Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients.

Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing. While Treg in peripheral blood and breast tumors are clonally distinct, Tconv clones, including tumor-antigen reactive effectors (Teff), are detected in both compartments. Tumor-infiltrating CD4+ cells accumulate into distinct transcriptome clusters, including early activated Tconv, uncommitted Teff, Th1 Teff, suppressive Treg and pro-tumorigenic Treg. Trajectory analysis suggests early activated Tconv differentiation either into Th1 Teff or into suppressive and pro-tumorigenic Treg. Importantly, Tconv, activated Tconv and Treg share highly-expanded clones contributing up to 65% of intratumoral Treg. Here we show that Treg in human breast cancer may considerably stem from antigen-experienced Tconv converting into secondary induced Treg through intratumoral activation.

Analysis of long-term survival in multiple myeloma after first-line autologous stem cell transplantation: impact of clinical risk factors and sustained response.

The widespread use of high-dose therapy and autologous stem cell transplantation (ASCT) as well as the introduction of novel agents have significantly improved outcomes in multiple myeloma (MM) enabling long-term survival. We here analyze factors influencing survival in 865 newly diagnosed MM patients who underwent first-line ASCT at our center between 1993 and 2014. Relative survival and conditional survival were assessed to further characterize long-term survivors. Achievement of complete response (CR) post-ASCT was associated with prolonged progression-free survival (PFS) in the whole cohort and with significantly superior overall survival (OS) in the subgroup of patients receiving novel agent-based induction therapy. Landmark analyses performed at 1, 3, and 5 years post-ASCT revealed that sustainment of any response had a highly significant influence on survival with no significant differences between sustained CR and sustained inferior responses. Furthermore, outcome was independently improved by administration of maintenance therapy. A subset of patients did experience long-term survival >15 years. However, conditional survival demonstrated a persistent risk of myeloma-associated death and cumulative relative survival curves did not show development of a clear plateau, even in prognostically advantageous groups. In conclusion, in this large retrospective study, sustained response after first-line ASCT was found to be a major prognostic factor for OS independent of depth of sustained response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions to prolong responses achieved post-ASCT may be essential to reach long-term survival, especially in the setting of persisting residual disease.

Parity improves anti-tumor immunity in breast cancer patients.

Compared to nulliparous women, parous women have an up to 50% lower lifetime risk of developing breast cancer. An endogenous mechanism to prevent the development of cancer is the destruction of tumor cells by T cells that recognize tumor-associated antigens (TAA). Since a number of TAA are also highly present in the breast and placenta of pregnant women, we investigated the induction and characteristics of spontaneous T cell responses against TAA during pregnancy. To this end, we collected peripheral blood from healthy nulliparous, primigravid and parous women, as well as from breast cancer patients. IFN-γ ELISpot assays were performed to measure the intensity and specificity of T cell responses against 11 different TAA. The impact of TAA-specific Treg cells on anti-TAA responses was assessed by performing the assay before and after depletion of CD4+CD25+ T cells. The antigenic specificities of these Treg cells were analyzed by the Treg specificity assay. Furthermore, we conducted flow cytometric analyses to determine the memory phenotype and cytokine secretion profile of TAA-specific T cells. Our results demonstrate that pregnancy induces functional and long-lived memory and effector T cells that react against multiple TAA. These persist for many decades in parous females, but are not found in age-matched females without children. We also detected TAA-specific Treg cells, which suppressed strong effector T cell responses after delivery. Nulliparous breast cancer patients displayed median TAA-specific effector T cell responses to be decreased threefold compared to parous patients, which could be restored in vitro after depletion of Treg cells.

Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients.

