Leigh Neumayer

Influence of spousal opinions on residency selection

Fourth-year medical students face the difficult task of choosing a residency consistent with their career goals. Our study investigates the input of the spouse on the residency selection. From July 1, 1988, to July 1, 1990, questionnaires were sent to all 69 spouses of fourth-year medical students at the University of Arizona Medical Center. Fifty-six were returned for a response rate of 81%. Of the 16 women and 40 men who responded (mean age: 27 years), 55 (98%) spouse stated that there had been family discussions on the choice of a residency program, and 41 (73%) respondents thought that they had significant input. When asked to rank the items that most influenced their support for a particular training program, career goals of the medical student (68%) and lifestyle (21%) were most important, whereas prestige, earning capacity, and program length were ranked lowest. Specific concerns expressed by spouses on the selection of a surgical residency included time commitment as the most commonly cited (79%), followed by fatigue (48%). A statistically significant correlation existed between those spouses actively discouraging the choice of general surgery and those objecting to the time commitment during residency (p less than 0.05). We conclude that spouses have significant preferences regarding the choice of a training program following medical school. Career goals and lifestyle appear to be the most important factors; however, despite concern about the time commitment, the majority of spouses are supportive of the selection of a surgical residency.

Immunophenotyping in the management of gastric lymphoma

Primary gastric lymphoma is a rare tumor in which surgical resection plays a major role in improving the response rate and reducing the incidence of bleeding and perforation after chemotherapy. In 17 consecutive patients, the diagnosis of gastric lymphoma was made by immunophenotyping snap-frozen endoscopic biopsy specimens. All neoplasms were B-cell lymphomas. Pan B surface marker antigens were present in all patients. Levels of Ki-67, a nuclear marker of tumor proliferation, were greater than 45% in two of the four patients who died after progression of their lymphoma. All patients alive had Ki-67 levels of less than 30%. A lower proliferation index, as measured by Ki-67, appears to be associated with better prognosis. Ten of 11 patients treated by resection prior to chemotherapy had no complications. Immunophenotyping is the key in the differential diagnosis when considering malignant lymphoma with gastric carcinoma and benign conditions such as pseudolymphoma.

Pancreatic cancer as a sentinel for hereditary cancer predisposition

BackgroundGenes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) predisposition have been shown to play a role in pancreatic cancer susceptibility. Growing evidence suggests that pancreatic cancer may be useful as a sentinel cancer to identify families that could benefit from HBOC or CRC surveillance, but to date pancreatic cancer is only considered an indication for genetic testing in the context of additional family history.MethodsPreliminary data generated at the Huntsman Cancer Hospital (HCH) included variants identified on a custom 34-gene panel or 59-gene panel including both known HBOC and CRC genes for respective sets of 66 and 147 pancreatic cancer cases, unselected for family history. Given the strength of preliminary data and corresponding literature, 61 sequential pancreatic cancer cases underwent a custom 14-gene clinical panel. Sequencing data from HCH pancreatic cancer cases, pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and high probability of pathogenic variants of uncertain significance (HiP-VUS).ResultsApproximately 8.6% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 11.5% carry a pathogenic variant or HiP-VUS.ConclusionWith the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases act as a useful sentinel cancer to identify asymptomatic at-risk relatives who could benefit from relevant HBOC and CRC surveillance measures.

Population-Based Relative Risks For Specific Family History Constellations Of Breast Cancer - Towards Individualized Risk Estimation

Purpose Using a large resource linking genealogy with decades of cancer data, RRs were estimated for breast cancer (BC) based on specific family history extending to first cousins. Methods RRs for BC were estimated in 640,366 females with breast cancer family histories that included number of first-(FDR), second-(SDR), and third-degree relatives (TDR), maternal and paternal relatives, and age at earliest diagnosis. Results RRs for first-degree relatives of BC cases ranged from 1.61 (=1 FDR affected, CI: 1.56, 1.67) to 5.00 (≥4 FDRs affected, CI: 3.35, 7.18). RRs for second degree relatives of probands with 0 affected FDRs ranged from 1.08 (≥1 SDR affected, CI: 1.04, 1.12) to 1.71 (≥4 SDRs affected, CI: 1.26, 2.27) and for second degree relatives of probands with exactly 1 FDR from 1.54 (0 SDRs affected, CI:1.47, 1.61) to 4.78 (≥ 5 SDRs; CI 2.47, 8.35). RRs for third-degree relatives with no closer relatives affected were significantly elevated for probands with >=5 affected TDRs RR=1.32, CI: 1.11, 1.57). Conclusions The majority of females analyzed had a family history of BC. Any number of affected FDRs or SDRs significantly increased risk for BC, and more than 4 TDRs, even with no affected FDRs or SDRs significantly increased risk. Risk prediction derived from specific and extended family history allows identification of females at highest risk even when they do not have a conventionally defined “high risk” family; these risks could be a powerful, efficient tool to individualize cancer prevention and screening.

