Phase II trial of piroxantrone in patients with recurrent and metastatic squamous cell carcinoma of the head and neck

Summary Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m² intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.     

PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells

PADGEM protein (PADGEM), also known as GMP140, is a platelet alpha- granule membrane protein that is translocated to the external membrane after platelet activation. Although the biosynthesis of this protein was originally thought to be confined to megakaryocytes, the synthesis of PADGEM in endothelial cells was recently demonstrated (McEver et al: Blood 70:1974a, 1987). We now describe the subcellular localization of this protein in endothelial cells. Immunofluorescence staining of permeabilized human umbilical vein endothelial cells with KC4, a well characterized monoclonal antibody to PADGEM, showed positively stained elongated structures similar in distribution and shape to Weibel-Palade bodies. Their identity as Weibel-Palade bodies was confirmed by double label immunofluorescence using KC4 and a polyclonal antiserum to von Willebrand factor (vWf), a protein known to be specifically stored in these organelles. All Weibel-Palade bodies were found to contain PADGEM. In contrast to strong perinuclear staining produced with anti- vWf antibodies, no significant perinuclear staining was obtained with KC4, indicating that relatively little PADGEM is present in the endoplasmic reticulum and in the Golgi apparatus. In endothelial cells treated with secretagogues that stimulate vWf release the elongated structures positive for PADGEM disappeared, further identifying these structures as Weibel-Palade bodies. This observation extends the parallels between Weibel-Palade bodies and alpha-granules and suggests a possible functional association between vWf and PADGEM.     

Quantitatively distinct requirements for signaling-competent cell spreading on engineered versus natural adhesion ligands.

To design synthetic microenvironments that elicit desired cell behaviors, we must better understand the molecular mechanisms by which cells interact with candidate biomaterials. Using cell lines with distinct alpha5beta1 integrin expression profiles, we demonstrate that this integrin mediates cell spreading on substrata coated with genetically engineered artificial extracellular matrix (aECM) proteins containing the RGD sequence (RGD-containing aECM protein [aRGD]) but lacking the PHSRN synergy site. Furthermore, aRGD-mediated adhesion stimulates an intracellular focal adhesion kinase (FAK) signal that is indicative of integrin tethering. Although both aRGD and the natural ECM protein fibronectin (FN) support alpha5beta1 integrin-mediated cell spreading, quantitative single-cell analysis revealed that aRGD-mediated spreading requires ten-fold greater threshold amount of integrin expression than FN-mediated spreading. Our analysis demonstrates that aRGD-based substrata mediate both biophysical (cell spreading) and biochemical (FAK signaling) events via the alpha5beta1 integrin, albeit with efficacy quantitatively distinct from that of natural ECM proteins that possess the full spectrum of adhesion and synergy domains.     

Interobserver Agreement for the Diagnosis of Venous Thromboembolism on Computed Tomography Chest Angiography and Indirect Venography of the Lower Extremities in Emergency Department Patients

Objectives: To determine interobserver agreement between radiologists for computed tomography (CT) angiography and venography. CT venography of the lower extremities combined with standard CT angiography of the chest may result in an increased overall diagnosis rate of venous thromboembolism (pulmonary embolism or deep venous thrombosis).
Methods: The study had a retrospective cohort design. The population consisted of emergency department patients who were evaluated for suspected pulmonary embolism. A random sample of 50 patients diagnosed and treated for venous thromboembolism and 50 age- and gender-matched patients whose CT angiograms and venograms were read as negative were enrolled. The original reading (R1) was compared with readings of two study radiologists: R2, a general radiologist, and R3, a radiologist with fellowship training in cross-sectional imaging. All readers were blinded to each other.
Results: Both R2 and R3 found both CT angiogram and venogram components technically adequate in 95% (95% CI = 89% to 98%) and 86% (95% CI = 78% to 92%) of studies, respectively. The agreement was very good for CT angiography (lowest agreement = 92%; lowest κ = 0.83) and was good for CT venography (85%, κ = 0.65). In nine cases, R1 read the CT angiogram as negative but the venogram as positive for DVT, whereas both R2 and R3 read both components as negative in four of these nine, suggesting a false-positive isolated DVT rate of 44% (95% CI = 19% to 73%). In no case did R1 read both scan components as negative when R2 and R3 agreed on presence of pulmonary embolism or DVT.
Conclusions: Diagnosis of pulmonary embolism on CT angiography is more reliable than diagnosis of isolated DVT on CT venography.     

Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma

Primary CD30(Ki-1)-positive anaplastic large-cell lymphoma (ALCL) is considered by some to be a distinct clinicopathologic entity associated with the t(2;5) (p23;q35). However, the specificity of t(2;5) for ALCL has not been carefully studied. Therefore, we performed a detailed analysis of all cases of ALCL with abnormal cytogenetics results in the Nebraska Lymphoma Study Group registry, as well as all other cases of non-Hodgkin's lymphoma with t(2;5) in the registry. We found the t(2;5) in only five of 10 cases of ALCL, four of whom were young patients. However, we also found the t(2;5) in 11 other cases of nonanaplastic lymphoma, including eight children with typical peripheral T-cell lymphomas of various types. The t(2;5) was also found in three older adults with B-cell lymphomas of various types. Thus, the t(2;5) was not specific for CD30+ ALCL. However, t(2;5) may define a clinicopathologic entity in children and young adults characterized by variable morphologies with a T-cell or indeterminate phenotype, CD30-positivity, nodal disease with frequent extranodal involvement, advanced stage, and an excellent response to therapy, including bone marrow transplantation for relapsed disease. The clinical relevance of the t(2;5) in older patients requires further study.     

Involved field radiation, fractionated total body irradiation, high dose cyclophosphamide, and autologous bone marrow transplantation in the treatment of malignant lymphomas

We report the results of intensive therapy and autologous bone marrow transplantation (BMT) in 23 patients with malignant lymphoma (eight Hodgkin's disease and 15 non-Hodgkin's lymphoma) who failed primary therapy. All patients had evidence of disease prior to transplant therapy: 10 had never achieved a complete remission and 13 were in relapse. The preparative regimen included involved field radiation followed by fractionated total body irradiation and high dose cyclophosphamide. A complete remission was achieved in 15 patients, 11 of whom continue in unmaintained complete remission from 27 to 72 months after BMT (median follow-up of 52 months). Of the remaining patients, five did not achieve a complete remission and three died of early toxicity. The event-free survival of the entire group is 47%. Disease status at the time of BMT was significantly correlated with patient outcome. The event-free survival of 13 patients in whom there was no objective evidence of tumor growth on conventional dose therapy was 77% compared with only 10% in patients with tumors progressing on conventional dose therapy (p less than 0.002). All six patients transplanted in untreated relapse continue in unmaintained remission, suggesting that debulking chemotherapy may not be necessary before BMT. Alternative approaches are needed in patients whose tumors progress on conventional dose therapy.     

Adaptive decisions in the use of hospital beds.

This article investigates the manner by which a physician adapts his decision on referral to hospital and length of hospital stay to variations in the pressure (access) to hospital beds. An index of adaptation is developed which measures the adaptation to pressure from standard bed-use statistics. An example of the index is given for psychiatric bed use in Canada.     

Emergency Medicine Practitioner Knowledge and Use of Decision Rules for the Evaluation of Patients with Suspected Pulmonary Embolism: Variations by Practice Setting and Training Level

Background Several clinical decision rules (CDRs) have been validated for pretest probability assessment of pulmonary embolism (PE), but the authors are unaware of any data quantifying and characterizing their use in emergency departments. Objectives To characterize clinicians' knowledge of and attitudes toward two commonly used CDRs for PE. Methods By using a modified Delphi approach, the authors developed a two‐page paper survey including 15 multiple‐choice questions. The questions were designed to determine the respondents' familiarity, frequency of use, and comprehension of the Canadian and Charlotte rules. The survey also queried the frequency of use of unstructured (gestalt) pretest probability assessment and reasons why physicians choose not to use decision rules. The surveys were sent to physicians, physician assistants, and medical students at 32 academic and community hospitals in the United States and the United Kingdom. Results Respondents included 555 clinicians; 443 (80%) work in academic practice, and 112 (20%) are community based. Significantly more academic practitioners (73%) than community practitioners (49%) indicated familiarity with at least one of the two decision rules. Among all respondents familiar with a rule, 50% reported using it in more than half of applicable cases. A significant number of these respondents could not correctly identify a key component of the rule (23% for the Charlotte rule and 43% for the Canadian rule). Fifty‐seven percent of all respondents indicated use of gestalt rather than a decision rule in more than half of cases. Conclusions Academic clinicians were more likely to report familiarity with either of these two specific decision rules. Only one half of all clinicians reporting familiarity with the rules use them in more than 50% of applicable cases. Spontaneous recall of the specific elements of the rules was low to moderate. Future work should consider clinical gestalt in the evaluation of patients with possible PE.     

Parapubic hernia: case report and review of the literature

Parapubic hernia is considered rare, with 18 hernias described in five articles published since 1971. The hernia results from iatrogenically or traumatically detached rectus abdominis muscles at the pubic bone and presents a therapeutic challenge because there is no strong aponeurotic anchoring structure in the defect's caudal aspect. We describe a patient with a large parapubic hernia repaired by a combined preperitoneal and onlay prosthetic method. This report adds another dimension to the prosthetic repair options in parapubic hernias and illustrates the effectiveness of the tension-free repair principle in their definitive management. Electronic Publication     

Advanced primary breast cancer: assessment at mammography of response to induction chemotherapy

The response to induction chemotherapy is an important prognostic factor in patients with nonmetastatic, locally advanced breast carcinomas. Assessment at mammography of the response of 60 breast cancers in 59 women was performed between 1974 and 1986. Responses were excellent in 13 tumors, moderate in 34, and poor in 13 (excellent moderate = 78%). Assessment of response of discrete masses in a fatty breast was easiest; assessment of response of tumor areas that were poorly defined-such as a focal area of architectural distortion or mass in dense breast parenchyma-was more difficult. Of 17 patients with excellent pathologic responses-that is, minimal or no residual tumor-15 (88%) had complete responses (no residual tumor) as determined with mammography, physical examination, or both. Mammography provides information complementary to physical examination and is essential in the accurate assessment of the response to chemotherapy of locally advanced breast cancer.