Considering the diverse functions of B cells, responses to tumor-associated antigens (TAA) have been thought to be the main source of B cell-mediated antitumor immunity. Polymorphic epithelial mucin (MUC1) is considered one of the most specific TAA in patients with breast cancer. The present study aims to dissect the level and subclasses of naturally occurring anti-MUC1 antibodies in regard to tumor biologic parameters, clinical characteristics and overall survival. In 288 primary, non-metastatic breast cancer patients, pretreatment serum levels of anti-MUC1 immunoglobulin G (IgG) and its subclasses G1-4 as well as immunoglobulin M (IgM) were analyzed via ELISA. With respect to overall survival (Kaplan-Meier analysis), tumor biologic parameters as hormone receptor status, human epidermal growth factor receptor 2 (Her2), Ki-67 expression and tumor grading have been correlated as well as clinical characteristics as nodal involvement, tumor stage and patients' age at the time of diagnosis. Median follow-up time was 148 mo (IQR: 73.1-158.5 mo). A significant increase in IgG antibody titers was correlated highly significantly with an improved overall survival of patients. In multivariate analysis, total IgG proved to be an independent prognostic marker for overall survival (p = 0.002). IgG subclass analysis did not reveal any correlation of IgG1, IgG3 and IgG4 levels with overall survival, while increased immunoglobulin G2 (IgG2) values, although statistically not significant, tended to correlate with prolonged patient survival. MUC1-specific IgM antibodies were shown not to be predictive of overall survival. Altogether, humoral immune responses appear to play a crucial part in the tumor immunity of breast cancer patients. The present data confirms the positive impact of tumor-specific IgG on prolonged overall survival in breast cancer patients. MUC1-antibody testing might be a useful tool to identify high-risk patients who may need adjuvant therapy and potentially might benefit from MUC1-directed immunotherapy.

T cell responses in early-stage melanoma patients occur frequently and are not associated with humoral response.

Endogenous tumor-specific T cells are detectable in patients with different tumor types including malignant melanoma (MM). They can control tumor growth, have impact on patient survival and correlate with improved clinical response to immune checkpoint therapy. Thus, they may represent a potent biomarker for respective treatment decisions. So far, major target antigens of endogenous MM-reactive T cells have not been determined systematically. Instead, autoantibodies are discussed as surrogate parameter for MM-specific T cells. Throughout a period of more than 60 days after tumor resection, we therefore determined in 38 non-metastasized primary MM patients and in healthy individuals by IFNγ ELISpot and bead-based fluorescent multiplex assay major target antigens of spontaneous T cell and humoral responses using a broad panel of MM antigens and assessed the presence and suppressive impact of MM-reactive regulatory T cells (Tregs). We show that MM-reactive T cells are frequent in MM patients, transiently increase after tumor removal and are mostly directed against Melan-A/MART-1, Tyrosinase, NA17-A and p53. MM-specific Tregs were only detected in few patients and inhibited MM-reactive T cells particularly early after tumor resection. Tumor-specific autoantibodies occurred in most patients, but did not correlate with T cell responses. Thus, endogenous antibodies may not be reliable surrogate parameters of MM-reactive T cells.

Antitumor T cell responses in bladder cancer are directed against a limited set of antigens and are modulated by regulatory T cells and routine treatment approaches.

Regulatory T cells (Tregs) play a key role in cancer immune escape. We identified target antigens of spontaneous tumor-specific T cell responses in urothelial carcinoma (UC) and evaluated their modulation by treatment and Treg. We determined Treg target antigens in UC. Fifty-six UC and 13 control patients were prospectively enrolled. Blood was drawn before and after routine treatment. Changes in Treg frequency were measured by fluorescence cytometry and the T effector cell (Teff) response against a set of nine tumor-associated antigens (TAAs) was monitored with an interferon-gamma ELISpot. Antigen specificity of Treg was determined by their increased capacity to inhibit after TAA-specific activation the proliferation of an autologous T cell population. The highest difference in the overall response rate for the total T cell population was observed for epidermal growth factor receptor (EGFR) (UC: 23% and controls: 0%). After depleting Treg, also new york esophageal (NYES)O1 (19 and 0%) and MUC20 (27 and 0%) were more frequently recognized in UC patients. In metastasized patients, the TAA-directed T cell response was augmented by Treg depletion. Tumor resection seemed to diminish Treg suppression of TAA-specific immunity, whereas chemotherapy had no effect. We demonstrated the existence of TAA-specific Treg in UC, which share antigen specificities with Teff. The coexistence of TAA-specific Treg and Teff was very rare. Treg frequencies in the peripheral blood were not changed by therapy. In summary, we identified potentially immunologically relevant TAA in UC. TAA-specific T cell responses against these antigens are suppressed by Treg. We identified TAA-specific Treg in UC patients, which do not cooccur with TAA-specific Teff.

