Hartmut Stützer

Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer

Molecular prognostic indicators for oropharyngeal squamous cell carcinoma (OSCC), including HPV‐DNA detection, epidermal growth factor receptor (EGFR) and p16 expression, have been suggested in the literature, but none of these are currently used in clinical practice. To compare these predictors, 106 newly diagnosed OSCC for the presence of HPV‐DNA and expression of p16 and EGFR were analyzed. The 5‐year disease‐free survival (DFS) and overall survival (OS) were calculated in relation to these markers and a multivariate Cox analysis was performed. Twenty‐eight percent of the cases contained oncogenic HPV‐DNA and 30% were positive for p16. The p16 expression was highly correlated with the presence of HPV‐DNA (p < 0.001). Univariate analysis of the 5‐year DFS revealed a significantly better outcome for patients with p16‐positive tumors (84% vs. 49%, p = 0.009). EGFR‐negative tumors showed a tendency toward a better prognosis in DFS (74% vs. 47%, p = 0.084) and OS (70% vs. 45%, p = 0.100). Remarkable and highly significant was the combination of p16 and EGFR expression status, leading to 5‐year DFS of 93% for p16+/EGFR− tumors vs. 39% for p16−/EGFR+ tumors (p = 0.003) and to a 5‐year OS of 79% vs. 38%, respectively (p = 0.010). In multivariate analysis p16 remained a highly significant prognostic marker for DFS (p = 0.030) showing a 7.5‐fold increased risk for relapse in patients with p16‐negative tumors. Our data indicate that p16 expression is the most reliable prognostic marker for OSCC and further might be a surrogate marker for HPV‐positive OSCC. HPV+/p16+ tumors tended to have decreased EGFR expression, but using both immunohistological markers has significant prognostic implications.

Fludarabine in Combination With Alemtuzumab Is Effective and Feasible in Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia: Results of a Phase II Trial

PURPOSE To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). PATIENTS AND METHODS A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment. RESULTS The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred. CONCLUSION The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.

Role of postoperative radiotherapy in the management of merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with a high potential of locoregional relapse after surgery alone. This report is an update of our experience in the treatment of MCC. From January 1990 to May 2000, 31 patients with MCC, 13 men and 18 women aged between 34 and 92 years, were treated at the University of Cologne, Germany. Primary tumor sites were in the head and neck region in 13 patients, limbs in 13, and trunk in 5. The tumors were stage I in 26 of 31 patients, stage II in 4 of 31 and stage III in 1 of 31. Treatment included surgery alone in 14 of 31 patients, adjuvant postoperative radiotherapy in 16 of 31 patients, 1 of them had incomplete surgery, and definitive radiotherapy in 1 of 31 patients (stage III). Median overall survival (OS) after first diagnosis was 32 months (95% confidence interval: 0-75 months) with a 3-year OS rate of 47% (95% CI: 25-69%). Six of 31 patients relapsed locally after a median of 4 months, 10 of 31 patients developed regional node metastases, and 7 of 31 patients distant metastases. Nine patients died as a direct result of MCC. Locoregional control and disease-free survival were significantly improved in the group with postoperative radiotherapy (p = 0.023). Uni- and multivariate analysis revealed that head and neck location of the tumor and the lack of postoperative radiotherapy are unfavorable prognostic factors. Postoperative radiotherapy to the primary tumor region and the regional lymphatics is effective in the prevention of locoregional recurrence. Prospective clinical trials should be performed to confirm these observations.

