Imaging of Neck Nodes in Head and Neck Cancers - a Comprehensive Update.

Cervical lymph node metastases from head and neck squamous cell cancers significantly reduce disease-free survival and worsen overall prognosis and, hence, deserve more aggressive management and follow-up. As per the eighth edition of the American Joint Committee on Cancer staging manual, extranodal extension, especially in human papillomavirus-negative cancers, has been incorporated in staging as it is important in deciding management and significantly impacts the outcome of head and neck squamous cell cancer. Lymph node imaging with various radiological modalities, including ultrasound, computed tomography and magnetic resonance imaging, has been widely used, not only to demonstrate nodal involvement but also for guided histopathological evaluation and therapeutic intervention. Computed tomography and magnetic resonance imaging, together with positron emission tomography, are used widely for the follow-up of treated patients. Finally, there is an emerging role for artificial intelligence in neck node imaging that has shown promising results, increasing the accuracy of detection of nodal involvement, especially normal-appearing nodes. The aim of this review is to provide a comprehensive overview of the diagnosis and management of involved neck nodes with a focus on sentinel node anatomy, pathogenesis, imaging correlates (including radiogenomics and artificial intelligence) and the role of image-guided interventions.

Is routine neck dissection warranted at salvage laryngectomy?

BACKGROUND: There is controversy regarding management of the neck at salvage laryngectomy. The aim of this study was to perform an analysis to determine the incidence of occult node positivity in this group and analyse factors affecting it. METHOD: A retrospective analysis of 171 patients who underwent salvage total laryngectomy between 2000 and 2015 for recurrent or residual disease following definitive non-surgical treatment and were clinico-radiologically node negative at the time salvage laryngectomy was carried out. RESULTS: A total of 171 patients with laryngeal or hypopharyngeal cancers underwent concurrent neck dissection at laryngectomy. There were 162 patients (94.7 per cent) who underwent bilateral neck dissection, and 9 patients (5.3 per cent) who underwent ipsilateral neck dissection. The occult lateral nodal metastasis rate was 10.5 per cent. Of various factors, initial node positive disease was the only factor predicting occult metastasis on univariable and multivariable analysis (p = 0.001). CONCLUSION: Risk of occult metastasis is high in patients who have node positive disease before starting radiotherapy. This group should be offered elective neck dissection.

Evolving multidisciplinary treatment of squamous cell carcinoma of the head and neck in India✰.

In this article, we highlight the evolution of a multimodal approach in the overall management of squamous cell carcinoma of the head and neck (SCCHN) in India; present advances in technology (newer surgical techniques), novel medical and radiotherapy (RT) approaches; review their roles for an integrated approach for treating SCCHN and discuss the current role of immunotherapy in SCCHN. For locally advanced (LA) SCCHN, the multidisciplinary approach includes surgery followed by RT, with or without chemotherapy (CT) or concurrent chemoradiotherapy. Improved surgical techniques of reconstruction and voice-preservation are being implemented. Advanced forms of high-precision conformal techniques like intensity-modulated radiotherapy are used to deliver highly conformal doses to tumors, sparing the surrounding normal tissue. Compared with RT alone, novel CT regimens and targeted therapeutic agents have the potential to improve locoregional control and survival and reduce treatment-induced toxicities. Several clinical trials have demonstrated efficacy, safety, and quality of life benefits of adding cetuximab to RT regimens in LASCCHN. Studies have also suggested a cetuximab-related laryngeal preservation benefit. At progression, platinum-based CT combined with cetuximab (a monoclonal anti-epidermal growth factor receptor antibody) is the only validated option available as the first-line therapy. Thus, an integrated multidisciplinary approach plays a key role in maximizing patient outcomes, reduction in treatment related morbidities that consequently impact quality of life of survivors.

Taxane-based Induction Chemotherapy Plus Concurrent Chemoradiotherapy in Nasopharyngeal Carcinoma: Prospective Results from a Non-endemic Cohort.

