Benefits of a Physician-Scientist-Tailored Curriculum at a Medical Student-Run Free Clinic.

We designed a curriculum to help sustain pre-clinical knowledge for MD/PhD trainees in their graduate training phase while securing regular providers for our student-run free clinic. MD/PhD involvement increased from 1.91 to 2.45 students-per-clinic-day following implementation, and participants affirmed increased preparedness and comfort entering medical school clinical clerkships.

"If I don't use a condom I would be stressed in my heart that I've done something wrong": Routine Prevention Messages Preclude Safer Conception Counseling for HIV-Infected Men and Women in South Africa.

Intended conception likely contributes to a significant proportion of new HIV infections in South Africa. Safer conception strategies require healthcare provider-client communication about fertility intentions, periconception risks, and options to modify those risks. We conducted in-depth interviews with 35 HIV-infected men and women accessing care in South Africa to explore barriers and promoters to patient-provider communication around fertility desires and intentions. Few participants had discussed personal fertility goals with providers. Discussions about pregnancy focused on maternal and child health, not sexual HIV transmission; no participants had received tailored safer conception advice. Although participants welcomed safer conception counseling, barriers to client-initiated discussions included narrowly focused prevention messages and perceptions that periconception transmission risk is not modifiable. Supporting providers to assess clients' fertility intentions and offer appropriate advice, and public health campaigns that address sexual HIV transmission in the context of conception may improve awareness of and access to safer conception strategies.

Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma.

Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾ 2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125-3.11 mg/m(2) on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1-36). MTD was determined to be 2.34 mg/m(2). Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ⩾ 3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ⩾ 3 events were reported. Plasma exposure increased dose proportionally from 0.5-3.11 mg/m(2); terminal half-life was 4-12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ⩾ 32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.

The average roughness and fractal dimension of articular cartilage during drying.

Cartilage is a unique material in part because of it biphasic properties. The structure of cartilage is a porous matrix of collagen fibers, permeated with synovial fluid which creates a gliding and near frictionless motion in articulating joints. However, during in vitro testing or surgery, there exists potential for cartilage to dehydrate, or dry out. The effects of this drying can influence experimental results. It is likely that drying also changes joint performance in vivo. In in vitro testing of equine cartilage explants exposed to open air, the average roughness of cartilage changes from 1.85 ± 0.78 to 3.66 ± 1.41 µm SD in a 5-h period. Significant changes in roughness in individual samples are seen within 10 min of exposure to open air. However, the multi-scale nature of cartilage, characterized by the fractal dimension, does not significantly change during the same period. The current study attempts to quantify the magnitude of error that is introduced when cartilage is removed from its native environment.

Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study.

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.

Multiclass cancer diagnosis using tumor gene expression signatures.

The optimal treatment of patients with cancer depends on establishing accurate diagnoses by using a complex combination of clinical and histopathological data. In some instances, this task is difficult or impossible because of atypical clinical presentation or histopathology. To determine whether the diagnosis of multiple common adult malignancies could be achieved purely by molecular classification, we subjected 218 tumor samples, spanning 14 common tumor types, and 90 normal tissue samples to oligonucleotide microarray gene expression analysis. The expression levels of 16,063 genes and expressed sequence tags were used to evaluate the accuracy of a multiclass classifier based on a support vector machine algorithm. Overall classification accuracy was 78%, far exceeding the accuracy of random classification (9%). Poorly differentiated cancers resulted in low-confidence predictions and could not be accurately classified according to their tissue of origin, indicating that they are molecularly distinct entities with dramatically different gene expression patterns compared with their well differentiated counterparts. Taken together, these results demonstrate the feasibility of accurate, multiclass molecular cancer classification and suggest a strategy for future clinical implementation of molecular cancer diagnostics.

Treatment of steroid-refractory acute graft-versus-host disease with anti-CD147 monoclonal antibody ABX-CBL.