Prognostic value of melanoma-associated antigen A9 in renal cell carcinoma.

OBJECTIVE: The aim of this study was to evaluate the prognostic relevance of melanoma-associated antigen (MAGE) A9 in renal cell carcinoma (RCC). MATERIAL AND METHODS: Immunohistochemical staining for MAGE A9 was evaluated in a tissue microarray containing 587 RCC tumour tissue samples. Nuclear MAGE A9 expression was reviewed using a semiquantitative score. Follow-up has been surveyed since 1990 in a prospectively conducted tumour database. The effect of MAGE A9 expression on cancer-specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. Subgroup analyses were performed for non-metastatic and metastatic disease. RESULTS: Median age in all patients was 63.2 years, 354 patients were male and 233 female, and 108 patients had metastatic disease. Median follow-up was 5.6 years for all patients and 9.0 years for patients still alive (range 0-19.9 years). High nuclear MAGE A9 expression was present in 326 tumour specimens (55.5%). In multivariate analyses high nuclear MAGE A9 expression was associated with poor CSS (p = 0.0027). Furthermore, tumour stage, lymph-node and distant metastasis, Fuhrman grade G3/4, Karnofsky index < 80% and male gender were associated with poor CSS. In subgroup analyses, results were concordant for patients with non-metastatic disease. In patients with metastatic disease, only Karnofsky index > 80% was a significant predictor for CSS; MAGE A9 expression could not be shown to be associated with CSS (p = 0.161). CONCLUSIONS: High nuclear MAGE A9 expression is independently associated with poor CSS in patients with non-metastatic RCC. The assessment of MAGE A9 expression can provide additional prognostic information and should be used in decision-making regarding adjuvant therapy in patients with non-metastatic disease.

Prognostic value of the periodontal risk assessment in patients with aggressive periodontitis.

OBJECTIVES: Aim of the study was to evaluate the predictive value of the modified periodontal risk assessment (PRA) in patients with aggressive periodontitis (AgP) for the first time. MATERIAL AND METHODS: A total of 86 Patients with AgP were re-examined 5-17 years after active periodontal treatment. Risk profile according to the modified PRA was assigned and regularity of maintenance monitored. Tooth loss, bone loss and recurrence of periodontitis were analysed in association with gender, diagnosis, compliance and risk profile using uni- and multivariate parametric regression and Cox proportional hazards models. RESULTS: A total of 14 patients showed a localized AgP, 60 a high-risk-profile and 19 were compliant with the proposed maintenance-interval. Of 2202 teeth 98 were lost. Multivariate analysis could not assign a statistically significant impact to risk-profile. By excluding Interleukin-1 composite genotype from the modified PRA a significant influence (p = 0.003, HR 2.74) was detected. The impact of compliance was shown to be nearly significant (p = 0.059, HR 2.0). In patients with generalized AgP a tendency for increased tooth loss was found. CONCLUSION: The prognostic value of the modified PRA could not be confirmed in patients with AgP. However, exclusion of Interleukin-1 composite genotype led to a model with significant influence on tooth loss.

An association between infantile haemangiomas and erythropoietin treatment in preterm infants.

BACKGROUND: Infantile haemangiomas are benign vascular neoplasms that occur frequently in premature infants. The authors hypothesised that in addition to gestational age and birth weight, erythropoietin therapy may influence the incidence of these soft tissue tumours in preterm infants. METHODS: 2563 infants born prematurely and admitted to the Division of Neonatology, University of Heidelberg Medical School were investigated in a retrospective analysis. Hospital charts for all infants were reviewed for clinical data. The primary endpoint was the percentage of infants who had received erythropoietin treatment and were diagnosed with a haemangioma. RESULTS: Haemangiomas were diagnosed in 4.3% (n=110) of the 2563 preterm infants. These 110 infants had a median gestational age of 29 weeks (IQR 27-33 weeks) and the female:male ratio was 1.8:1. A higher incidence of haemangiomas (12-15%) was detected in premature infants with a lower gestational age (<31 weeks). Erythropoietin therapy was shown to be an independent risk factor after adjusting for all other known factors and oxygen therapy in multivariable analysis (HR 2.82, 95% CI 1.55 to 5.12). Subgroup analysis revealed that the effect was more pronounced in male than female infants (HR 3.61, 95% CI 1.52 to 8.57). CONCLUSIONS: This retrospective study demonstrates that erythropoietin treatment is associated with an increase in the incidence of these benign vascular tumours after adjusting for all other factors.