AIMS: To report the outcomes of induction chemotherapy (ICT) followed by chemoradiotherapy (CTRT) for a large cohort of locoregionally advanced nasopharyngeal cancer (LA-NPC) from a non-endemic region. MATERIALS AND METHODS: Between January 2008 and July 2015, 201 patients with histologically proven, non-metastatic NPC were treated with ICT followed by CTRT at our institute. All the patients received two to three cycles of a taxane-based ICT regimen. Radiotherapy was delivered using an intensity-modulated radiotherapy (IMRT) technique in all patients. RESULTS: After a median follow-up of 37 months (range: 7-110 months), the 3-year disease-free survival (DFS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival of the entire cohort was 72, 85, 83 and 87.4%, respectively. On multivariate analysis, histology was an independent predictor of DFS, LRFS and overall survival, with keratinising squamous cell carcinoma histologies predicting a worse outcome. The nodal stage was an independent predictor of DFS, DMFS and overall survival. Age, gender, ethnicity, tumour stage and response to ICT did not significantly affect any of the outcomes. Grade 2 or worse subcutaneous fibrosis was seen in 19% of patients at last follow-up and grade 2 or worse xerostomia was seen in 24% of patients. Thirty-nine per cent of patients developed clinical hypothyroidism at last follow-up. CONCLUSION: ICT followed by concurrent CTRT in the IMRT era provides excellent locoregional control, distant control and overall survival rates in patients with LA-NPC. However, distant failure continues to be a problem and may require further systemic intensification.

Deleting Suppressor of Cytokine Signaling-3 in chondrocytes reduces bone growth by disrupting mitogen-activated protein kinase signaling.

OBJECTIVE: To investigate the impact of deleting Suppressor of Cytokine Signaling (SOCS)-3 (SOCS3) in chondrocytes during murine skeletal development. METHOD: Mice with a conditional Socs3 allele (Socs3fl/fl) were crossed with a transgenic mouse expressing Cre recombinase under the control of the type II collagen promoter (Col2a1) to generate Socs3Δ/Δcol2 mice. Skeletal growth was analyzed over the lifespan of Socs3Δ/Δcol2 mice and controls by detailed histomorphology. Bone size and cortical bone development was evaluated by micro-computed tomography (micro-CT). Growth plate (GP) zone width, chondrocyte proliferation and apoptosis were assessed by immunofluorescence staining for Ki67 and TUNEL. Fibroblast growth factor receptor-3 (FGFR3) signaling in the GP was assessed by immunohistochemistry, while the effect of SOCS3 overexpression on FGFR3-driven pMAPK signaling in HEK293T cells was evaluated by Western blot. RESULTS: Socs3Δ/Δcol2 mice of both sexes were consistently smaller compared to littermate controls throughout life. This phenotype was due to reduced long bone size, poor cortical bone development, reduced Ki67+ proliferative chondrocytes and decreased proliferative zone (PZ) width in the GP. Expression of pMAPK, but not pSTAT3, was increased in the GPs of Socs3Δ/Δcol2 mice relative to littermate controls. Overexpression of FGFR3 in HEK293T cells increased Fibroblast Growth Factor 18 (FGF18)-dependent Mitogen-activated protein kinase (MAPK) phosphorylation, while concomitant expression of SOCS3 reduced FGFR3 expression and abrogated MAPK signaling. CONCLUSION: Our results suggest a potential role for SOCS3 in GP chondrocyte proliferation by regulating FGFR3-dependent MAPK signaling in response to FGF18.

An Audit for Radiotherapy Planning and Treatment Errors From a Low-Middle-Income Country Centre.

AIMS: To report the findings of an audit for radiotherapy errors from a low-middle-income country (LMICs) centre. This would serve as baseline data for radiotherapy error rates, their severity and causes, in such centres where modern error reporting and learning processes still do not exist. MATERIALS AND METHODS: A planned cross-sectional weekly audit of electronic radiotherapy charts at the radiotherapy planning and delivery step for all patients treated with curative intent was conducted. Detailed analysis was carried out to determine the step of origin of error, time and contributing factors. They were graded as per indigenous institutional (TMC) radiotherapy error grading (TREG) system and the contributing factors identified were prioritised using the product of frequency, severity and ease of detection. RESULTS: In total, 1005 consecutive radically treated patients' charts were audited, 67 radiotherapy errors affecting 60 patients, including 42 incidents and 25 near-misses were identified. Transcriptional errors (29%) were the most common type. Most errors occurred at the time of treatment planning (59.7%), with "plan information transfer to the radiation oncology information system" being the most frequently affected sub-step of the radiotherapy process (47.8%). More errors were noted at cobalt units (52/67; 77.6%) than at linear accelerators. Trend analysis showed an increased number of radiotherapy incidents on Fridays and near-misses on Mondays. Trend for increased radiotherapy errors noted in the evening over other shifts. On severity grading, most of the errors (54/60; 90%) were clinically insignificant (grade I/II). Inadequacies and non-adherence towards standard operating procedures, poor documentation and lack of continuing education were the three most prominent causes. CONCLUSION: Preliminary data suggest a vulnerability of LMIC set-up to radiotherapy errors and emphasises the need for the development of longitudinal prospective processes, such as voluntary reporting and a continued education system, to ensure robust and comprehensive safe practises on par with centres in developed countries.

