Faculty Publications

BACKGROUND: The results of radiation on the local control of triple receptor-negative breast cancer (negative estrogen [ER], progesterone [PR], and HER-2/neu receptors) was studied. METHODS: Conservative surgery and radiation were used in 753 patients with T1-T2 breast cancer. Three groups were defined by receptor status: Group 1: ER or PR (+); Group 2: ER and PR (-) but HER-2 (+); and Group 3: triple-negative (TN). Factors analyzed were age, menopausal status, race, stage, tumor size, lymph node status, presentation, grade, extensive in situ disease, margins, and systemic therapy. The primary endpoint was 5-year locoregional recurrence (LRR) isolated or total with distant metastases. RESULTS: ER- and PR-negative patients were statistically significantly more likely to be black, have T2 disease, have tumors detectable on both mammography and physical examination, have grade 3 tumors, and receive chemotherapy. There were no significant differences noted with regard to ER- and PR- patients by HER-2 status. There was a significant difference noted in rates of first distant metastases (3%, 12%, and 7% for Groups 1, 2, and 3, respectively; P = .009). However, the isolated 5-year LRR was not significantly different (2.3%, 4.6%, and 3.2%, respectively; P = .36) between the 3 groups. CONCLUSIONS: Patients with TN breast cancer do not appear to be at a significantly increased risk for isolated LRR at 5 years and therefore remain appropriate candidates for breast conservation.

Hepatitis delta virus (HDV) is a subviral agent dependent upon hepatitis B virus (HBV). HDV uses the envelope proteins of HBV to achieve assembly and infection of target cells. Otherwise, the replication of the RNA genome of HDV is totally different from that of its helper virus, and involves redirection of host polymerase activity. This chapter is concerned with recent developments in our understanding of the genome replication process.

PURPOSE: Research regarding new pharmacologic findings in regards to the treatment of postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting (PDNV) are discussed. SUMMARY: PONV and PDNV have many important negative outcomes, including medical complications and financial consequences. Great strides in basic research have identified a plethora of mechanisms involved in regulating and processing the emetic reflex, and subsequent development of antiemetic treatments has lessened these burdens. The currently available antiemetic agents are not able to individually ameliorate PONV, so guidelines have been developed that recommend administering a combination of antiemetic treatments from different drug classes as prophylaxis, especially for high-risk patients. Recent research has indicated that due to the unique structural characteristics of palonosetron that impact receptor binding, this 5-HT(3) receptor antagonist has a pharmacokinetic and pharmacologic profile different from other inhibitors within the drug class. Implications of the high affinity, allosteric, and positive cooperative binding properties of palonosetron include longer and tighter binding to the 5-HT(3) receptor, making palonosetron a very efficient antagonist and less likely to be displaced by the binding of serotonin. CONCLUSION: Ongoing research is warranted in order to better prevent and manage PONV and PDNV.

PURPOSE: The aims of this study were to evaluate the factors contributing to errors in the treatment of cancer patients undergoing radiation therapy and to develop a grading system that allows for the comparison of errors. METHODS: Deviations in the prescribed treatment of patients undergoing radiation therapy were collected during 2003 in the Department of Radiation Oncology at Fox Chase Cancer Center. The deviations were classified according to responsibility as follows: therapist, physician, dosimetrist, physicist, machine, or all. The deviations in treatment were graded on an increasing scale ranging from 1 to 4, according to severity. Error analysis was made corresponding to treatment machine, therapist, dosimetrist, type of treatment, palliative or definitive treatment, type of cancer, time of occurrence, and machine census at the time of occurrence. RESULTS: A total of 33,757 patient treatments were delivered on 4 linear accelerators with 3,646 dose calculations performed by the physics staff during 2003. All treatments, both intensity-modulated radiation therapy and conventional therapy, were considered in this analysis. A total of 25 quality control (QC) events occurred during the study period. The crude error rate for therapists was 0.041%, and the crude error rate for dosimetrists and physicists was 0.22%. There were 17 level I errors (2 machine, 1 block mismounting, 4 dosimetrist, 1 all, and 9 therapist), 5 level II errors (3 dosimetrist, 1 therapist and dosimetrist, and 1 therapist), and 3 level III errors (3 therapist). Fifteen of the 25 QC events and 8 of 13 therapist events occurred after 12 pm. A correlation did not exist between the time of occurrence and machine census at the time of the QC events. However, more level I events occurred after 12 pm than before 12 pm. CONCLUSIONS: A review of QC events occurring during the course of radiation treatments allowed a change in the process of care to prevent the occurrence of some QC events. The QC event rate experienced by the department compares favorably with published results from similar academic centers. The periodic review of QC events allows for the opportunity to identify processes that can be adapted to reduce the occurrence of QC events in the future.