Effect of the osteotome technique in cases of deficient edentulous ridge.

PURPOSE: The use of dental implants may be limited by lack of sufficient bone. The effectiveness of the alveolar ridge bone-spreading technique in the maxilla was compared with the standard technique. Bone spreading is a technique in which hand osteotomes are used to progressively enlarge the remaining deficient edentulous ridge to enable placement of dental implants. MATERIALS AND METHODS: In the test group (bone spreading), 72 patients received 126 implants. Thirty-six patients with 63 implants placed with conventional implant preparation served as a control group. Measurements of outcome were implant failure and complications after therapy. Kaplan-Meier curves were used to depict time from implant placement to implant failure or complication. RESULTS: Six complications were observed after placement of the implants (3 implant failures, peri-implant inflammation in 2 implants, and 1 exposure of rough implant surface). There was a trend toward more implant failures in the control group. CONCLUSIONS: Results of the ridge-spreading technique seem to be similar to those of the standard technique. However, these results should be regarded with caution because of the small number of complications.

Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma.

BACKGROUND: The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. Here, we studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC). METHODS: EZH2 protein expression in RCC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing RCC tumor tissue and corresponding normal tissue samples of 520 patients. For immunohistochemical assessment of EZH2 expression, nuclear staining quantity was evaluated using a semiquantitative score. The effect of EZH2 expression on cancer specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. RESULTS: During follow-up, 147 patients (28%) had died of their disease, median follow-up of patients still alive was 6.0 years (range 0-16.1 years). EZH2 nuclear staining was present in tumor cores of 411 (79%) patients. A multivariate Cox regression analysis revealed that high nuclear EZH2 expression was an independent predictor of poor CSS (> 25-50% vs. 0%: HR 2.72, p = 0.025) in patients suffering from non-metastatic RCC. Apart from high nuclear EZH2 expression, tumor stage and Fuhrman's grading emerged as significant prognostic markers. In metastatic disease, nuclear EZH2 expression and histopathological subtype were independent predictive parameters of poor CSS (EZH2: 1-5%: HR 2.63, p = 0.043, >5-25%: HR 3.35, p = 0.013, >25%-50%: HR 4.92, p = 0.003, all compared to 0%: HR 0.36, p = 0.025, respectively). CONCLUSIONS: This study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC.

Correlation of positioning and clinical results in Oxford UKA.

In a prospective clinical study, 59 patients with anteromedial osteoarthritis of the knee (61 knee joints) underwent minimally invasive medial Oxford unicompartmental arthroplasty phase 3. Clinical and radiographic examinations of 56 knees were carried out at five (4-7) years. American Knee Society (AKS) scores improved from mean 45.5 (20-80) points (knee score) and 55 (15-100) points (function score) before surgery to 90 (30-100) points in both scores after surgery. The position of each implant was determined on screened radiographs using an image intensifier. The implant position was analysed according to the Oxford X-ray rating system. We evaluated nine measures, and there was no detectable correlation between implant position and clinical result. However, long-term studies are needed before it is possible to elaborate an evidence-based guideline on positioning.

Functional midterm outcome in 131 consecutive cases of surgical clubfoot treatment.

