apoptosis resistance. Bag-1 may contribute to the resistance of more advanced epidermal SCC to chemotherapy.

Isolated submandibular metastasis from a contralateral thyroid papillary microcarcinoma: an unusual case.

Papillary carcinoma is the most common form of thyroid cancer. It is a relatively indolent disease, which commonly remains clinically silent until its incidental histological diagnosis in surgical material or at autopsy. A tumour less than 10 mm in size is termed a papillary microcarcinoma. Papillary microcarcinoma may present with clinical symptoms, most commonly jugulodigastric and pretracheal lymphadenopathy with or without palpable thyroid nodules. Isolated submandibular metastases are rare. We present the case of a submandibular metastasis arising from a solitary 3 mm papillary microcarcinoma of the thyroid on the contralateral side in a 46-year-old woman. We describe the ultrasound and MRI characteristics of the submandibular mass. The ultrasound findings in particular were suggestive of a thyroid malignancy and prompted detailed examination of the thyroid gland. Clinical and radiological examination of the thyroid was normal. To the best of our knowledge, we present the first report of a papillary microcarcinoma of the thyroid presenting as a contralateral and isolated submandibular mass.

TGF-beta signal transduction in oro-facial health and non-malignant disease (part I).

The transforming growth factor-beta (TGF-beta) family of cytokines consists of multi-functional polypeptides that regulate a variety of cell processes, including proliferation, differentiation, apoptosis, extracellular matrix elaboration, angiogenesis, and immune suppression, among others. In so doing, TGF-beta plays a key role in the control of cell behavior in both health and disease. In this report, we review what is known about the mechanisms of activation of the peptide, together with details of TGF-beta signal transduction pathways. This review summarizes the evidence implicating TGF-beta in normal physiological processes of the craniofacial complex-such as palatogenesis, tooth formation, wound healing, and scarring-and then evaluates its role in non-malignant disease processes such as scleroderma, submucous fibrosis, periodontal disease, and lichen planus.

The role of TGF-beta in epithelial malignancy and its relevance to the pathogenesis of oral cancer (part II).

The role of transforming growth factor-beta (TGF-beta) in epithelial malignancy is complex, but it is becoming clear that, in the early stages of carcinogenesis, the protein acts as a potent tumor suppressor, while later, TGF-beta can function to advance tumor progression. We review the evidence to show that the pro-oncogenic functions of TGF-beta are associated with (1) a partial loss of response to the ligand, (2) defects of components of the TGF-beta signal transduction pathway, (3) over-expression and/or activation of the latent complex, (4) epithelial-mesenchymal transition, and (5) recruitment of signaling pathways which act in concert with TGF-beta to facilitate the metastatic phenotype. These changes are viewed in the context of what is known about the pathogenesis of oral cancer and whether this knowledge can be translated into the development of new therapeutic modalities.

Chondrosarcoma of the pelvis. A review of sixty-four cases.

BACKGROUND: Treatment of pelvic chondrosarcoma is a difficult problem for the musculoskeletal oncologist. Poor rates of survival and high rates of local recurrence after surgical treatment have been reported in previous studies. The present study was designed to review the long-term oncologic and functional outcomes of surgical management in a large series of patients with pelvic chondrosarcoma who were treated at a single institution. METHODS: The cases of sixty-four patients with localized pelvic chondrosarcoma that had been surgically treated between 1975 and 1996 were reviewed retrospectively. The study was limited to patients who had received no previous treatment for chondrosarcoma. There were forty-one male and twenty-three female patients who had a mean age of forty-seven years (range, fifteen to eighty-eight years). The patients were followed for a minimum of three years or until death. The median duration of follow-up of the living patients was 140 months (range, thirty-nine to 295 months). RESULTS: Thirty-three of the sixty-four patients were first seen with grade-1 chondrosarcoma; twenty-three, with grade-2; one, with grade-3; and seven, with grade-4 (dedifferentiated chondrosarcoma). Thirteen patients had a hemipelvectomy to achieve local tumor control, whereas fifty-one patients underwent a limb-salvage procedure. Twelve patients (19%) had local recurrence, and eleven (17%) had distant metastases. At the time of the final follow-up, forty-four patients (69%) were alive without evidence of disease, thirteen (20%) had died of the disease, six (9%) had died of unrelated causes, and one (2%) was alive with disease. Less than a wide surgical margin correlated with local recurrence (p = 0.014). High-grade tumors correlated with poor overall survival (p < 0.001). All patients who had a limb-salvage procedure were able to walk at the time of the final follow-up, and they had a mean functional score of 77%, according to the system of the Musculoskeletal Tumor Society. CONCLUSIONS: Aggressive surgical resection of pelvic chondrosarcoma results in long-term survival of the majority of patients. There is a high correlation between tumor grade and overall or disease-free survival.

