Opportunities and Limits in Salvage Surgery in Persistent or Recurrent Head and Neck Squamous Cell Carcinoma.

Except for HPV-induced cancers of the oropharynx, survival rates in patients with squamous cell carcinoma of the head and neck (HNSCC) have not changed substantially over the last decades. Salvage surgery plays an important role where primary treatment was unsuccessful since 50% of advanced-stage patients relapse after nonsurgical primary treatment. Depending on a variety of factors, a considerable number of patients in whom primary treatment was not successful can still be cured by salvage surgery. It is the goal of this review to elucidate these factors with the aim to counsel patients and their relatives realistically about the chances of being cured.

Comparison of PI3K Pathway in HPV-Associated Oropharyngeal Cancer With and Without Tobacco Exposure.

OBJECTIVES: The aim of the study was to evaluate whether HPV associated OPSCC with tobacco exposure follows a different carcinogenic pathway compared to HPV associated OPSCC without tobacco exposure and to investigate its prognostic significance. The question was addressed with focus on components of the PI3K pathway. METHODS: 184 patients with newly diagnosed OPSCC treated with curative intent were consecutively enrolled. The expression level of p16, p53, PI3K, mTOR, and PTEN was assessed by immunohistochemistry and analyzed in relation to the risk factors HPV status and tobacco exposure. RESULTS: 94 of 184 (51%) patients were p16 positive, p53 overexpression was detected in 48 of 184 (26%) cases. PI3K overexpression with 70 of 184 (38%) cases was significantly higher in p16 positive tumors. mTOR overexpression was present in 90 of 184 (49%) cases and significantly higher in p16 negative tumors. PTEN loss was found in 42 of 184 (23%) cases without association to p16 expression. p16 positive OPSCC showed lower rates of p53 expression and mTOR expression as well as higher rates of PI3K expression irrespective of tobacco exposure. Survival analysis showed a distinct intermediate survival rate of p16 positive smokers. The markers PI3K, mTOR, and PTEN did not have a significant impact on survival. CONCLUSION: HPV associated OPSCC with tobacco exposure follows the same expression level of the PI3K pathway as HPV associated OPSCC without tobacco exposure. The impaired survival rate of the intermediate risk group cannot be explained by different expression patterns of PI3K, mTOR, and PTEN. LEVEL OF EVIDENCE: 2b.

A patient with a history of breast cancer and multiple bone lesions: a case report.

BACKGROUND: Long-term severe hyperparathyroidism leads to thinning of cortical bone and cystic bone defects referred to as osteitis fibrosa cystica. Cysts filled with hemosiderin deposits may appear colored as "brown tumors." Osteitis fibrosa cystica and brown tumors are occasionally visualized as multiple, potentially corticalis-disrupting bone lesions mimicking metastases by bone scintigraphy or 18F-fluorodeoxyglucose positron emission tomography. CASE PRESENTATION: We report a case of a 72-year-old white woman who presented with malaise, weight loss, and hypercalcemia. She had a history of breast cancer 7 years before. The practitioner, suspecting bone metastases, initiated bone scintigraphy, which showed multiple bone lesions, and referred her to our hospital for further investigations. Laboratory investigations confirmed hypercalcemia but revealed a constellation of primary hyperparathyroidism and not hypercalcemia of malignancy; in the latter condition, a suppressed rather than an increased value of parathyroid hormone would have been expected. A parathyroid adenoma was found and surgically removed. The patient's postoperative course showed a hungry bone syndrome, and brown tumors were suspected. With the background of a previous breast cancer and lytic, partly corticalis-disrupting bone lesions, there was a great concern not to miss a concomitant malignant disease. Biopsies were not diagnostic for either malignancy or brown tumor. Six months after the patient's neck surgery, imaging showed healing of the bone lesions, and bone metastases could be excluded. CONCLUSIONS: This case shows essential differential diagnosis in a patient with hypercalcemia and multiple bone lesions. Whenever multiple, fluorodeoxyglucose-avid bone lesions are found, malignancy and metabolic bone disease should both be included in the differential diagnosis. Fluorodeoxyglucose-avid and corticalis-disrupting lytic lesions also occur in benign bone disease. There may be very few similar cases with heterogeneous and widespread bone lesions reported in the literature, but we think our patient's case is particularly remarkable for its detailed imaging and the well-documented course.

Use of inpatient rehabilitation for cancer patients in Switzerland: who undergoes cancer rehabilitation?