Invasion of the mandible in gingivobuccal complex cancers: Histopathological analysis of routes of tumour entry and correlation with preoperative assessment.

OBJECTIVES: To determine the most accurate imaging modality predicting mandibular invasion in gingivobuccal (GB) complex cancers. To determine patterns of invasion and routes of tumour entry into the mandible by detailed histopathologic analysis. MATERIAL AND METHODS: Prospective observational study of GB Complex cancers juxtaposed with the mandible clinically necessitating some form of mandibular resection. Orthopantomogram (OPG), Multi Detector Computed Tomography (MDCT), DENTA scan and Single Photon Emission Computed Tomography scan (SPECT) were performed after which the patient was subjected to surgery. Histopathological assessment was systematically performed with serial cuts of the mandibular segment. RESULTS: Of 70 patients, MDCT was the most accurate with area under curve (AUC) of 0.833. OPG, DENTA and SPECT had AUC of 0.714, 0.786 and 0.738 respectively. Mean calculated difference of involved height was -0.025 cm by MDCT (p value 0.87), -0.2 cm by OPG (p value 0.09) and 0.12 by DENTA scan (p value 0.41). Mean difference of involved length was -0.51 cm (p value 0.08) and -1.02 cm (p value 0.04) for MDCT and OPG respectively. 50% of tumour invasion was through the occlusal route while large tumours demonstrated multiple routes of entry. CONCLUSION: -Gingivobuccal complex cancers are homogenous with respect to mandibular invasion, preferred route of tumour entry being the occlusal surface. -Multidetector CT scan is fairly accurate in detecting mandibular involvement and predicting extent of involvement. -Oncological safety can be achieved by positioning the bone cuts corresponding to the adjacent soft tissue margins in segmental mandibulectomy.

A nomogram for predicting the risk of neck node metastasis in pathologically node-negative oral cavity carcinoma.

OBJECTIVE: To generate a nomogram for predicting the risk of neck node metastasis in pathologically node-negative patients using a combination of variables comprising of protein expression, ultrastructural alterations and clinicopathological parameters. MATERIALS AND METHODS: Surgically removed oral tumours (n = 103) were analysed for the expression of desmosomal and hemidesmosomal assembly proteins by immunohistochemistry and ultrastructural alterations by transmission electron microscopy (TEM). Protein expression, ultrastructural alterations and clinicopathological variables were used to construct nomogram from the training set in 75 patients. Clinical utility of the nomogram was validated in a discrete set of 28 patients. RESULTS: Univariate and multivariate analyses were performed on the training set, and obtained significant variables comprising of integrin ß4 expression (p = .027), number of hemidesmosomes (p = .027)/desmosomes (p = .046), tumour differentiation grade (p = .033) and tumour thickness (p = .024) were used for construction of the nomogram. The area under the curve was calculated for both training 0.821 (95% CI 0.725-0.918) and validation sets 0.880 (95% CI 0.743-1.000). The nomogram demonstrated a predictive accuracy of 73.3% and 78.6% with the sensitivity of 81.4% and 83.3% in the training and validation sets, respectively. CONCLUSIONS: The nomogram constructed on postsurgical tumour samples will be a value addition to histopathology for the detection of neck node metastasis in pathologically node-negative patients.

Alterations in the functional neural circuitry supporting flexible choice behavior in autism spectrum disorders.