A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma.

This paper examines the genetic defects associated with inherited cancer syndromes and their relevance to oral cancer. Tumour suppressor genes are now thought of as either gatekeepers or caretakers according to whether they control cell growth directly by inhibiting cell proliferation and/or promoting cell death (gatekeepers) or whether they maintain the integrity of the genome by DNA repair mechanisms (caretakers). In disorders such as xeroderma pigmentosum, ataxia telangiectasia, Bloom syndrome and Fanconi's anaemia, where there are defective caretaker genes, there is an increased incidence of second primary malignancies, including oral cancer. By contrast, with the exception of Li Fraumeni syndrome, abnormalities of gatekeeper genes do not predispose to oral cancer. Not only do Li Fraumeni patients develop second primary malignancies, but defects of the p53 pathway (p53 mutation, MDM2 over-expression, CDKN2A deletion) appear to be a ubiquitous feature of sporadic oral cancer as it occurs in the West. The findings suggest that genetic instability is of fundamental importance in the pathogenesis of oral cancer.

Profilin enhances Cdc42-induced nucleation of actin polymerization.

We find that profilin contributes in several ways to Cdc42-induced nucleation of actin filaments in high speed supernatant of lysed neutrophils. Depletion of profilin inhibited Cdc42-induced nucleation; re-addition of profilin restored much of the activity. Mutant profilins with a decreased affinity for either actin or poly-l-proline were less effective at restoring activity. Whereas Cdc42 must activate Wiskott-Aldrich Syndrome protein (WASP) to stimulate nucleation by the Arp2/3 complex, VCA (verpolin homology, cofilin, and acidic domain contained in the COOH-terminal fragment of N-WASP) constitutively activates the Arp2/3 complex. Nucleation by VCA was not inhibited by profilin depletion. With purified N-WASP and Arp2/3 complex, Cdc42-induced nucleation did not require profilin but was enhanced by profilin, wild-type profilin being more effective than mutant profilin with reduced affinity for poly-l-proline. Nucleation by the Arp2/3 complex is a function of the free G-actin concentration. Thus, when profilin addition decreased the free G-actin concentration, it inhibited Cdc42- and VCA-induced nucleation. However, when profilin was added with G-actin in a ratio that maintained the initial free G-actin concentration, it increased the rate of both Cdc42- and VCA-induced nucleation. This enhancement, also seen with purified proteins, was greatest when the free G-actin concentration was low. These data suggest that under conditions present in intact cells, profilin enhances nucleation by activated Arp2/3 complex.

Loss of differentiation of 4NQO-induced rat malignant oral keratinocytes correlates with metastatic dissemination and is associated with a reduced cellular response to TGF-beta1 and an altered receptor profile.