The role of regional hyperthermic cytostatic perfusion in the treatment of extremity melanoma

To evaluate the effectiveness of regional hyperthermic cytostatic perfusion in patients with malignant melanomas of the extremities, 107 patients were included in a prospective randomized study. In a control group (A, n = 54) the tumors were widely excised, and the regional lymph nodes were dissected. The patients in the perfusion group (B, n = 53) received additional hyperthermic (42°C) perfusion with melphalan. The disease‐free survival time was chosen as the criterion for success. An intermediate evaluation (average follow‐up observation period of 550 days) revealed a highly significant difference between the groups (P = 0.0001): 21 recurrences in the control group versus four recurrences in the perfusion group. In a second analysis 3 1/2 years after premature discontinuation, 26 recurrences were diagnosed in Group A, whereas only six recurrences were noted in Group B (P = 0.0001). A retrospective analysis of the entire test group revealed the following figures. In Group A seven recurrences in Stage I were diagnosed, seven in Stage II, and 12 in Stage III. In Group B one was observed in Stage I, one in Stage II, and four in Stage III. The level of significance was calculated to be P = 0.05 in Stage I, P = 0.05 in Stage II, and P = 0.01 in Stage III. The results of the study show that additional perfusion in the treatment of extremity melanomas is superior to conventional methods.

Early surfactant in spontaneously breathing with nCPAP in ELBW infants--a single centre four year experience.

Objective: To evaluate whether the experience with a method to administer surfactant during spontaneous breathing with nasal continuous positive airway pressure (nCPAP) as primary respiratory support in infants with respiratory distress syndrome (RDS) influences the frequency of its use and affects the outcome of patients.

Prognostic relevance of localization and grading in intracranial ependymomas of childhood.

Intracranial ependymomas represent one of the most frequent brain tumors in childhood. Their preferred midline localization and their often controversially discussed classification prompted the present study of 67 intracranial ependymomas in children less than 15 years of age who were operated on from 1951 to 1990. Clinical data and follow-up of all children were retrospectively analyzed by calculation and statistical comparison of progression-free survival (PFS). According to the WHO classification as revised in 1993, 1 grade I subependymoma, 38 grade II ependymomas, and 28 grade III anaplastic (malignant) ependymomas were differentiated. Grade II ependymomas were predominantly located in the IV ventricle and in the supratentorial midline, which often made complete tumor resection impossible. In contrast, the majority of grade III tumors, most often situated in the cerebral hemispheres, could be totally removed. Operative mortality was higher in grade II than in grade III tumors. After recovery from operation, PFS was mainly determined by the histological grading. Median postoperative PFS was 120 months in grade II, but only 18 months in grade III ependymomas (P = 0.1417). Thus, despite varying therapeutic concepts, analysis of this 40-year collective study confirms the prognostic relevance of localization and WHO grading in the case of intracranial ependymoma in children.

Rationale and Baseline Characteristics of PREVENT: A Second-Generation Intervention Trial in Subjects At-Risk (Prodromal) of Developing First-Episode Psychosis Evaluating Cognitive Behavior Therapy, Aripiprazole, and Placebo for the Prevention of Psychosis

Antipsychotics, cognitive behavioral therapy (CBT), and omega-3-fatty acids have been found superior to control conditions as regards prevention of psychosis in people at-risk of first-episode psychosis. However, no large-scale trial evaluating the differential efficacy of CBT and antipsychotics has been performed yet. In PREVENT, we evaluate CBT, aripiprazole, and clinical management (CM) as well as placebo and CM for the prevention of psychosis in a randomized, double-blind, placebo-controlled trial with regard to the antipsychotic intervention and a randomized controlled trial with regard to the CBT intervention with blinded ratings. The hypotheses are first that CBT and aripiprazole and CM are superior to placebo and CM and second that CBT is not inferior to aripiprazole and CM combined. The primary outcome is transition to psychosis. By November 2010, 156 patients were recruited into the trial. The subjects were substantially functionally compromised (Social and Occupational Functioning Assessment Scale mean score 52.5) and 78.3% presented with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition axis I comorbid diagnosis. Prior to randomization, 51.5% of the participants preferred to be randomized into the CBT arm, whereas only 12.9% preferred pharmacological treatment. First, assessments of audiotaped treatment sessions confirmed the application of CBT-specific skills in the CBT condition and the absence of those in CM. The overall quality rating of the CBT techniques applied in the CBT condition was good. When the final results of the trial are available, PREVENT will substantially expand the current limited evidence base for best clinical practice in people at-risk (prodromal) of first-episode psychosis.

OUTCOMES OF NOSOCOMIAL BLOODSTREAM INFECTIONS IN ADULT NEUTROPENIC PATIENTS: A PROSPECTIVE COHORT AND MATCHED CASE-CONTROL STUDY

OBJECTIVE To examine the clinical and epidemiologic features, excess length of stay, extra costs, and mortality attributable to bloodstream infection (BSI) in neutropenic patients with hematologic malignancies. DESIGN Prospective cohort and matched case-control study. PATIENTS All adult neutropenic patients with hematologic malignancies admitted to Cologne University Hospital between May 1, 1997, and April 30, 1998, were prospectively observed. Case-patients were defined as patients with nosocomial BSI; control-patients were selected among patients without BSI. RESULTS During the study period, the BSI rate in neutropenic patients was 14.3 per 100 neutropenic episodes. Eighty-four case-patients were included. Matching was successful for 96% of the cohort; 81 matched pairs were studied. The mean total length of stay was significantly longer for patients with BSI than for control-patients (37 vs 29 days; P = .002). Extra costs attributable to the infection averaged 3,200 dollars (U.S.) per patient. The crude mortality rates of case-patients and control-patients were 16% and 4%, respectively (P = .013), with an attributable mortality of 12% (odds ratio, 11). Eighty-seven percent of patients met the criteria for sepsis according to the American College of Chest Physicians/Society of Critical Care Medicine. Severe sepsis or septic shock occurred in 13% of patients and was correlated with mortality (55% vs 10% in patients without severe sepsis or septic shock; P = .01). CONCLUSIONS Nosocomial BSI in neutropenic patients is significantly associated with an excess length of hospital stay, extra costs, and excess mortality. Severe sepsis and septic shock are closely correlated with an adverse outcome.

Fluor-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in malignant melanoma: Diagnostic comparison with conventional imaging methods

Purpose: To assess the diagnostic value of fluor-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in screening for melanoma metastases. Material and Methods: The case records of 94 melanoma patients who had been examined by whole-body FDG-PET between 1995 and 1999 were evaluated retrospectively. Forty patients showed evidence of lymphogenous and 42 of hematogenous metastasis. The maximal interval between PET and the diagnostic procedure under comparison was 2 weeks. Confirmation of the findings was based on histology or the clinical or radiological course. Results: In 24 patients, all diagnostic examinations including CT had been performed within 2 weeks from PET. In no case did PET change the staging. In 13 patients, PET agreed with morphological diagnosis in the number of metastatically invaded organs. This included 3 patients without metastases. The estimated number of organs invaded by metastases was higher with PET in 5 patients and higher with morphological imaging techniques in 6 patients. Among the PET findings with higher or equivocal counts of organs with metastases there were 2 confirmed false-positive findings. Conclusion: In a selected patient population, FDG-PET was found to be inferior to CT for diagnosing lung and liver metastases. The supplementary use of FDG-PET is not generally of value once metastasis has been established.

Has there been any improvement in the staging of gastric cancer?. Findings from the German gastric cancer TNM study group

This multicenter observational study examined the survival of 1420 patients with histologically proven carcinoma of the stomach. From April 1982 through October 1984, 1360 (95%) patients underwent surgery, 988 (72%) had resections, and 372 (28%) minor surgical procedures. The percentage of patients who have been followed until death or 3 to 5 years was 99.4%. Patients were staged preoperatively and intraoperatively and by pathologists using the old (1978) and new (1987) TNM stage groupings and 5‐year survival was analyzed. Subgroups of patients who changed their stage group according to the new stage definitions were analyzed separately. Only age was an important prognostic factor for survival in Stage IA (P < 0.05) and Stage IB (P < 0.01). Residual tumor after surgery was most important for survival in Stage I1 (P < 0.01) and Stage IIIA (P < 0.001). This indicates that improvements of stage definitions for individual prognosis can only be achieved by adding data concerning the presence or absence of residual tumor (R classification). Cancer 64:2465–2481, 1989.