Window-of-Opportunity Study of Valproic Acid in Breast Cancer Testing a Gene Expression Biomarker

Purpose The anticancer activity of valproic acid (VPA) is attributed to the inhibition of histone deacetylase. We previously published the genomically derived sensitivity signature for VPA (GDSS-VPA), a gene expression biomarker that predicts breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study that examined the tolerability of VPA and the ability of the GDSS-VPA to predict biologic changes in breast tumors after treatment with VPA. Patients and Methods Eligible women had untreated breast cancer with breast tumors larger than 1.5 cm. After a biopsy, women were given VPA for 7 to 12 days, increasing from 30 mg/kg/d orally divided into two doses per day to a maximum of 50 mg/kg/d. After VPA treatment, serum VPA level was measured and then breast surgery or biopsy was performed. Tumor proliferation was assessed by using Ki-67 immunohistochemistry. Histone acetylation of peripheral blood mononuclear cells was assessed by Western blot. Dynamic contrast-enhanced magnetic resonance imaging scans were performed before and after VPA treatment. Results Thirty women were evaluable. The median age was 54 years (range, 31-73 years). Fifty-two percent of women tolerated VPA at 50 mg/kg/d, but 10% missed more than two doses as a result of adverse events. Grade 3 adverse events included vomiting and diarrhea (one patient) and fatigue (one patient). The end serum VPA level correlated with a change in histone acetylation of peripheral blood mononuclear cells (ρ = 0.451; P = .024). Fifty percent of women (three of six) with triple-negative breast cancer had a Ki-67 reduction of at least 10% compared with 17% of other women. Women whose tumors had higher GDSS-VPA were more likely to have a Ki-67 decrease of at least 10% (area under the curve, 0.66). Conclusion VPA was well tolerated and there was a significant correlation between serum VPA levels and histone acetylation. VPA treatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. Inhibition of histone deacetylase is a valid strategy for drug development in triple-negative breast cancer using gene expression biomarkers.

A Phase I Study of Neoadjuvant Chemotherapy With Nab-Paclitaxel, Doxorubicin, and Cyclophosphamide in Patients With Stage II to III Breast Cancer

Background: The aims of this study were to assess the safety and tolerability of nanoparticle albumin bound paclitaxel (nab‐paclitaxel), doxorubicin, and cyclophosphamide as combination therapy for breast cancer patients in the neoadjuvant setting and to assess the overall clinical response and pathologic complete response (pCR). Patients and Methods: Twenty‐six women with newly diagnosed stage II to III histologically or cytologically proven adenocarcinoma of the breast with negative HER2 status were enrolled. Patients were treated with nab‐paclitaxel 100 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 on day 1 and nab‐paclitaxel 100 mg/m2 on day 8 in a 21‐day cycle for 6 cycles total. Results: Most adverse events attributed to treatment were decreased white blood cell count, neutropenia, anemia, thrombocytopenia, and lymphopenia with a median duration of 8 days. Fifteen of 23 (65.2%; 95% confidence interval [CI], 45.7%‐84.6%) had a complete clinical response and 8 of 23 (34.7%; 95% CI, 15.2%‐54.1%) had a partial clinical response for an overall clinical response rate of 100%. Thirteen of 23 patients (56.5%; 95% CI, 36.2%‐76.7%) had a pCR. All 10 triple‐negative breast cancer (TNBC) patients (100%) achieved a pCR. Conclusion: The regimen of nab‐paclitaxel, doxorubicin, and cyclophosphamide chemotherapy was well tolerated and resulted in high clinical as well as pathologic responses, particularly in TNBC. Micro‐Abstract: We investigated a novel combinatorial approach using old drugs doxorubicin, cyclophosphamide and nab‐paclitaxel in the neoadjuvant setting. Patients were enrolled in Alabama and Utah in a standard 3+3 phase I design. The clinical response rate was 100%; the pathologic complete response (pCR) was over 56%. All 10 patients with triple negative disease (TNBC) achieved pCR (100%). Toxicities were as expected for chemotherapy. This approach warrants further studies in TNBC.