INTRODUCTION: Since introduction and widespread use of the Ponseti method in the last decade, the need for surgical treatment of clubfeet is nowadays limited to resistant cases. In the time before, surgery via dorsomedial release was a very common treatment option. METHOD: Very few long-term follow-up studies cover the outcome of surgical methods, which is particularly interesting, as clinical results rather worsen with time. In the present study, 98 children (131 clubfeet), who underwent surgical correction using the Imhauser method at the age of 4.5 months were included. Follow-up time was 8.2 years (0-11.8 years) at average. RESULTS: Data could be retrieved from 46 patients (71 feet), only 5 patients (7 feet) were lost to follow-up. The rate of relapses was high, as 47 patients (53 feet) needed surgical revision for recurrence, while clinical scores showed a good result in the Laaveg and Ponseti Score and the Foot-Function-Index. Isokinetic testing and clinical data indicated a significant weakness of the treated foot, when compared to the healthy side in 12 patients with unilateral deformity. The presented study supports like others the issue that the clinical outcome of a surgical, posteromedial release in terms of relapses is disappointing. This fact is apparently not sufficiently reflected in the current clinical scores, which showed rather good results. CONCLUSION: As the question of evaluation methods for results of clubfoot treatment remains controversial, isokinetic testing is an easy to use alternative that provides detailed information about functional limitations and may help in reducing the need for repeated radiographic examinations.

Prognostic factors influencing long-term survival of patients undergoing nephron-sparing surgery for nonmetastatic renal-cell carcinoma (RCC) with imperative indications.

BACKGROUND: We assessed the effect of T stage, Fuhrman's grade, multifocality, bilaterality, positive surgical margins, and synchronism of bilateral tumors on cancer-specific survival of patients with nonmetastatic renal-cell carcinoma (RCC) undergoing nephron-sparing surgery for imperative indications. METHODS: We retrospectively analyzed 168 patients who underwent nephron-sparing surgery for imperative RCC indications between 1974 and 2002. A total of 85 patients had bilateral RCCs; in 27 patients, the tumors were multifocal. Multivariate Cox proportional hazards models were fitted to assess the features associated with cancer-specific survival. RESULTS: The median follow-up was 99 months (range, 2-326 months). Patients were followed until January 2008. A total of 52 patients died of their cancer during follow-up. Multivariate analyses of the total group only revealed Fuhrman's grade 3 (hazard ratio [HR] 2.94) and bilateral occurrence of RCC (HR 1.82) as independent prognostic factors. In a subgroup analysis of patients with bilateral occurrence of RCC, we observed a tendency toward positive surgical margins (HR 2.89, P = 0.08) being another negative prognostic factor. There was no difference in cancer-specific survival between patients with synchronous and metachronous bilateral RCC presence (HR 1.08). CONCLUSIONS: Fuhrman's grade 3 and bilateral occurrence of RCC were the only statistically significant prognostic factors for cancer-specific survival in patients undergoing nephron-sparing surgery for imperative indications for nonmetastatic RCC. The presence of sporadic multifocal tumors and the synchronous occurrence of bilateral tumors have no influence on cancer-specific survival, while positive surgical margins may have an impact in the subset of patients with bilateral RCC.

Uncemented grit-blasted straight tapered titanium stems in patients younger than fifty-five years of age. Fifteen to twenty-year results.

BACKGROUND: Total hip arthroplasty without cement is frequently performed in young active patients, but only limited outcomes data are available after durations of follow-up of more than fifteen years. METHODS: We retrospectively evaluated the clinical and radiographic results of a consecutive series of 154 total hip arthroplasties (in 141 patients) performed with an uncemented grit-blasted straight tapered titanium femoral stem combined with a threaded socket in patients under the age of fifty-five years. The median duration of follow-up was seventeen years. Clinical results were evaluated with use of the Harris hip score. The canal fill index was used as the criterion to determine the adequacy of stem sizing. Kaplan-Meier survivorship analysis was performed to predict long-term outcomes. RESULTS: The stem was undersized, with a canal fill index of < or =80%, in forty-one hips (27%). Late aseptic loosening of the stem occurred in four femora, and the femoral component was undersized in all four. These four stems were stable for ten years and then underwent progressive subsidence, which was associated with pain. Five stems were revised because of a late postoperative periprosthetic fracture following trauma. Localized proximal femoral osteolysis was seen in seven hips without signs of loosening. Survivorship of the stem with revision for any reason as the end point was estimated to be 90% (95% confidence interval, 87% to 97%) at twenty years. Survivorship with aseptic loosening as the end point was estimated to be 95% (95% confidence interval, 91% to 99%) at twenty years. Sixty-seven (44%) of the threaded uncemented acetabular components were revised during the follow-up period. CONCLUSIONS: After a minimum duration of follow-up of fifteen years, the survival of this type of femoral component is excellent in individuals younger than fifty-five years. The main mode of stem failure was a periprosthetic fracture due to trauma, or late aseptic loosening in a small percentage of the hips in which the femoral implant was undersized. The high rate of failure of the acetabular components was attributable to a poor design that is no longer in use.