QUESTION UNDER STUDY: Rehabilitation for cancer patients aims to reduce physical disability and mental distress resulting from the disease and its treatment. However, little is known about the use of cancer inpatient rehabilitation in Switzerland in relation to sociodemographic and medical characteristics. The main purpose of this study was to evaluate whether there are differences in sociodemographic and medical characteristics between patients who underwent inpatient rehabilitation (users) and those who did not (nonusers). METHODS: A total of 238 cancer patients from the University Hospital Zurich were included. The sociodemographic and medical characteristics of inpatient rehabilitation users were assessed and compared with those of nonusers. We analysed the differences between inpatient rehabilitation users and nonusers. RESULTS: Of the patients included, 101 (42.4%) used inpatient rehabilitation. They were less likely to be employed (p = 0.029), stayed longer in hospital (p <0.001), and were more likely to have semiprivate or private supplementary health insurance (p = 0.030) than nonusers. There were differences in cancer site (p = 0.001). Patients with tumours of the digestive organs or of the thoracic organs were more likely to use rehabilitation, whereas breast cancer patients were less likely to use it. Stratified analyses showed that male patients with semiprivate or private supplementary health insurance (p = 0.037), lower education (p = 0.039), and lower likelihood of employment (p = 0.051) were more likely to use rehabilitation. Women with an advanced tumour stage used inpatient rehabilitation more often (p = 0.012). CONCLUSIONS: Findings show the influence of duration of hospitalisation, insurance type, cancer site, employment status, and gender on the use of inpatient cancer rehabilitation. The results indicate the need of structured standardised procedures for medical referral to be implemented based on screening.

Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients.

BACKGROUND: The genetic heterogeneity of developmental delay and cognitive impairment is vast. The endocytic network is essential for neural development and synaptic plasticity by regulating the sorting of numerous transmembrane proteins. Disruption of the pathway can lead to neuronal pathology. Endosomal biogenesis relies on two Rab proteins, Rab5 and Rab7, which bind to two hexameric tethering complexes, the endosomal class C core vacuole/endosome tethering complex (CORVET) and the late endosomal/lysosomal homotypic fusion and protein sorting complex (HOPS). Both complexes consist of four core proteins and differ by their specific Rab-binding proteins. OBJECTIVES: To identify the molecular basis of a neurological disease, which consists of global developmental stagnation at 3-8 months, increasing appendicular spasticity, truncal hypotonia and acquired microcephaly, with variable seizure disorder, accompanied by thin corpus callosum, paucity of white matter and delayed myelination in eight patients from four unrelated Ashkenazi-Jewish (AJ) families. METHODS: Exome analysis, homozygosity mapping and Mup1-GFP transport assay in mutant yeast. RESULTS: Homozygosity for a missense mutation, p.Cys846Gly, in one of the endosomal biogenesis core proteins, VPS11, was identified in all the patients. This was shown to be a founder mutation with a carrier frequency of 0.6% in the AJ population. The homologous yeast mutant had moderate impairment of fusion of the late endosome to the vacuole in Mup1-GFP transport assay. CONCLUSIONS: We speculate that in neuronal cells, impairment of fusion of the late endosome to the vacuole would attenuate the degradation of plasma membrane receptors, thereby underlying the progressive neuronal phenotype in our patients. The VPS11 p.Cys846Gly mutation should be added to the AJ carrier screening panel.

Post-treatment surveillance of head and neck cancer: pitfalls in the interpretation of FDG PET-CT/MRI.

QUESTIONS UNDER STUDY: We investigated non-malignancy-associated (¹8F)fluoro-deoxy-D-glucose (FDG) uptake in the head and neck cancer (HNC) post-treatment follow-up with positron emission tomography - computed tomography / magnetic resonance imaging (PET-CT/MRI). A retrospective study on HNC patients undergoing follow-up or re-staging PET-CT/MRI examinations was performed. Thereby, FDG-positive regions were morphologically correlated to the CT and MRI images and a statement regarding tumour persistence/recurrence. METHODS: FDG-positive lesions were assessed according to their anatomical localisation and categorised as true positive, true negative, false positive or false negative findings. The gold standard for verification of an FDG-positive lesion was the cytological or histopathological examination of the region of interest. The most likely aetiology was assessed according to the following categories: (1.) physiological uptake (2.) post-surgical, inflammatory uptake, (3.) post-irradiation, inflammatory uptake and (4.) reactive, not otherwise specified. RESULTS: Tumour recurrence / tumour persistence was found in 14/87 patients (16.1%). A total of 159 non-malignancy-associated FDG-positive lesions were found. Every PET-CT/MRI examination revealed 2.1 ± 1.5 FDG-positive lesions in the head and neck. A total of 107 FDG-positive lesions (67.3%) were categorised as physiological, 52 FDG-positive lesions (32.7%) as inflammatory (post-surgical: n = 14, 8.8%; post-irradiation: n = 9, 5.7%; reactive, not otherwise specified: n = 29, 18.2%). Eight patients (11.8%) underwent invasive diagnostic procedures to clarify indistinct findings. CONCLUSIONS: Post-treatment follow-up of HNC patients requires interdisciplinary management and familiarity with the patient's past medical history. Awareness of common confounders of FDG positivity often allows clarification of indistinct lesions. However, a substantial number of approximately 12% of FDG-positive lesions remain unclear unless invasive diagnostic procedures are performed.

Generation of an intramolecular three-color fluorescence resonance energy transfer probe by site-specific protein labeling.

Fluorescence resonance energy transfer (FRET) is a valuable tool for studying protein structure, folding and interactions. The steep distance dependence of the FRET efficiency requires the donor and acceptor to be in close proximity (1-7.5 nm) to exhibit sufficient energy transfer. One possibility to overcome this limitation is the usage of a FRET cascade that utilizes more than one FRET pair. Essential for realizing this FRET cascade is the site-specific introduction of multiple fluorophores to a given protein, which remains a great challenge. In this study, orthogonal labeling techniques, including fluorescent protein tagging, oxime ligation and kinetically controlled cysteine conjugation, are employed to introduce three fluorophores at specific sites of Rab1b GTPase, yielding a triple-labeled FRET probe. The generated protein probe exhibits efficient energy transfer from the primary donor enhanced green fluorescent protein over the intermediate acceptor rhodamine to the final acceptor Dy630. The labeling strategy opens up a new avenue for multi-color labeling of proteins, facilitating long-distance FRET studies.

Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx.

In patients with early head and neck squamous cell carcinoma (HNSCC), occult lymph node metastasis is difficult to predict by clinical or pathological parameters. However, such parameters are necessary to select patients either for elective neck dissection or the sentinel lymph node (SLN) procedure. The membrane glycoprotein podoplanin is normally expressed in lymphatic endothelial cells. Recently, expression of podoplanin by cancer cells was demonstrated to promote tumor cell motility and tumor lymphangiogenesis in vitro. The value of cancer cell-expressed podoplanin was to be determined as a predictive marker for SLN metastasis in early HNSCC of the oral cavity and oropharynx. One hundred twenty patients with HNSCC of the oral cavity and oropharynx undergoing a SLN biopsy were enrolled in this prospective clinical trial of SLN biopsy. Cancer cell-expressed podoplanin was determined by immunohistochemistry using tissue microarrays. Podoplanin expression was quantified by the intensity reactivity score and categorized into expression and nonexpression. SLN examination revealed occult metastasis in 45 patients (37.5%). Twenty-nine of 120 (24.2%) primary HNSCC showed podoplanin expression. Podoplanin expression correlated significantly with SLN metastasis (p = 0.029) and remained a significant predictor for lymph node status even after controlling for tumor stage (p = 0.028). As a predictive marker for SLN metastasis, however, podoplanin expression reached a sensitivity of a mere 36% and a specificity of 83%. Podoplanin expression is associated with metastasis to lymph nodes in vivo. Podoplanin immunohistochemistry in early HNSCC of the oral cavity and oropharynx may help to select patients for the SLN procedure and to identify patients with increased risk for presence of occult lymph node metastasis in the neck.

Soft-tissue sarcomas of the head and neck: a retrospective analysis of the Alberta experience 1974 to 1999.

BACKGROUND: Soft-tissue sarcomas (STS) of the head and neck constitute a heterogeneous group of rare malignant tumors occurring in an uncommon site. The most common subtypes of STS in the head and neck are malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, and fibrosarcoma. Evidence based subtype-specific treatment decisions are often not possible. METHODS: The medical records of 110 patients diagnosed with head and neck sarcomas were reviewed. All were treated at one of the two major Cancer Centers in Alberta, Canada, between 1974 and 1999. Potential prognostic factors including age, sex, tumor size, histology, grade, tumor location (superficial or deep), and use of adjuvant treatment were evaluated. Cox proportional hazards models were developed to study the impact of these covariates on survival. RESULTS: The median duration of follow-up was 61.5 months. Five year overall, disease specific, and relapse free survival were 65.8%, 83.4%, and 74.2%, respectively. With use of a Cox proportional-hazards model, tumor stage and grade were important prognostic factors affecting survival. CONCLUSIONS: Tumor size and grade were important prognostic factors affecting survival. Tumor location in relation to the superficial fascia (depth) was the best predictor of outcome. The overall and disease-free survival in this patient group was excellent. However, this likely caused by the high proportion of patients with low-grade tumors in our study.