This study examined the metastatic capacity of clonal populations of 4NQO-induced rat malignant oral keratinocytes following orthotopic transplantation to athymic mice. Polygonal and spindle cells formed well-differentiated squamous cell carcinomas (keratin positive and vimentin negative) and undifferentiated spindle cell tumours (keratin negative and vimentin positive), respectively, in almost 100% of animals at the site of inoculation (floor of mouth). Transplantation of 5x 10(6) cells of either cell type at high cell density resulted in approximately 50% of animals forming pulmonary metastases. By contrast, inoculation of 2x 10(6) differentiated polygonal cells resulted in the formation of significantly fewer pulmonary metastases than the undifferentiated spindle cells. A single well-differentiated clone of polygonal cells and 3 of 4 of the undifferentiated spindle cell lines produced comparable levels of TGF-beta1. One undifferentiated spindle cell line expressed significantly more TGF-beta1 and, following transplantation orthotopically, fewer animals formed pulmonary metastases despite the formation of primary tumours in almost all grafted animals, suggesting that TGF-beta1 can act as a tumour suppressor in this cell type. All cell lines produced comparable amounts of TGF-beta2. The clones of polygonal cells were markedly inhibited and the spindle cells were only partially inhibited by exogenous TGF-beta1. Both cell types expressed high-affinity TGF-beta cell surface receptors; the ratio of type I to type II TGF-beta receptors was 1.0:<3.0 in the spindle cells and 1.0:17.9 in the polygonal clone. The results suggest that differentiated rat malignant oral keratinocytes are less aggressive and have a decreased potential to metastasise than their undifferentiated spindle cell counterparts. This may be attributable, in part, to a change in TGF-beta receptor profile leading to the partial loss of response to exogenous TGF-beta1.

Mechanism of Cdc42-induced actin polymerization in neutrophil extracts.

Cdc42, activated with GTPgammaS, induces actin polymerization in supernatants of lysed neutrophils. This polymerization, like that induced by agonists, requires elongation at filament barbed ends. To determine if creation of free barbed ends was sufficient to induce actin polymerization, free barbed ends in the form of spectrin-actin seeds or sheared F-actin filaments were added to cell supernatants. Neither induced polymerization. Furthermore, the presence of spectrin-actin seeds did not increase the rate of Cdc42-induced polymerization, suggesting that the presence of Cdc42 did not facilitate polymerization from spectrin-actin seeds such as might have been the case if Cdc42 inhibited capping or released G-actin from a sequestered pool. Electron microscopy revealed that Cdc42-induced filaments elongated rapidly, achieving a mean length greater than 1 micron in 15 s. The mean length of filaments formed from spectrin-actin seeds was <0.4 micron. Had spectrin-actin seeds elongated at comparable rates before they were capped, they would have induced longer filaments. There was little change in mean length of Cdc42-induced filaments between 15 s and 5 min, suggesting that the increase in F-actin over this time was due to an increase in filament number. These data suggest that Cdc42 induction of actin polymerization requires both creation of free barbed ends and facilitated elongation at these ends.

The Ranawat Award. Sulcus morphology of the distal femur.

Traditional images of the distal femur place the intercondylar groove midway between the condyles. The location of the sulcus of the intercondylar groove in a large Sudanese skeletal population was verified using a custom stereotactic device. The results of this study show that the femoral sulcus is lateral to the midplane between the 2 femoral condyles. This study also shows that the configuration of the sulcus is linear and is oriented between the traditional anatomic and mechanical axes of the femur.

Voltage-dependent calcium currents and cytosolic calcium in equine airway myocytes.