ABX-CBL, an immunoglobulin M murine monoclonal antibody, recognizes CD147 and initiates cell killing through complement-mediated lysis. In a dose-finding trial, 27 patients with steroid-refractory acute graft-versus-host disease (GVHD) received ABX-CBL at 0.01 (presumed no effect dose), 0.1, 0.2, or 0.3 mg/kg per day, and an additional 32 patients were given ABX-CBL at 0.2 or 0.15 mg/kg per day. All patients had undergone allogeneic transplantation for malignant or nonmalignant disorders and received GVHD prophylaxis, generally with methotrexate- and cyclosporine-containing regimens. None responded to methylprednisolone, given for a minimum of 3 days. ABX-CBL was started 20 to 236 (median, 47) days after transplantation; it was given for 7 consecutive days and was followed by 2 infusions per week for 2 more weeks. Among 51 patients evaluable for efficacy, 26 (51%) responded, including 13 with complete responses (CR) and 13 with partial responses (PR). CR lasting 14 days or longer or PR lasting 7 days or longer occurred in 21 (41%; 8 CR, 13 PR) patients, including 19 of 43 (44%) patients who received 0.1 to 0.3 mg/kg ABX-CBL and 2 of 8 (25%) patients given 0.01 mg/kg per day. Myalgias at doses 0.2 mg/kg or greater were dose limiting and resolved without sequelae. Causes of death included organ failure, progressive GVHD, and infection. No death was attributed to ABX-CBL. At 6 months after the initiation of ABX-CBL therapy, 26 (44%) patients were surviving. These results are encouraging. Further studies on the use of ABX-CBL in the management of GVHD are warranted.

De novo deletion of chromosome 18q in a baby with harlequin ichthyosis.

Harlequin ichthyosis, (MIM 242500), is a rare, autosomal recessive skin disorder due to an inborn error of epidermal keratinization. The gene for this condition has not been localized. We present a case of HI in which there was a de novo deletion of chromosome 18q: the karyotype was 46, XY, del(18)(q21.3). We postulate that the gene for HI may lie at, or distal to 18q21.3 and that the deletion observed in this case may have unmasked this autosomal recessive disorder.

Molecular classification of multiple tumor types.

Using gene expression data to classify tumor types is a very promising tool in cancer diagnosis. Previous works show several pairs of tumor types can be successfully distinguished by their gene expression patterns (Golub et al. 1999, Ben-Dor et al. 2000, Alizadeh et al. 2000). However, the simultaneous classification across a heterogeneous set of tumor types has not been well studied yet. We obtained 190 samples from 14 tumor classes and generated a combined expression dataset containing 16063 genes for each of those samples. We performed multi-class classification by combining the outputs of binary classifiers. Three binary classifiers (k-nearest neighbors, weighted voting, and support vector machines) were applied in conjunction with three combination scenarios (one-vs-all, all-pairs, hierarchical partitioning). We achieved the best cross validation error rate of 18.75% and the best test error rate of 21.74% by using the one-vs-all support vector machine algorithm. The results demonstrate the feasibility of performing clinically useful classification from samples of multiple tumor types.

Mitoxantrone and fludarabine in the treatment of patients with non-Hodgkin's lymphoma failing primary therapy with a doxorubicinor mitoxantrone-containing regimen.

Patients with recurrent lymphoma of any grade were treated with mitoxantrone (12 mg/m2 given intravenously (IV) over 15-30 minutes on day 1) followed by fludarabine at a dose of (25 mg/m 2 given IV over 30 minutes on days 1-3) every 28 days fludarabine at a dose of (25 mg/m2 given IV over 30 minutes on days 1-3) every 28 days. All patients had failed one prior chemotherapy regimen that contained either doxorubicin or mitoxantrone, total dose not exceeding 350 mg/m2 doxorubicin or 80 mg/m2 mitoxantrone. mitoxantrone. Thirty one patients (22 with intermediate- or high-grade and 9 with low-grade NHL) were enrolled. Median age was 63 years (range: 21 to 87). The objective response rate for patients with intermediate/high-grade NHL was 55% (27% with CR) and 89% (56% with CR) for patients with low-grade NHL. Median time to disease progression was 5.1 months for patients with intermediate/high-grade NHL and 10.8 months for patients with low-grade NHL. Median time to death for patients with intermediate/high-grade disease was 11.4 months. Median time to death for patients with low-grade NHL was not calculable as only one death (due to respiratory failure) occurred in this group 6.5 months after study start. The regimen was well tolerated. Grade 3/4 neutropenia was reported in 80% (24 of 30) of patients and Grade 3/4 thrombocytopenia in 19% (6 of 31) of patients. Nine hospitalizations for adverse events (primarily fever and neutropenia) occurred among eight patients, all with intermediate/high-grade NHL, during a total of 118 cycles of therapy. Further studies of this combination regimen in patients with intermediate/high-grade NHL and studies combined with monoclonal antibodies in low-grade NHL are warranted.

