No abstract

A phase I study with recombinant human tumor necrosis factor alpha (rhuTNF-alpha; Knoll AG, Ludwigshafen, FRG) in patients with advanced malignant disease was undertaken to evaluate drug toxicity (organ specificity, time course, predictability, reversibility, maximal tolerated dose), effectiveness, antigenicity and pharmacokinetics. TNF was administered as a test dose followed by daily i.v. infusions for 5 days, every 3 weeks (single i.v. infusion lasting 10 min, TNF dissolved in 50 ml 5% human albumin). Dosage was increased in groups of 3 or 4 patients from 0.04 mg/m2 to 0.28 mg/m2. A total of 19 patients with different cancers, including seven large-bowel carcinomas, three chronic myelogenous leukemias, three hypernephromas, two small-cell lung cancers, one malignant melanoma, one malignant lymphoma, one rhabdomyosarcoma and one fibrosarcoma were treated. Major side-effects were chills and fever (maximum 40.4 degrees C, median 38.7 degrees C, 19/19), headache (12/19), nausea and vomiting (12/19) and pronounced (greater than 20%) hypotension (4/19). Acute side-effects could be diminished by paracetamol or indomethacin pretreatment, and with one possible exception no tachyphylaxis to TNF was noted. Mild renal toxicity was seen during TNF treatment. Pharmacokinetic studies showed a serum half-life (t1/2) ranging from 11 min to 17 min for doses from 0.04 mg/m2 to 0.16 mg/m2 and prolonged clearance with t1/2 ranging from 54 min to 70 min in the 0.20-0.28 mg/m2 dose range. No objective antitumor effects were observed in this phase I study.

Surgical decompression was effective in improving symptoms in severe lumbar idiopathic spinal epidural lipomatosis.

M.M. and M.B. contributed equally to the present manuscriptWhat's known on the subject? and What does the study add?• Only little and partly contradictory data are currently published about the prognostic role of immunohistochemically detectable proliferation-associated biomarkers in surgically treated squamous cell carcinoma of the penis (SCCP), and no data are available at present about their usefulness for refining the delineation between different Broders' grading categories (e.g. still G2 or just G3 SCCP?). Moreover, the accuracy of various conventional histopathological parameters for predicting cancer-specific survival (CSS) in surgically treated SCCP has not been systematically evaluated yet.• Based on the so far largest study cohort encompassing 158 consecutive patients with surgically treated PSCCs characterised by means of a central histopathological review, our data add the following to the currently available literature: (i) Ki-67, mini-chromosome maintenance 2 protein (MCM2), and geminin indicate a more aggressive behaviour in SCPP but do not represent independent prognostic parameters in the multivariable analysis in terms of CSS, (ii) these three biomarkers are not helpful for refining the delineation between different Broders' grading categories at the immunohistochemical level, and (iii) the conventional histopathological parameters staging, grading, nodal involvement, and lymphovascular invasion are independent prognostic parameters that together achieve a predictive accuracy of 82% for CSS. Objective• To assess the role of cell proliferation-associated biomarkers to predict cancer-specific survival (CSS) in patients with surgically treated squamous cell carcinoma of the penis (SCCP). Patients and Methods• A multicentre study enrolling 158 consecutive patients with surgically treated SCCP was performed. lymphovascular invasion (LVI) and nodal status, whereas geminin expression only correlated with tumour grade.• The 5-year CSS for the entire study cohort was 62%.• Univariable analysis showed a significant prognostic impact of Ki-67 (P = 0.026), MCM2 (P = 0.007), and geminin (P = 0.036).• In multivariable analysis, only pT (hazard ratio [HR] 1.67; P = 0.003) and pN stage (HR 2.62; P = 0.015) as well as tumour grade (HR 1.89; P = 0.036) and LVI (HR 2.66; P = 0.028) were identified as independent prognostic parameters for CSS.• The accuracy of the Cox model for CSS prediction was 0.820 (95% confidence interval 0.741-0.898).

Introduction: We assessed the reproducibility and prognostic impact of the Broders' grading system (BGS) in a cohort of 147 patients with surgically treated penile squamous cell carcinomas. Materials and Methods: Conventionally stained histology slides were graded according to the BGS in two rounds by two study pathologists. Reproducibility was assessed using ĸ statistics. Multivariable analyses were calculated to predict cancer-specific survival (CSS). The ‘mean grade' per pathologist per round was calculated by allocating grade points to each study case (G1-G4: 1-4 points) and dividing the sum of all grade points by the number of cases examined. Results: The BGS showed substantial interobserver variation (59-87% with ĸ = 0.38-0.69) but almost perfect intraobserver reproducibility (91% with ĸ = 0.86 and 96% with ĸ = 0.94, respectively). The ‘mean grade' per pathologist remained nearly constant in both rounds of examination (differences ≤0.05 grade points) but differed between the two pathologists (up to 0.4 grade points). In multivariable analyses, the prognostic impact of the BGS in terms of CSS was strongly pathologist-dependent. Conclusions: Clinically and prognostically relevant interobserver discordance concerning the BGS seems, at least in part, to be attributable to inherent ‘aggressive' versus ‘reserved' grading characteristics of individual pathologists.