PURPOSE OF REVIEW: Surgical excision remains the standard of care for treatment of localized small renal masses (SRMs). Laparoscopic and percutaneous minimally invasive ablative technologies are being increasingly employed in current urologic practice. We review recent literature regarding focal ablative treatments of SRMs. RECENT FINDINGS: Most cryoablations are performed using a laparoscopic approach, whereas radiofrequency ablation (RFA) of the SRM is more commonly administered percutaneously. Pretreatment biopsy is performed more often for lesions treated by cryoablation than RFA with a significantly higher rate of indeterminate or unknown pathology for SRMs undergoing RFA versus cryoablation (P < 0.0001). Currently available data suggest that cryoablation results in lower retreatments (P < 0.0001), less local tumor progressions (P < 0.0001) and may be associated with a decreased risk of metastatic progression compared with RFA. It is unclear whether these differences are a function of the technologies or their application. Given the excellent results reported for active surveillance of the SRM in selected patients, the extent to which focal ablation alters the natural history of SRMs has not yet been established. SUMMARY: Currently, data on the ability of interventions for SRMs to affect the natural history of these masses are lacking. Prospective randomized evaluations of available clinical approaches to SRMs are needed.

Birt-Hogg-Dube (BHD) syndrome is a tumor-suppressor gene disorder characterized by skin tumors, cystic lung disease and renal cell carcinoma. Very little is known about the molecular pathogenesis of BHD. Clinical similarities between BHD and tuberous sclerosis complex (TSC) suggest that the BHD and TSC proteins may function within a common pathway. The TSC proteins inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1), and in Schizosaccharomyces pombe, Bhd and Tsc1/Tsc2 have opposing roles in the regulation of amino-acid homeostasis. We report here that in mammalian cells, downregulation of BHD reduces the phosphorylation of ribosomal protein S6, an indicator of TORC1 activity. To determine whether folliculin, the product of the BHD gene, regulates mammalian target of rapamycin activity in vivo, we generated a mouse with targeted inactivation of the Bhd gene. The mice developed spontaneous oncocytic cysts and tumors composed of cells that resemble the renal cell carcinomas in BHD patients. The cysts and tumors had low levels of phospho-S6. Taken together, these data indicate that folliculin regulates the activity of TORC1, and suggest a new paradigm in which both inappropriately high and inappropriately low levels of TORC1 activity can be associated with renal tumorigenesis.

Background: The mass media is increasingly important in shaping a range of health beliefs and behaviors. Objective. We examined the association among mass media health information exposure (general health, cancer, sun protection information), skin cancer beliefs, and sun protection behaviors. Methods: We used a general population national probability sample comprised of 1633 individuals with 110 skin cancer history (Health Information National Trends Survey, 2005, National Cancer Institute) and examined univariate and multivariate associations among family history of skin cancer, mass media exposure, skin cancer beliefs, and sun protection (use Of Sunscreen, shade seeking, and use of sun-protective clothing). Results: Mass media exposure was higher in younger individuals, and among those who were white and more highly educated. More accurate skin cancer beliefs and more adherent sun protection practices were reported by older individuals, and among those who were white and more highly educated. Recent Internet searches for health or sun protection information were associated With sunscreen use. Limitations: Study limitations include the self-report nature of sun protection behaviors and cross-sectional study design. Conclusion: We identify demographic differences in mass media health exposure, skin cancer beliefs, and sun protection behaviors that will contribute to planning skin cancer awareness and prevention messaging across diverse population subgroups. (J Am Acad Dermatol 2009;61:783-92.)