Restricted and repetitive behaviors, and a pronounced preference for behavioral and environmental consistency, are distinctive characteristics of autism spectrum disorder (ASD). Alterations in frontostriatal circuitry that supports flexible behavior might underlie this behavioral impairment. In an functional magnetic resonance imaging study of 17 individuals with ASD, and 23 age-, gender- and IQ-matched typically developing control participants, reversal learning tasks were used to assess behavioral flexibility as participants switched from one learned response choice to a different response choice when task contingencies changed. When choice outcome after reversal was uncertain, the ASD group demonstrated reduced activation in both frontal cortex and ventral striatum, in the absence of task performance differences. When the outcomes of novel responses were certain, there was no difference in brain activation between groups. Reduced activation in frontal cortex and ventral striatum suggest problems in decision-making and response planning, and in processing reinforcement cues, respectively. These processes, and their integration, are essential for flexible behavior. Alterations in these systems may therefore contribute to a rigid adherence to preferred behavioral patterns in individuals with an ASD. These findings provide an additional impetus for the use of reversal learning paradigms as a translational model for treatment development targeting the domain of restricted and repetitive behaviors in ASD.

Role of the pectoralis major myofascial flap in preventing pharyngocutaneous fistula following salvage laryngectomy.

OBJECTIVE: This study aimed to assess the utility of onlay pectoralis major myofascial flap in preventing pharyngocutaneous fistula following salvage total laryngectomy. METHODS: A retrospective analysis was performed of 172 patients who underwent salvage laryngectomy for recurrent carcinoma of the larynx or hypopharynx between 1999 and 2014. One hundred and ten patients underwent primary closure and 62 patients had pectoralis major myofascial flap onlay. RESULTS: The overall pharyngocutaneous fistula rate was 43 per cent, and was similar in both groups (primary closure group, 43.6 per cent; onlay flap group, 41.9 per cent; p = 0.8). Fistulae in the onlay flap group healed faster: the median and mean fistula duration were 37 and 55 days, respectively, in the primary closure group and 20 and 25 days, respectively, in the onlay flap group (p = 0.008). CONCLUSION: Use of an onlay pectoralis major myofascial flap did not decrease the pharyngocutaneous fistula rate, although fistula duration was shortened. A well-designed randomised-controlled trial is needed to establish parameters for its routine use in clinical practice.

Barriers in conducting clinical trials in oncology in the developing world: A cross-sectional survey of oncologists.

BACKGROUND: Several obstacles impede oncologists from performing clinical trials in the developing world. This study aimed to identify these barriers in order of importance and suggest possible remedial measures. MATERIALS AND METHODS: Design - cross-sectional survey. Two part questionnaire capturing experience of oncologists in practice and conducting trials (Part 1) and perceived barriers pertaining to investigator (training, time), patient (strict follow-up protocol), infrastructure (funds) and professional environment (encouragement from seniors) (Part 2) were administered to oncologists in two different settings: (1) Online portal (Survey Monkey) (2) In person during a national conference (Best of American Society of Clinical Oncology). Responses were captured on a Likert scale (1-5). RESULTS: (436/3021) 14.04% responded. A total of 313 (71.8%) had experience in conducting trials, but these were mainly industry-sponsored or small nonpractice changing studies. Lack of patient follow-up was the most significant barrier (inter quartile range [IQR] 4-5) followed by inadequate training, time and funds (IQR 2-5) and lack of encouragement (IQR 2-4) in decreasing order of frequency. Lack of adequate training was a barrier across all specialties (113 [71.97%] radiation oncologists, 71 [60.68%] medical oncologists and 73 [71.56%] surgical oncologists). More than half of the respondents without experience in clinical trials worked in academic institutions (50.48%). They perceived time constraint as a barrier more than their counterparts into private practice (175/242 [72.31%] vs. 119/177 [66.47%] respectively). CONCLUSION: Inability to maintain patient follow-up, lack of protected time and funds, inadequate training were the most significant barriers. Most of these can be addressed.

Positron emission tomography thyroid incidentaloma: Is it different in Indian subcontinent?

BACKGROUND: Positron emission tomography (PET) forms an integral part in work-up and follow-up of various malignancies. With the increased use of PET in oncology, finding of an incidental focal thyroid uptake (incidentaloma) is not unusual and presents a diagnostic challenge. AIM: The aim of the following study is to evaluate the frequency and radio-pathologic correlation of focal 18-fluoro deoxyglucose uptake (FDG) on PET within the thyroid from a large series. MATERIALS AND METHODS: Retrospective review of 37,000 consecutive patients who underwent FDG-PET at tertiary cancer center in India. Radiological, pathological, PET scan and follow-up details were evaluated. Statistical analyzes were carried out using Mann Whitney test and Pearson correlation. RESULTS: Abnormal thyroid uptake was seen in 78 (0.2%) patients. Nearly 61 (0.16%) scans had focal and 17 (0.04%) had diffuse FDG uptake. A total of 57 patients with focal uptake were available for further evaluation. No further evaluation was done in 24 (42.1%) patients who had advanced index malignancy. Of the remaining 33 patients 26 were benign and seven were a cause for concern (four primary thyroid cancers, one follicular neoplasm with hurthle cell change and two metastatic cancers). There was no significant correlation in Standardized uptake value (SUV) max of benign and malignant lesion (P = 0.5 on Mann Whitney) or size (r = 0.087 Pearson correlation co-efficient P= 0.667). CONCLUSION: Incidence of PET incidentaloma is low in this large cohort of Indian patients. Nearly 27% of focal incidentaloma were malignant. There was no correlation between the SUVmax, size and malignancy.

Fluorodeoxyglucose-positron emission tomography in carcinoma nasopharynx: Can we predict outcomes and tailor therapy based on postradiotherapy fluorodeoxyglucose-positron emission tomography?

BACKGROUND: Positron emission tomography-computed tomography (PET-CT) is an emerging modality for staging and response evaluation in carcinoma nasopharynx. This study was conducted to evaluate the impact of PET-CT in assessing response and outcomes in carcinoma nasopharynx. MATERIALS AND METHODS: Forty-five patients of nonmetastatic carcinoma nasopharynx who underwent PET-CT for response evaluation at 10-12 weeks posttherapy between 2004 and 2009 were evaluated. Patients were classified as responders (Group A) if there was a complete response on PET-CT or as nonresponders (Group B) if there was any uptake above the background activity. Data regarding demographics, treatment, and outcomes were collected from their records and compared across the Groups A and B. RESULTS: The median age was 41 years. 42 out of 45 (93.3%) patients had WHO Grade 2B disease (undifferentiated squamous carcinoma). 24.4%, 31.1%, 15.6, and 28.8% patients were in American Joint Committee on Cancer Stage IIb, III, Iva, and IVb. All patients were treated with neoadjuvant chemotherapy followed by concomitant chemoradiotherapy. Forty-five patients, 28 (62.2%) were classified as responders, whereas 17 (37.8%) were classified as nonresponders. There was no significant difference in the age, sex, WHO grade, and stage distribution between the groups. Compliance to treatment was comparable across both groups. The median follow-up was 25.3 months (759 days). The disease-free survival (DFS) of the group was 57.3% at 3 years. The DFS at 3 years was 87.3% and 19.7% for Group A and B, respectively (log-rank test, P < 0.001). Univariate and multivariate analysis revealed Groups to be the only significant factor predicting DFS (P value 0.002 and < 0.001, respectively). In Group B, the most common site of disease failure was distant (9, 53%). CONCLUSION: PET-CT can be used to evaluate response and as a tool to identify patients at higher risk of distant failure. Further, this could be exploited to identify patients who may need treatment intensification. This needs to be validated prospectively.

Predictivity of human papillomavirus positivity in advanced oral cancer.

