P16 positivity and regression grade predict survival after neoadjuvant radiotherapy of OSCC.

OBJECTIVES: Survival after preoperative radiotherapy in locally advanced head and neck squamous cell cancer is associated with pathological response. The prognostic importance of p16 expression in these patients has not been established yet. MATERIALS AND METHODS: Ninety-seven patients with oral squamous cell carcinoma, treated preoperatively with radiotherapy in combination with chemotherapy or cetuximab, were included in this retrospective analysis. Survival rates were estimated by the Kaplan-Meyer method. Pathological response was evaluated by histological analysis and p16 expression by immunohistochemistry. RESULTS: Overall survival after 2 years was 66% for the entire group, 92% in the p16-positive and 62% in the p16-negative group, respectively. 12.4% of the tumours were p16-positive. P16 expression (HR 6.98, p = .05) and regression grade (HR 2.94, p = .001) had a statistically significant impact on prognosis. 83.3% of p16-expressing tumours were pathological responders. All p16-positive patients with pathological response were alive within the observation period. CONCLUSION: P16 expression is associated with prognosis in preoperatively irradiated OSCC patients. The association between p16 positivity, regression grade and improved survival provides a rationale for de-intensification strategies in patients with head and neck cancer who respond well to neoadjuvant therapy, a concept that is being tested in prospective clinical trials.

Complete local tumor control after curettage of chondroblastoma-a retrospective analysis.

BACKGROUND: Chondroblastoma is an uncommon benign bone tumor with an incidence of 1 to 2% among all primary bone tumors. In the past, treatment for chondroblastoma has been highly variable leading to different rates of recurrences. Therefore we aimed to determine: (1) the rate of recurrence, (2) the complication rate, (3) and functional outcome after intralesional curettage of chondroblastoma. HYPOTHESES: Intralesional curettage with high speed burring and packing can avoid local recurrences. PATIENTS AND METHODS: Experiences of 22 patients with chondroblastoma of the bone were retrospectively reviewed. The patient group consisted of 16 men; 6 women; mean age 24years (range; 12-58years) affecting in 15 the lower- (68%) and in seven the upper extremity (32%). RESULTS: There was no local recurrence or malignant transformation. All patients underwent intralesional curettage, followed by defect filling presenting in 19 patients (87%) excellent clinical and oncological results (mean MSTS 98.9). Complications were seen in two patients. Pain was the main revealing symptom of the chondroblastoma (n=16, 73%). Mean follow-up of all patients was 114months (range, 25 to 480months). DISCUSSION: Aggressive curettage and packing provided excellent local tumor control and functional results in our patients with chondroblastoma. Malignant transformation is extremely rare, however, present in literature but was not seen in any of our patients. LEVEL OF EVIDENCE: Level IV, retrospective study.

[Squamous cell carcinoma in Dupuytren's disease--a case report]. / Höherdifferenziertes verhornendes Plattenepithelkarzinom in einer Palmarfibromatose (M. Dupuytren)--Fallbericht.

Squamous cell carcinoma in the palm is an extremely rare entity. In the following case report we describe the occurrence of a squamous cell carcinoma in the presence of Dupuytren's disease. A 49-year-old man was operated on the right hand for ulcerating Dupuytren's disease. A squamous cell carcinoma was diagnosed by performing obtaining a fast section intraoperatively. The patient had an invasive, highly differentiated keratinizing squamous cell carcinoma. The lesion was resected together with the Dupuytren lesion and the defect covered with a full-thickness graft. Postoperatively the patient was irradiated. He is free of recurrence for three years now. To our knowledge, this is the first published report of a squamous cell carcinoma in the presence of Dupuytren's disease.

Uptake of (18)F-FLT and (18)F-FDG in primary head and neck cancer correlates with survival.