Cancer survivors have cancer surveillance and preventive screening needs that require monitoring. Little is known regarding their patterns of care in community primary care practices. Secondary analysis of 750 baseline patient surveys and medical record audits for patients ages 50+ years in 25 community-based primary care practices (N = 109 survivors and 641 noncancer patients). Patient self-reported screening rates for breast cancer (72%), colorectal cancer (81%) and prostate cancer (77%) were higher for cancer survivors compared to noncancer patients (69%, 67%, 53%, respectively). Screening rates documented in the primary care records were lower for all cancers. Cancer survivors were more likely than others to report having been screened for colorectal cancer (P = 0.002) even after excluding colorectal cancer survivors from the analysis (P = 0.034). Male cancer survivors were more likely to report being screened for prostate cancer than those without cancer (P < 0.001), even after excluding prostate cancer survivors (P = 0.020). There were no significant differences in either self-reported or medical record report of breast cancer screening rates among cancer survivors and noncancer patients. Cancer survivors were more likely to self-report receipt of cancer screening than noncancer patients. Medical record reports of cancer screening were lower than self-reports for cancer survivors and noncancer patients. Identifying factors that affect cancer screening among cancer survivors is important and has implications for intervention design.

BACKGROUND: It long has been recognized that married patients have improved cancer survival when compared with unmarried patients. This has been postulated as being due to increased support, potentially leading to better compliance with therapy. Conversely, some data exist pointing to a relationship between marital discord and decreased immunity. We examined whether unmarried patients have a different prognosis by whether they are 1) never married, 2) divorced, 3) widowed, or 4) separated at time of diagnosis. METHODS: The public access data of the Surveillance, Epidemiology and End Results (SEER) registry were queried for cancer survival across all 17 registries between 1973 and 2004. SEER last updated data in April 2007. Records of 3.79 million patients were included in the analysis. We specifically analyzed 5-year and 10-year relative survival (RS; 5yRS, 10yRS), defined as observed survival divided by observed survival of an age-matched, race-matched, and gender-matched population without disease, for all cancer patients by marital status, with specific subset analyses as indicated. RESULTS: Among unmarried patients, those separated at time of diagnosis had the lowest survival, followed by widowed, divorced, and never married patients. 5-year and 10-year RS of separated patients was 72% and 64% than that of married patients, respectively. This relationship persists when data are analyzed by gender. CONCLUSIONS: Separated marital status is associated with a significant decrement in cancer survival, even in comparison with other unmarried groups. While other socioeconomic variables could contribute to this phenomenon, further research into the immunologic correlates of the acutely stressful condition of marital separation should be conducted. Cancer 2009;115:5108-16. (C) 2009 American Cancer Society.

Objective. To determine the activity and pharmacodynamics (PD) of bortezomib in platinum-sensitive epithelial ovarian or primary peritoneal cancer (EOC/PPC). Patients and methods. Eligible women with recurrent EOC/PPC progressing between 6 and 12 months after initial chemotherapy were treated with bortezomib on days 1, 4, 8, and 11 [1.5 (cohort I) and 1.3 (cohort II) mg/m(2)/dose]. Patients must have had initial chemotherapy only. Response Evaluation Criteria in Solid Tumors (RECIST) was assessed by computed tomography (CT) scan every 2 cycles. 20S proteasome activity was quantified in three pre-treatment and a 1-hour post-treatment (cycle one, day 1) whole blood lysates. Results. Initially, 26 evaluable patients were treated at the 1.5 mg/m2/dose level. Objective response rate was 3.8% (1/26), a partial response. An additional 10 patients (38.5%) had stable disease. Given concerns that treatment discontinuations due to toxicity limited drug exposure/activity a second Cohort of 29 evaluable patients was accrued at 1.3 mg/m(2)/dose. The 1.3 mg/m(2)/dose regimen is currently approved as an indication for multiple myeloma and mantle cell lymphoma. Treatment was more tolerable, although objective responses remained low at 6.9% (2/29, partial responses). Second stage accrual was not warranted at either dose. Bortezomib effectively inhibited 20S proteasome activity in whole blood lysates between 37 and 92% in 24/25 (96%) patients in cohort I, and 14-84% in 27/28 (96%) patients in cohort II who provided satisfactory pre- and post-treatment specimens for testing. Conclusion. Bortezomib has minimal activity as a single-agent in the treatment of recurrent platinum-sensitive EOC/PPC. Treatment with bortezomib at 1.5 mg/m(2)/dose was not feasible in this patient population due to excess toxicity. Bortezomib was well tolerated at 1.3 mg/m(2)/dose. (C) 2009 Elsevier Inc. All rights reserved.