Physiological basis of flow dependence of Gorlin formula valve area in aortic stenosis: analysis using an hydraulic model of pulsatile flow.

BACKGROUND AND AIM OF THE STUDY: The study aim was to clarify the basis of the cardiac output dependence of aortic valve area calculated with the Gorlin formula which has been reported in patients with aortic stenosis. Clinical and experimental studies which have attempted to differentiate between a change in physical orifice area, versus a defect in the Gorlin formula as the cause of cardiac output related variations in Gorlin valve area in aortic stenosis have yielded conflicting results. METHODS: We employed a numerical model of pulsatile flow in which the total instantaneous transvalvular gradient was the sum of the convective and viscous pressure losses and pressure recovery beyond the stenosis. By analogy with other hydraulic devices, viscous losses due to stenosis were modeled by the term KfV(EXP), where V is flow velocity. Kf and EXP were determined for various orifices by adjusting these two parameters to obtain excellent fit between curves of the orifice discharge coefficient based upon the expression KfV(EXP), and empirically measured orifice discharge coefficient curves which have been published in the engineering literature. Mean systolic transvalvular gradient was calculated from the total instantaneous transvalvular gradient values for an assumed jet area, and an assumed systolic time-velocity flow profile. This mean gradient was substituted into the Gorlin equation to find the apparent Gorlin valve area at cardiac outputs varying from 0 to 10 l/min for a range of where V is assumed true areas between 0.5 and 2.0 cm2. RESULTS: For functional valve areas <1.5 cm2, viscous losses resulted in at most a 10-12% fall in apparent Gorlin valve area when cardiac output was decreased from 5 to 2.5 l/min. In addition, maximum viscous losses did not result in a pressure-flow relationship which was closer to linear than to quadratic. which the CONCLUSION: Clinically significant changes in valve area with flow are due to orifice area changes rather than Gorlin formula flow variability. Moreover beyond the Gorlin valve area is preferred over valve 'resistance' for assessing stenosis severity. In low cardiac output states, output should be increased to the normal range before Gorlin valve area is measured.

High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study.

BACKGROUND: The efficacy of high-dose chemotherapy with progenitor-cell rescue for women with breast cancer is a controversial issue. Although historically controlled trials have suggested a survival advantage for high-dose chemotherapy, several randomised studies have yet to confirm this advantage. Two studies, however, by Bezwoda, of patients with high-risk and metastatic disease, seemed to show a significant survival advantage for high-dose compared with conventional-dose chemotherapy for metastatic and high-risk primary breast cancer. METHODS: To corroborate the study results before starting a large international confirmatory study, a US team did an on-site review of records for patients in the high-risk study. Limited numbers of records were made available for review, all of which were for patients who received the high-dose-chemotherapy regimen. FINDINGS: There was much disparity between the reviewed records and the data presented at two international meetings. In addition, the reviewers saw no signed informed consent, and the institutional review committee had no record of approval for the investigational therapy. After the site visit, Bezwoda admitted scientific misconduct by using a different control chemotherapy regimen from that described in presented data. INTERPRETATION: The Bezwoda study should not be used as the basis for further trials to test the efficacy of the cyclophosphamide, mitoxantrone, etoposide regimen for high-dose chemotherapy in women with high-risk primary breast cancer. This review validates the essential nature of on-site audits, especially in single-institution studies.

Facial analysis: a comprehensive approach to treatment planning in aesthetic dentistry.

Patient aesthetic expectations and smile enhancement can be achieved through the use of facial analysis. This process allows each member of the restorative team (i.e., clinician, specialist, dental technician) to diagnose the patient and develop a comprehensive treatment plan for his or her specific needs. Treatment planning according to facial architecture and dental configuration allows function and harmonious aesthetics to be improved. This article demonstrates a predictable means to evaluate the components of an attractive face for use as a guide during aesthetic dental treatment.

Growth of oncology physician practice management companies.

The practice of oncology is changing dramatically, spurred on by managed care initiatives throughout the United States. As a result, physicians are faced with multiple demands from insurers, managed care organizations, and patients. In response to these demands, oncology physician practice management companies have entered the cancer market. This article describes the driving factors leading to consolidation in practice settings, the risks and benefits to oncologists of affiliating with these companies, and the organizational characteristics of four of these larger corporations. This review article is of broad interest to oncologists practicing in the United States and is meant to provide a useful reference for considering a physician practice management company as a business partner.

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow autotransplants in newly diagnosed multiple myeloma.

There is controversy whether high-dose therapy and a bone marrow autotransplant or conventional chemotherapy is a better treatment for newly diagnosed multiple myeloma. Data from 1 comparative study and 1 randomized trial provide insufficient subject-level data to advise specific people whether to have an autotransplant. We analyzed appropriate use of high-dose therapy and bone marrow autotransplants in people with newly diagnosed, multiple myeloma using a modified Delphi-panel group judgment process. The panel consisted of 9 myeloma experts from diverse geographic sites and practice settings who reviewed Boolean MEDLINE searches of multiple myeloma and chemotherapy or autotransplants. The panel rated a metric of 64 clinical setting developed by permuting age, performance score, disease-stage and disease-related prognostic variables and response to initial therapy. Each panelist rated appropriateness of high-dose therapy and an autotransplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate, 9, most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Autotransplants were rated appropriate in persons <55 years old with stage 3 disease and a complete or partial response or stable disease after initial chemotherapy, inappropriate in persons with stage 1 or 2 disease, a performance score <70% and a complete or partial response or stable disease after initial chemotherapy and uncertain in all other settings.

Considerations in the use of polymer and fiber-based indirect restorative materials.

Restorative materials and techniques are constantly refined in order to address the aesthetic expectations of patients. Second-generation laboratory-fabricated composite materials have recently been developed to combine the advantages of porcelain with composite resin. This class of biomaterial can be utilized in a variety of direct and indirect clinical applications than include inlay/onlay restorations, full-coverage crowns, fixed partial dentures, and implant-supported prostheses. This article reviews considerations for the use of these materials from clinical indications through cementation.

Echocardiography allows safer venous cannulation during excision of large right atrial masses.

BACKGROUND: Excision of large right atrial masses requires bicaval cannulation and cardiopulmonary bypass. Safe venous cannulation can be accomplished only by knowing the exact intracavitary location and extension of the mass to avoid fragmentation. Transthoracic echocardiography and intraoperative transesophageal echocardiography, although helpful, cannot always define the exact intracavitary relationships of the tumor. METHODS: We have used both intraoperative transesophageal and epicardial echocardiography to guide venous cannulation in 4 patients with large right atrial masses. Both echo images are used by the surgeon to select the exact site and method of cannulation to avoid fragmentation of the mass. Epicardial echocardiography complemented the images obtained by transesophageal echocardiography. RESULTS: The technique of combined transesophageal and epicardial echocardiography allowed safe venous cannulation in all 4 patients. Each of the right atrial masses was safely excised using case-specific cannulation techniques guided by the echocardiographic images. CONCLUSIONS: We propose the routine use of both intraoperative transesophageal and epicardial echocardiography in guiding venous cannulation for safe excision of large right atrial masses.

Photodynamic therapy using SnET2 for basal cell nevus syndrome: a case report.

A 26-year-old man with basal cell nevus syndrome presented to the Rocky Mountain Cancer Center (Denver, Colorado) for treatment of several basal cell carcinomas with photodynamic therapy using tin ethyl etiopurpurin (SnET2). The patient was of northern European descent, had type I skin (always burns, never tans), and had a 10-year history of multifocal basal cell carcinomas. The patient had a family history of Gorlin's syndrome (basal cell nevus syndrome); the syndrome had been diagnosed in this patient in 1985. The patient was enrolled in a Phase I/II clinical trial. He was given 1.2 mg/kg (94 mg total) of SnET2 via intravenous infusion; he returned to the clinic the following day for red light application. Thirteen lesions, in 12 treatment fields, were illuminated with light totaling 200 J/cm2 at a fluence of 150 mW/cm2. At the 3-month follow-up examination, all tumors were graded as having a complete response by modified AIDS Clinical Trial Guidelines oncologic standards. No evidence of recurrence has been noted during the 6-month follow-up period.