UNLABELLED: The aim of the study was to determine the practicability of (18)F-FLT in tumours of the head and neck area in terms of visualization, a possible correlation between FLT uptake and proliferation fraction as determined by Ki-67 immunostaining, and if tumoural FLT-uptake has a prognostic meaning, as determined by a correlation to patient survival time. Results were compared to (18)F-FDG. PATIENTS, METHODS: 20 patients with previously untreated lesions of the head and neck area, which were clinically highly suspicious to be malignant, underwent PET scans with (18)F-FLT and (18)F-FDG, a CT of the head and neck area, and a biopsy. Tumour tracer uptake was determined by standardized uptake value (SUV) normalized to body weight and /non-tumor ratios (T/N). (18)F-FDG and (18)F-FLT uptake were compared with histopathologic and immunohistochemical results. RESULTS: 19 patients had malignant tumours; one patient had a benign cystadenoma (so called Warthin's tumour) of the parotid gland. One negative lesion turned out to be a malignant T1 stage squamous cell carcinoma in both PET scans, the Warthin's tumour was false positive with (18)F-FDG but showed only faint uptake with (18)F-FLT, resulting in a sensitivity of 95 % for both tracers. Of all lesions, maximum SUVs of (18)F-FLT ranged from 1.53 to 11.70 (mean +/- SD 5.81 +/- 2.28) those of FDG from 2.63 to 16.50 (mean +/- SD 8.91 +/- 3.58), p < 0.001. (18)F-FLT-T/N ranged from 0.94 to 5.85 (mean +/- SD, 3.18 +/- 1.21), (18)F-FDG-T/N was from 0.92 to 7.50 (mean +/- SD, 3.6 +/- 1.74), n.s. The mean survival time was 18 months in a maximum follow up time of 36 months. A significant correlation between both PET tracers and survival was detected, but no correlation between the amount of Ki-67 positive cells and FLT. CONCLUSION: In head and neck cancer in the primary setting (18)F-FLT does not provide additional visual information in comparison to (18)F-FDG.(18)F-FLT uptake is inversely correlated with patient survival, as well as (18)F-FDG.

Livin and Bcl-2 expression in high-grade osteosarcoma.

AIMS: The evaluation of prognosis in patients with osteosarcoma is limited to clinical parameters. Although numerous molecular markers have been studied, none are currently in routine clinical use. The aim of this study was to determine if Livin and Bcl-2, acting as antiapoptotic proteins through different mechanisms, are expressed in osteosarcoma, and whether they can be used as prognostic markers in human osteosarcoma. METHODS: Tumor specimens of 29 patients with high-grade central osteosarcoma, with complete clinical follow-up for a minimum of 5 years, were studied. The localization and distribution of Livin and Bcl-2 were investigated using immunohistochemistry. Results were correlated with the histological response to chemotherapy, 5-year disease-free and 5-year overall survival. RESULTS: Bcl-2 was expressed only in the cytoplasm of 16/29 cases and there was no statistically significant correlation between expression and any of the studied parameters. Livin was detected in 17/29 cases, in the cytoplasm of all 17 and in the nucleus of only 3 cases. Nuclear expression was significantly correlated with a decreased overall survival (P < 0.0002) compared with those patients without nuclear expression. CONCLUSIONS: The results of this study indicate that Bc1-2 and Livin are highly expressed in osteosarcoma cells and that possibly, the evaluation of nuclear Livin expression might be a useful prognostic marker in osteosarcoma.

Low-turnover bone disease in hypercalcemic hyperparathyroidism after kidney transplantation.

Hypercalcemia in persistent secondary hyperparathyroidism after kidney transplantation is considered to result from increased bone resorption. Bone biopsies' studies, however, have never been performed in these patients. Bone biopsies after double tetracycline labeling were obtained from 17 patients with hypercalcemic hyperparathyroidism and an estimated glomerular filtration rate > 30 mL/min/1.73 m2. Serologic bone markers, calcitriol, intact fibroblast growth factor-23 (iFGF-23), and serum and 24h urine concentration of calcium and phosphate were measured in all patients. Tubular maximum for phosphate corrected for GFR (TmP/GFR), and the fractional excretion of calcium (FeCa) were calculated. High-turnover renal osteodystrophy (ROD) was present in nine and low-turnover ROD in eight patients. The bone formation rate was significantly associated with bone alkaline phosphatase, c-telopeptide and osteocalcin. In patients with high turnover ROD, osteocalcin was also significantly higher than in patients with decreased bone formation. The FeCa was normal or below normal in 14/17 patients. TmP/GFR was below normal in all patients. Neither intact PTH nor iFGF-23 was associated with TmP/GFR, FeCa or any histomorphometric bone parameter. We conclude that hypercalcemia of posttransplant hyperparathyroidism can be associated with high or low turnover bone disease. Decreased calcium excretion suggests an additive tubular effect on hypercalcemia.

Diagnosis of renal osteodystrophy.

The idiom renal osteodystrophy (ROD) represents a heterogeneous pattern of bone disturbances caused by chronic renal insufficiency and concomitant diseases. For the clinical decision of therapy it is most important to differentiate between high and low or adynamic turnover ROD because the therapeutically consequences of these two ends of the ROD spectrum are fundamentally different. Bone histology remains the gold standard for the exact classification of ROD. Serological markers of bone metabolism are not suited for the accurate nomenclature of ROD but are useful for the sequential follow up of ROD after a clear diagnosis has been made. Similarly, radiological diagnosis of ROD using dual energy X-ray absorptiometry (DEXA) or quantitative computer tomography scan (q-CT) is inaccurate and thus more suited for the routine follow up of established disease. Besides mineralization, bone strength and the rate of fractures are strongly determined by the architecture of the bone matrix. This information, however, is also only available on bone biopsy sections and cannot be estimated by non-invasive diagnostic methods. In summary, bone biopsy should be used more liberally for correct classification of bone disease. The sequential follow up and guidance of therapy success can be performed by non-invasive procedures such as biochemical bone marker determination in blood. X-ray imaging and densitometry is suitable only for sequential evaluation of osteoporosis.

Preoperative radiochemotherapy and radical resection for stages II to IV oral and oropharyngeal cancer: grade of regression as crucial prognostic factor.

The purpose of this study was to assess the prognostic value of histological response to preoperative radiochemotherapy in an established multimodal therapy concept for advanced oral and oropharyngeal cancer. Two hundred and twenty-two patients who underwent preoperative radiochemotherapy (RCT: 50 Gy, mitomycin C and fluorouracil) and radical surgery were retrospectively evaluated. Resected tumours of all patients were histologically analysed and response to RCT was classified in histopathological grades of regression (RG). In a multivariate statistical analysis, RG was compared with established factors regarding their predictive value for overall and disease-specific survival. The 5-year overall survival probability in the different groups of histopathological regression grades were: RG1 (no vital tumour): 73.4%, RG2 (minimal tumour remnants encompassing less than 5%): 72.1%, RG3 (5-50% vital tumour cells): 41.9%, RG4 (more than 50% vital tumour): 37.9%. For disease-specific survival probability no significant differences were found between both groups of "responders" (RG1 and RG2) nor between "non-responders" (RG3 and RG4), whereas responders and non-responders differed significantly from each other (log-rank test; p < 0.001). T-classification, N-classification and disease stage, histological grading, tumour site, age, and sex had less prognostic value than RG in a Cox regression model. In the neoadjuvant multimodal therapy concept, histological response to preoperative RCT is a crucial prognostic factor even when surgical R0-resection is accomplished. Thus, non-responders have to be regarded as high-risk patients for recurrence and may benefit from further therapy.

Quantification of dose perturbation by plaque in vascular brachytherapy.

BACKGROUND: Dose prescription and reporting in vascular brachytherapy (VBT) is based on the assumption that the vessel wall is water equivalent, which does not consider a possible dose perturbation by plaque. As the extent of this perturbation is unknown, we aimed to quantify dose attenuation by atherosclerotic plaque for beta- and gamma-radiation. MATERIAL AND METHODS: The dose delivered from Strontium-90/Yttrium-90 ((90)Sr/Y) and Iridium-192 ((192)Ir) sources with and without human peripheral arteries ((90)Sr/Y: n = 38, (192)Ir: n = 7) surrounding the respective delivery catheter was determined with radiochromic films. Plaque and vessel wall thickness were measured using light microscopy. From the ratio-attenuated doseunattenuated dose (dose perturbation factor: DPF) we determined averaged attenuation coefficients for atherosclerotic plaque (micro(P)) and the residual part of the vessel wall (micro(W)) by regression analysis based on the function DPF = exp(-micro(P) * plaque thickness -micro(W) * residual wall thickness). RESULTS: Attenuation in case of (192)Ir was less than the measurement uncertainties. For beta-radiation correlation was found by discrimination between calcified and noncalcified plaque. Classifying noncalcified plaque as normal arterial tissue, the regression coefficient was r = 0.845 at micro(P)= 0.5356 mm(-1) and micro(W) = 0.0663 mm(-1). CONCLUSIONS: Vascular brachytherapy with beta radiation in calcified arteries results in significant dose attenuation within the vessel wall, which can be calculated on knowing the vascular morphometry. Thus, plaque thickness should be taken into account in treatment planning and retrospective analyses.

Aggressive fibromatosis of the mandible: a case report.

An extensive tumour in a 7-year-old girl, leading to severe disfigurement, proved to be an aggressive fibromatosis on histological examination. Eighteen months after surgery there was no evidence of recurrent disease. This suggests that tumour resection and reconstruction of the mandible had been successful. Contrary to some reports, tumour resection led to curative therapy whereas radiotherapy failed.

Conservative treatment of large cystic lesions of the mandible: a prospective study of the effect of decompression.

Our aim was to evaluate prospectively the effects of decompression as the primary treatment of large mandibular cysts, irrespective of their histological type. Twenty patients with large mandibular cysts completed treatment successfully. After a mean duration of decompression of 446 days, cysts had shrunk by a mean of 81%. Mean follow-up was 527 days after removal of the decompression stent and removal of the cyst. There were no recurrences. The advantages of this approach are simplicity, immediate gathering of information on the type of cyst with simultaneous start of treatment, low morbidity and low incidence of complications during treatment. Despite the length of the treatment, we recommend the use of decompression stents in the treatment of large mandibular cysts.

Survivin expression in human osteosarcoma is a marker for survival.

AIMS: Osteosarcoma is the most frequent malignant bone tumor with a peak incidence in the second and third decade of life. Evaluation of prognosis of patients with osteosarcoma is limited to clinical parameters whereas molecular markers of tumor aggression have not yet been identified. Inhibition of apoptotic cell death could play a role in the development or progression of neoplasia. Survivin is a member of the inhibitor of apoptosis (IAP) protein gene family and is expressed both during normal fetal development and in human cancer. METHODS: The localization and distribution of survivin was investigated immunohistochemically in high-grade osteosarcomas by an indirect immunoperoxidase method. RESULTS: Survivin was detected in the cytoplasm in 23/40 and in the nucleus in 20/40 cases of osteosarcoma. Nuclear localization of survivin expression was significantly correlated with a prolonged survival (P=0.0347) but cytoplasmic staining showed no correlation with patient outcome. CONCLUSIONS: The results of this study indicates that the evaluation of survivin expression might be a useful prognostic marker in osteosarcoma. Patients with osteosarcoma exhibiting nuclear survivin expression could potentially benefit from stratification of neoadjuvant chemotherapy.

MRI of the cartilage.

With the introduction of fat-suppressed gradient-echo and fast spin-echo (FSE) sequences in clinical routine MR visualization of the hyaline articular cartilage is routinely possible in the larger joints. While 3D gradient-echo with fat suppression allows exact depiction of the thickness and surface of cartilage, FSE outlines the normal and abnormal internal structures of the hyaline cartilage; therefore, both sequences seem to be necessary in a standard MRI protocol for cartilage visualization. In diagnostically ambiguous cases, in which important therapeutic decisions are required, direct MR arthrography is the established imaging standard as an add-on procedure. Despite the social impact and prevalence, until recent years there was a paucity of knowledge about the pathogenesis of cartilage damage. With the introduction of high-resolution MRI with powerful surface coils and fat-suppression techniques, visualization of the articular cartilage is now routinely possible in many joints. After a short summary of the anatomy and physiology of the hyaline cartilage, the different MR imaging methods are discussed and recommended standards are suggested.

[Coxarthrosis]. / Koxarthrose.

Osteoarthritis of the hip joint is a very common disease. There is a minor prevalence of males. By etiology one can distinguish primary (idiopathic) from secondary osteoarthritis. Secondary are due to well-known etiologies as overweight, repetitive traumata, malposture, muscle- and tendon-imbalance etc. Osteoarthritis includes not only cartilage abnormalities, but also such of the subchondral-region, synovialis, synovial fluid and periarticular muscles. The cartilage shows in osteoarthritis typically edema and swelling, defects with tears, fibrillation, and "baldness" and (or) cartilagenous repair-islands and joint space narrowing as well, while subchondrally micro-edema, necrosis, ev. microfractures, "cysts", demineralisation followed by sclerosis, osteophyte-formation and deformity is seen. With conventional radiographs and CT joint space narrowing, subchondral cysts, sclerosis and osteophytes and deformities are well delineated, MRI however allows visualization of subtle bone marrow and cartilage abnormalities. Clinically, the diagnosis of pre-osteoarthritis becomes more and more important. This includes e.g. deformities and malpostures, labrum-pathologies and structural imbalances. There are three prognostic different types of hip-osteoarthritis depending on the migration of the head of the hip joint: the most common are the latero-cranial and the medio-caudal ones, while the central one is found very rarely. Basic imaging method are conventional radiographs, and CT, followed by MRI. The diagnosis of an "activated osteoarthritis" is made by bone-scintigraphy or MRI with i.v. application of contrast-media. The labrum- and cartilage diagnosis should be done with MRI or MR-arthrography. Functional computer-animated analysis will be of great diagnostic value in the near future. MRI indications are differences between clinical results and imaging, missing clinical improvement of an "activated" osteoarthritis under standard therapy, unclear joint-pain and before any arthroscopy.

Pathophysiology and imaging in inflammatory and blastomatous synovial diseases.

Variable pathologies are subsumed under the term "synovial disease", including common pathologies such as rheumatoid arthritis. While formerly radiologists had to rely on conventional radiographs and bone scintigraphy with their inherent problems in visualizing soft tissue, noninvasive imaging of the synovium has recently improved substantially with the technical development of MRI and (Doppler) ultrasound. These imaging modalities allow differentiation of characteristic pathologic features based on a profound knowledge of normal anatomy and pathophysiology.

The expression of bone morphogenetic proteins in osteosarcoma and its relevance as a prognostic parameter.

AIMS: The expression of bone morphogenetic proteins (BMPs) was analysed in 47 osteosarcomas to determine differences in the expression of BMP subtypes and to correlate expression with response to chemotherapy, in addition to the disease free and overall survival of patients. METHODS: The expression of BMPs was examined immunohistochemically in 47 biopsy specimens of osteosarcoma using commercially available antibodies against different subtypes (BMP-2/4 (A-20), BMP-3 (N-19), BMP-4 (N-19), BMP-5 (N-19), BMP-6 (N-19), BMP-7 (N-19), BMP-8 (N-19)). The avidin-biotin-immunoperoxidase method was used for all antibodies. RESULTS: The expression of BMP subtypes varied considerably: 28 of the 47 tumours expressed BMP-2/4, 24 expressed BMP-3, 41 expressed BMP-5, 31 expressed BMP-6, 43 expressed BMP-7, and 42 expressed BMP-8. High expression of BMP-6 was found in those parts of the osteosarcoma with a chondroid differentiation (p = 0.016, Mann-Whitney test). No correlation was observed between the response to chemotherapy and the expression of BMPs (p > 0.05, Mann-Whitney test). Univariate analysis showed no correlation between overall survival or progression free survival and the expression of BMPs (p > 0.05, log rank test). CONCLUSIONS: BMP-7 and BMP-8 are highly expressed in osteosarcoma. Moreover, high expression of BMP-6 correlates with a chondroid differentiation. In contrast to conclusions derived from previous studies in which small numbers of tumours were investigated, these results indicate that the expression of BMPs does not help to predict the outcome of patients.

Platelet-derived growth factor-alpha receptor expression supports the growth of conventional chondrosarcoma and is associated with adverse outcome.

Bone cells are important targets of platelet-derived growth factors (PDGFs) because they stimulate proliferation of osteoblasts and chondrocytes. In this study we wanted to determine the expression of PDGF-AA and PDGF-alpha receptor in conventional chondrosarcomas and to compare the results with those obtained from benign enchondromas and non-neoplastic cartilage tissue. Sixty-seven chondrosarcomas, 20 enchondromas, and 5 specimens of healthy cartilage as well as 7 specimens of hypertrophic callus cartilage were immunohistochemically analyzed for the expression of PDGF-AA and PDGF-alpha receptor, respectively. Additionally, the proliferation activity was examined with the MIB-1 antibody. Clinical follow-up data were available from 53 patients. A significant overexpression of receptor and factor was found in chondrosarcomas as compared with enchondromas (PDGF-AA p = 0.013, PDGF-alpha receptor p <0.001). MIB-1 values were significantly higher in chondrosarcomas (p <0.001). In healthy joint cartilage no staining was detectable, whereas reactive cartilage of callus formation showed high expression levels. PDGF-alpha receptor expression was significantly higher in grade 3 chondrosarcomas compared with grade 2 (p = 0.022) and grade 1 tumors (p = 0.002). Survival analysis documented a significantly shorter overall survival for patients with high PDGF-alpha receptor expression (p = 0.0172, log-rank test). Because PDGF-alpha receptor expression positively correlates with the aggressiveness of chondrosarcoma, it may be considered as a possible target for novel therapeutic strategies.

[Differential diagnostic problems in assessment of benign bone tumors]. / Differenzialdiagnostische Problematik bei der Befundung benigner Knochentumoren.

The diagnosis of benign bone tumors can cause many problems and a definitive histological diagnosis is often impossible without the knowledge of clinical datas, age of the patient and anatomical location of the tumor. Therefor cooperation between pathologist, orthopedic surgeon and radiologist is necessary, to reduce the risk of misinterpretation of benign and malignant bone tumors. Benign bone tumors often show a heterogenous histology and overlapping morphology between different entities has to be kept in mind, as well as the sampling error in biopsy- and frozen section material. In most cases the pathologist has to rely on conventional stainings because the immunohistochemistry stainings are often not helpful.

Leiomyoma in the space of Retzius: a report of 2 cases.

Leiomyomas most frequently occur in the genitourinary and gastrointestinal system. This report discusses clinical and pathologic findings of 2 leiomyomas in the pubovesical space, a location that has not been described before. Different operative approaches were used for excision. Immunohistochemical examination for the presence of estrogen and progesterone receptors was performed.

Fatal late coronary thrombosis after implantation of a radioactive stent: postmortem angiographic and histologic findings--case report.

Postmortem angiography and histologic analysis of a fatal coronary thrombosis 4 months after implantation of a radioactive stent are described. Histologic findings suggested incomplete re-endothelialization in the segment with the stent. Ionizing radiation may delay re-endothelialization after revascularization, thus maintaining the thrombogenicity of the irradiated vessel segment. Thus, prolonged antiplatelet therapy should be considered after intravascular radiation therapy.