BACKGROUND AND OBJECTIVE: Human papillomavirus (HPV) is a known prognostic factor world over in patients of carcinoma oropharynx. The role of HPV in oral cancers has not been investigated adequately. We tried to identify standard clinicopathological features in oral cancer, which would predict HPV-positivity. METHODS: This was a retrospective analysis of 124 cases of T4 oral cancer patients at our center. HPV-positive was defined in accordance with positive p16 immunohistochemistry done on pretreatment local tumor site biopsy. Age, sex, habits (smoking history and oral tobacco), Eastern Cooperative Oncology Group performance status (ECOG PS), T stage, N stage, grade, and site were selected, for testing of prediction for HPV-positivity. The analysis was performed by R studio version 3.1.1. Two-sample test for equality of proportions with continuity correction was used to identify factors predicting for HPV-positivity. P = 0.05 was considered as significant. RESULTS: Of 124 patients, 16 patients (12.9%) were HPV-positive. The median age of the whole cohort was 43 years (interquartile range 37-52 years) with 15 females (12.1%). All had squamous cell carcinoma (100%). The grade of the tumor was well differentiated in 9 patients (7.2%), moderately differentiated in 98 patients (79.1%), and poorly differentiated in 17 patients (13.7%). The ECOG PS 0 in 19 patients (15.3%), 1 in 104 patients (83.9%), and 2 in 1 patient (0.8%). The subsite of the tumor was buccal mucosa in 74 patients (59.7%), anterior two-third of tongue in 33 patients (26.6%), and others in 17 patients (13.7%). None of the tested factors except the use of oral tobacco were statistically significantly associated with HPV-positivity. History of tobacco usage had a statistical trend toward ability to predict HPV-positivity. The proportion of patients with HPV-positive oral cancer in patients without history usage of oral tobacco was 31.3% while it was 10.2% in patients with previous history of tobacco use (P = 0.03). CONCLUSION: Standard clinicopathological variables could not predict for HPV-positivity. Negative history of tobacco (smokeless) usage showed statistical trends toward ability to predict HPV-positivity in oral cancer patients.

Delay in seeking specialized care for oral cancers: experience from a tertiary cancer center.

OBJECTIVE: Advanced oral cancers are a challenge for treatment, as they require complex procedures for excision and reconstruction. Despite being occurring at a visible site and can be detected easily, many patients present in advanced stages with large tumors. Timely intervention is important in improving survival and quality of life in these patients. The aim of the present study was to find out the causes of delay in seeking specialist care in advanced oral cancer patients. MATERIALS AND METHODS: A prospective questionnaire based study was done on 201 consecutive advanced oral squamous cancer patients who underwent surgery at our hospital. All patients had either cancer of gingivobuccal complex (GBC) or tongue and had tumors of size more than 4 cm (T3/T4) and were treatment naοve at presentation. RESULTS: Even though most patients observed abnormal lesions in their mouth, majority delayed the decision to visit a physician early. A significant percentage of patients (50%) also reported a delayed diagnosis by the primary care physician before being referred to a tertiary care center for definitive treatment. The average total duration from symptoms to treatment was 7 months. CONCLUSION: The main reasons of this delay in receiving treatment were due to patients themselves (primary delay) or due to time taken by the primary physician to diagnose the condition (secondary delay). Oral self-examination can be helpful in detecting oral cancers early.

Microbial colonization of Provox voice prosthesis in the Indian scenario.

INTRODUCTION: Tracheoesophageal speech using the voice prosthesis is considered to be the "gold standard" with success rates as high as 90%. Despite significant developments, majority eventually develop dysfunction due to microbial deterioration. We did a pilot study of 58 laryngectomy patients who developed prosthesis dysfunction. MATERIALS AND METHODS: A total of 58 laryngectomy patients who had their dysfunctional prosthesis removed were included in this study. Dysfunctional prostheses were removed and examined. Esophageal and tracheal flanges were examined separately. After obtaining pure fungal and bacterial cultures, the yeast strains were identified. Bacteria were identified with the light microscope and gram staining. We analyzed prosthesis lifespan and probable factors affecting it. RESULTS: Central leak was found in 43% cases while in 57% peri-prosthetic leakage was the most common reason for prosthesis replacement. Microbial analysis revealed a combination of yeast and bacteria in approximately 55% culture samples. Out of these, almost 90% had the presence of single yeast species with bacteria. Pure fungal culture was identified in rest of the 45% cultures while none detected pure bacterial forms. Candida tropicalis was the solitary yeast in 81% while Candida albicans was seen in 10% as the solitary yeast. Bacterial isolates revealed Klebsiella pneumonia in 19%, Escherichia coli in 8% while Staphylococcus aureus was grown in 1% cultures. The consumption of curd (P = 0.036, 95% confidence intervals [CI]: 2.292-64.285) to have a significant correlation of the mean prosthesis lifespan. Consumption of curd (P = 0.001, 95% CI: 0.564-2.008) and history of prior radiotherapy (P = 0.015, 95% CI: 0.104-0.909) had a significant bearing on the Provox prosthesis lifespan. CONCLUSIONS: Candida is the most common organism grown on voice prosthesis in Indian scenario. Consumption of curd and history of prior radiotherapy significantly affect Provox prosthesis lifespan.