1. The relationship between voltage-dependent calcium channel current (I(Ca)) and cytosolic free calcium concentration ([Ca2+]i) was studied in fura-2 AM-loaded equine tracheal myocytes at 35 degrees C and 1.8 mM Ca2+ using the nystatin patch clamp method. The average cytosolic calcium buffering constant was 77 +/- 3 (n = 14), and the endogenous calcium buffering constant component is likely to be between 15 and 50. 2. I(Ca) did not evoke significant calcium-induced calcium release (CICR) since (i)[Ca2+]i scaled with the integrated I(Ca) over the full voltage range of evoked calcium currents, (ii) increases in [Ca2+]i associated with I(Ca) were consistent with cytoplasmic buffering of calcium ions entering through voltage-dependent calcium channels (VDCCs) only, (iii) there was a fixed instantaneous relationship between transmembrane calcium flux (J(Ca)) and the change in cytosolic free calcium concentration (delta [Ca2+]i) during I(Ca), (iv) caffeine (8 mM) triggered 8-fold higher calcium transients than I(Ca), and (v) I(Ca) evoked following release of intracellular calcium by caffeine resulted in an equivalent delta[Ca2+]i-J(Ca) relationship. 3. The time constant (T) for the decay in [Ca2+]i was 8.6 +/- 1.5 s (n = 8) for single steps and 8.6 +/- 1.1 s (n = 13) following multiple steps that increased [Ca2+]i to much higher levels. Following application of caffeine (8 mM), however, [Ca2+]i decay was enhanced (T = 2.0 +/- 0.2 s, n = 3). The rate of [Ca2+]i decay was not voltage dependent, was not decreased in the absence of extracellular Na+ ions, and no pump current was detected. 4. We conclude that under near physiological conditions, neither CICR nor Na(+)-Ca2+ exchange play a substantial role in the regulation of I(Ca)-induced increases in [Ca2+]i, and that, even following release of intracellular calcium by caffeine, Na(+)-Ca2+ exchange does not play an appreciable role in the removal of calcium ions from the cytosol.

Mycobacterium chelonae infection following a total knee arthroplasty.

Infection following total knee arthroplasty is a major cause of implant failure, with an incidence of infections between 1 and 12%. Although there have been no previously reported cases of infection with Mycobacterium chelonae following total knee arthroplasty, this mycobacterium appears to be a potential pathogen in arthroplasty. When infection following total knee arthroplasty is evident but standard cultures come back negative, atypical mycobacterium infection should be considered. Mycobacterium chelonae does not grow in the normally allotted culture time, so false negative results are common. Once identified, M. chelonae is difficult to treat because of its resistance to standard drug therapies. Details of the first reported successful diagnosis and treatment of an infection with M. chelonae following a total knee arthroplasty are reported.

Actin polymerization induced by GTP gamma S in permeabilized neutrophils is induced and maintained by free barbed ends.

To address the mechanisms through which agonists stimulate actin polymerization, we examined the roles of monomer sequestering proteins and free barbed ends on actin polymerization induced by guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) in neutrophils permeabilized with streptolysin O. Addition of profilin (without GTP gamma S) caused a net decrease in F-actin. Thus, merely making profilin available in the cell was not sufficient to induce actin polymerization. On the other hand, addition of profilin hardly affected the polymerization induced by GTP gamma S, while thymosin beta 4 or DNase I decreased this polymerization. These data suggested that GTP gamma S induced polymerization by increasing the availability of barbed ends. In the presence of cytochalasin B, profilin did inhibit polymerization induced by GTP gamma S, demonstrating that GTP gamma S did not inhibit profilin's monomer sequestering ability. The F-actin induced by GTP gamma S was not limited by a time-dependent loss of G-actin or G-proteins from permeabilized cells since, following stimulation with suboptimal concentrations of GTP gamma S, addition of more GTP gamma S induced further polymerization. Barbed ends remained free after F-actin reached plateau since (a) cytochalasin B caused depolymerization of induced F-actin and (b) profilin did not depolymerize induced F-actin unless the cells were first treated with cytochalasin to cap barbed ends. The data indicate that GTP gamma S maintains an increased level of F-actin by keeping at least a few barbed ends available for polymerization.

DNase I increases the rate constant of depolymerization at the pointed (-) end of actin filaments.

We show here that DNase is distinguished from other known actin-binding proteins by its unique ability to increase the depolymerization rate constant of actin at the pointed filament end, thereby speeding up depolymerization of filaments capped at their barbed ends. This action requires relatively high DNase concentrations, 3 orders of magnitude higher than those needed to block elongation, although 10 times lower than those needed for DNase binding to the side of the filament. We propose that a high DNase concentrations, steric interference between the two DNase molecules, bound to the ends of both strands of the two-start actin helix, destabilizes actin binding to the filament.