Intraoperative fluorescence staining of malignant brain tumors using 5-aminofluorescein-labeled albumin.

OBJECTIVE: The newly developed conjugate 5-aminofluorescein (AFL)-human serum albumin (HSA) was investigated in a clinical trial for fluorescence-guided surgery of malignant brain tumors to assess its efficacy and tolerability. METHODS: AFL, covalently linked to human serum albumin at a molar ratio of 1:1, was administered intravenously 0.5 to 4 days before surgery at 0.5 or 1.0 mg/kg of body weight to 13 patients aged 38 to 71 years who were suspected of having malignant gliomas. Fluorescence guidance using a 488-nm argon laser was performed during surgery at will. The extent of tumor resection was verified by early postoperative magnetic resonance imaging. Fluorescent and nonfluorescent samples were collected for neuropathology. Blood samples for laboratory and pharmacokinetic analyses were taken over the course of 4 weeks. RESULTS: Fluorescence staining of tumor tissue was bright in 11 patients (84%), resulting in complete resection of fluorescent tumor tissue in 9 patients (69%). In 2 patients, residual fluorescent tumor tissue was also confirmed by magnetic resonance imaging. Neither bleaching nor penetration of AFL-HSA into the surrounding brain edema or into necrotic tissue was seen. The agreement between fluorescence and histopathology in tumor samples and samples of the tumor border was 83.3%. There were no toxic side effects. The quality of fluorescence was independent of the dose administered. The optimal time for surgery is between 1 and 4 days after AFL-HSA administration. CONCLUSION: Tumor fluorescence using AFL-HSA made fluorescence-guided brain tumor resection possible, demonstrating that albumin is a suitable carrier system for selective targeting of aminofluorescein into malignant gliomas.

Perinephric and renal sinus fat infiltration in pT3a renal cell carcinoma: possible prognostic differences.

OBJECTIVE: To evaluate the influence of perinephric (PN) and renal sinus (RS) fat infiltration on cancer-specific survival beyond other prognostic factors, as the Tumour-Node-Metastasis (TNM) classification system defines stage T3a renal cell carcinoma (RCC) as infiltration of perirenal fat and/or direct infiltration of the adrenal gland. Perirenal fat invasion is differentiated into RS and PN fat infiltration, but not further classified for the prognosis. PATIENTS AND METHODS: From 1990 to October 2007 106 patients with advanced RCC (T3a) were followed prospectively at one academic centre; all had a radical nephrectomy. To identify prognostic effects of PN, RS or RS + PN fat infiltration, univariable and multivariable Cox proportional hazard regression models were applied, including lymph node status, metastases, presence of sarcomatoid features and tumour necrosis, Fuhrman's grade, Karnofsky performance status, and tumour size. RESULTS: PN fat invasion alone was present in 58, RS in 21, and PN + RS in 27 patients. The median follow-up was 2.9 years; 49 patients died from RCC. In univariable and multivariable analyses RS fat infiltration was an unfavourable prognostic factor (adjusted hazard ratio, HR, 2.24, P = 0.019). Univariable analysis of RS + PN fat infiltration showed the worst prognostic effect (HR 3.25, P < 0.001). In multivariable analysis this combination was an independent prognostic factor (HR 2.75, P = 0.007), as was the presence of metastasis (HR 5.64, P < 0.001). In this group of RS + PN fat infiltration the 5-year cancer-specific survival was 31%. CONCLUSION: Univariable and multivariable analyses showed that the combination of RS and PN fat infiltration is an independent unfavourable prognostic marker. We recommend that perirenal fat infiltration should be further differentiated into RS fat or PN infiltration in the TNM classification. This will better stratify patient prognosis and might allow those in need of adjuvant therapy to be identified.

Is the body mass index a predictor of adverse outcome in prostate cancer after radical prostatectomy in a mid-European study population?

OBJECTIVES: To evaluate the effect of body mass index (BMI) on the histopathological and clinical outcome in prostate cancer. PATIENTS AND METHODS: In a prospective urological cancer database, 620 patients with prostate cancer had a radical prostatectomy (RP) as a curative treatment. The patients were categorized into three groups of BMI (kg/m(2)); 25.0-30.0 (343, 'overweight') and >30.0 (87, 'obese'). We evaluated the histopathological features and the clinical follow-up after RP. The median (range) age of the men was 64.4 (41.1-80.1) years and the median follow-up 5.5 (0.1-15.1) years. The preoperative median prostate-specific antigen (PSA) levels for normal, overweight and obese patients were 9.0 (0.3-133.0), 8.9 (0.4-230.0) and 9.2 (0.5-194.0) ng/mL, respectively. RESULTS: Serum PSA levels were no different among the three groups (P = 0.92). The normal, overweight and obese patients had organ-confined prostate cancer in 53.7%, 57.1% and 58.6%, respectively (P = 0.34) and had lymph node metastases in 7.9%, 7.6% and 4.6% (P = 0.58). Tumour grading was no different for the three groups (P = 0.25). The PSA recurrence-free, prostate cancer-specific and overall survival for the three BMI groups did not differ significantly (each P > 0.05). CONCLUSION: The BMI cannot be shown to be a predictor of adverse prognosis either for histopathological features or for the clinical outcome, e.g. PSA-free, prostate cancer-specific and overall survival, in a mid-European study population after RP.

Induction chemotherapy with paclitaxel and cisplatin followed by radiotherapy for larynx organ preservation in advanced laryngeal and hypopharyngeal cancer offers moderate late toxicity outcome (DeLOS-I-trial).

A prospective multicenter phase-II trial (12 centers) was performed by the German larynx organ preservation group (DeLOS) to evaluate the effect of induction chemotherapy (ICHT) with paclitaxel/cisplatin (TP), followed by accelerated-hyperfractionated (concomitant boost) radiotherapy (RT) in responders. The trial was focused on larynx preservation, tumor control, survival, salvage surgery and late toxicity in patients with advanced larynx/hypopharynx carcinoma eligible for total laryngectomy (LE). Seventy-one patients (40 larynx, 87.5% St. III, IV; 31 hypopharynx, 93.4% St. III, IV) were enrolled into the study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22) according to the DeLOS protocol. Patients with complete or partial tumor response proceeded to RT (69.9 Gy in 5.5 weeks). Non-responders received a LE followed by postoperative RT (56-70 Gy in 5.5-7 weeks). The response rate to ICHT for larynx cancer was 69.6% (7.1% complete, 62.5% partial response) and for hypopharyngeal cancer was 84.3% (6.9% complete, 77.4% partial response). Overall survival after 36 months was 60.3% (95% CI, 48.4-72.2%), after 42 months was 56.5% (95% CI, 44.2-68.8%). Laryngectomy-free survival was as follows: after 36 months, 43.0% (95% CI, 30.9-55.0%); after 42 months, 41.3% (95% CI, 29.3-53.3%). Both parameters did not show different outcomes after distinguishing larynx from hypopharynx. LE was indicated in 15 non-responders after ICHT. Five of the 15 non-responders refused the laryngectomy. Two of the five received RT instead and had no evidence of disease 42 months after RT. Late toxicity (dysphagia III, IV LENT SOMA score in laryngectomy-free survivors: after 6 months, 1.8%; 12 months, 11.4%; 18 months, 14.5%; 24 months, 8.1%; 36 months, 16%) and salvage surgery (4 pharyngocutaneous fistulas in 27 operations) were tolerable. In a large portion of patients eligible for LE, the larynx could be preserved with satisfying functional outcome. Good responders after ICHT had also a good general outcome with relatively rare severe late toxicities. Due to a slight increase of relevant late dysphagia, functional outcome regarding swallowing and tracheotomy free breathing should be more focused in future larynx organ preservation trials.