BACKGROUND: The family of zinc finger-containing GATA transcription factors plays critical roles in cell lineage specification during early embryonic development and organ formation. GATA4 and GATA6 were found to be frequently lost in ovarian cancer, and the loss is proposed to account for dedifferentiation of the cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: We further investigated the expression of GATA4 and GATA6 in ovarian surface epithelial lesions and histological subtypes of ovarian carcinomas by immunostaining. GATA4 and GATA6 were found to be absent in high percentages (80 to 90%) of serous, clear cell, and endometrioid ovarian cancer examined. In contrast, both were found positive in 11 out of 12 cases of mucinous carcinomas, suggesting the expression of the GATA factors can distinguish mucinous cancer from other histological subtypes. GATA4 was frequently lost in preneoplastic lesions such as morphologically normal inclusion cysts and epithelial hyperplasia adjacent to malignant cells. The loss of GATA6 correlates closely with neoplastic morphological transformation of ovarian surface epithelia. In culture, GATA4 expression was progressively reduced upon passaging primary ovarian surface epithelial cells, which correlated with changes in histone modification of the GATA4 locus. A reduced GATA6 gene dosage as in GATA6 (+/-) mice led to an increased pre-neoplastic changes and inclusion cysts in the ovaries, suggesting the loss of GATA6 contributes to ovarian cancer development. CONCLUSIONS/SIGNIFICANCE: This study suggests that the expression status of GATA4 and GATA6 may dictate distinct pathologic pathways leading to serous or mucinous ovarian carcinomas. The readily loss of GATA4 expression through changes in chromatin conformation suggests a potential non-phenotypic initiating event, leading to subsequent loss of GATA6, morphological transformation, and ultimate tumorigenesis.

Purpose: This study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the i.v. pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors. Experimental Design: In part 1, patients received escalating doses of danusertib (24-hour infusion every 14 days) without filgrastim (granulocyte colony-stimulating factor, G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was done in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3). Results: Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose-limiting toxicity in part 1 without G-CSF. Most other adverse events were grade 1 to 2, occurring at doses >= 360 mg/m(2) with similar incidence in parts 1 and 2. The maximum tolerated dose without G-CSF is 500 mg/m(2). The recommended phase 2 dose in part 2 with G-CSF is 750 mg/m(2). Danusertib showed dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18 to 26 hours. pH3 modulation in skin biopsies was observed at >= 500 mg/m(2). One patient with refractory small cell lung cancer (1,000 mg/m(2) with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline. Conclusions: Danusertib was well tolerated with target inhibition in skin at >= 500 mg/m(2). Preliminary evidence of antitumor activity, including a partial response and several occurrences of prolonged stable disease, was seen across a variety of advanced refractory cancers. Phase II studies are ongoing. (Clin Cancer Res 2009;15(21):6694-701)

BACKGROUND: Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles. OBJECTIVES: Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer. METHODS: We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 mu g BPA/kg body weight/day. For turmorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age. RESULTS: The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1-3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age. CONCLUSIONS: The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1-3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure.