Faculty Bibliography

BACKGROUND AND OBJECTIVE/OBJECTIVE:Radiation therapy (RT) is part of standard adjuvant treatment for breast cancer. Earlier studies demonstrated increased cardiac morbidity and mortality from this. Coronary Calcium scanning utilizing Multidetector Computed Tomography (MDCT) can detect early atherosclerosis in coronary arteries by identifying the amount of calcifications. In our study we employed these tools to detect occult atherosclerosis at least 5 years following breast RT. METHODS:We evaluated 20 asymptomatic patients, <60 years old, treated with RT at least 5 years prior to enrollment. Nine received RT to the left and 11 to the right chest wall. The median interval between RT and calcium scan was 8 years. All patients were treated with external beam RT using tangential technique. All patients underwent MDCT to compute volumetric and Agatston calcium scores of the coronary arteries and the aorta. RESULTS:Eleven patients had RT to the right chest wall, and eight had a calcium score of 0, while two had minimally elevated scores and one patient had a significantly elevated score. Meanwhile nine patients had RT to the left chest wall, and seven had a calcium score of 0. None had significantly elevated scores. In the aorta, 11 of 20 patients had a score of 0, while 8 of 20 had minimally elevated scores. CONCLUSION/CONCLUSIONS:In contrast to studies demonstrating increased cardiovascular morbidity, our pilot study did not detect significant occult atherosclerosis using MDCT of the coronaries and aorta of patients assessed five or more years following radiation for treatment of breast cancer.

The dependency of certain breast cancers on estrogen is undeniably one of the most important observations in oncology. Since this early observation, there has been a tremendous effort to define the precise roles of the estrogen receptor (ER) in the pathogenesis of breast cancer. Estrogen signaling pathways can also be exploited as effective targets for cancer treatment. Both ligand-dependent and ligand-independent receptor activation pathways have been successfully blocked by hormonal therapies including selective ER modulators such as tamoxifen, by blocking and accelerating the degradation of ER (fulvestrant), and by depleting tissue levels of estrogen (aromatase inhibitors). Because of the immense prognostic and predictive value of the ER and PR receptor, accurately defining hormone dependency is also of paramount importance. Despite this avalanche of discovery and development resulting in improved outcome for the patient, resistance to these therapies, both intrinsic and acquired, is well known. Uncovering the various mechanisms of resistance has deepened scientific understanding of posttranslational modifications of these receptors, as well as their cross talk with other receptor families such as the HER-2/neu receptor. The recent discovery that orphan estrogen-related receptors may also play an important role in breast cancer is just starting to be appreciated. A clear understanding of the historical perspective and the intricacies of ER structure and function is required to improve current therapeutic strategies for breast cancer.

Background. To our knowledge, the hormone receptor status of noncontiguous ductal carcinoma in situ (DCIS) occurring concurrently in ER/PgR-negative invasive cancer has not been studied. The current study was undertaken to investigate the ER/PgR receptor status of DCIS of the breast in patients with ER/PgR-negative invasive breast cancer. Methods. We reviewed the immunohistochemical (IHC) staining for ER and PgR of 187 consecutive cases of ER/PgR-negative invasive breast cancers, collected from 1995 to 2002. To meet the criteria for the study, we evaluated ER/PgR expression of DCIS cancer outside of the invasive breast cancer. Results. A total of 37 cases of DCIS meeting the above criteria were identified. Of these, 16 cases (43.2%) showed positive staining for ER, PgR, or both. Conclusions. In our study of ER/PgR-negative invasive breast cancer we found that in 8% of cases noncontiguous ER/PR-positive DCIS was present. In light of this finding, it may be important for pathologists to evaluate the ER/PgR status of DCIS occurring in the presence of ER/PgR-negative invasive cancer, as this subgroup could be considered for chemoprevention.

BACKGROUND:Delayed gastric emptying (DGE) occurs in 14% to 61% of patients after pylorus-preserving pancreaticoduodenectomy, but its pathogenesis is unclear. We hypothesized that DGE may be due to pylorospasm secondary to vagal injuries at operation and may be preventable by the addition of pyloromyotomy. METHODS:Patients operated on consecutively between April 2000 and August 2003 were studied. Pyloromyotomy was of the Fredet-Ramstedt type combined with antroplasty. DGE-free recovery was defined as tolerance of a diet for three successive days by postoperative day 8. The symptom of nausea was used as a basis for nasogastric tube removal and diet resumption. A gastric emptying test (GET) with solid food was obtained. Patients with difficulty swallowing were fed via a feeding tube. RESULTS:There were 47 patients. Two patients were excluded because of death (n = 1) and ileus with pancreatic fistula (n = 1). Diagnoses were pancreatic cancer (n = 23), chronic pancreatitis (n = 11), ampullary cancer (n = 5), mucinous cystic neoplasm (n = 5), and duodenal villous adenoma (n = 3). Median times to nasogastric tube removal, start of liquid diet, and start of solid diet were postoperative days 2, 3, and 5, respectively. Two patients had tube feedings. Preoperative GET was abnormal in 51%, and postoperative GET was abnormal in 37%. The average length of stay was 9.5 days (median, 7 days). DGE occurred in only one patient (2.2%). There were no late complications during a 6-month follow-up. CONCLUSIONS:The addition of pyloromyotomy to pylorus-preserving pancreaticoduodenectomy is effective in preventing DGE. Results are supportive of the hypothesis that DGE may be caused by operative injuries of the vagus innervating the pyloric region.

The highly metastatic human pancreatic cell line L3.6 was used to study mechanisms for antitumor activity with various chemotherapeutic drug combinations. The most effective drugs were daunorubicin (IC50 0.4 microM), doxorubicin (IC50 22 microM), paclitaxel (IC50 5.3 microM) and 5-fluorouracil (IC50 5.4 microM). The most effective drug combination was equitoxic concentrations of paclitaxel and daunorubicin. Kinetic analysis demonstrated that both paclitaxel and daunorubicin had to be added simultaneously for maximum cytotoxicity. Daunorubicin treatment alone demonstrated ROS (reactive oxygen species) induction and cellular morphological changes more consistent with chemical damage in a total of 93% of the cells and apoptotic changes in 20% of the cell population. The apoptosis induced by daunorubicin does not appear to be caspase-dependent, as demonstrated by the lack of conversion of the procaspases 8 and 3. Within 24 h of treatment with paclitaxel, Bcl-2 formed a doublet at 26 kilodaltons and the expression was abrogated with daunorubicin and the combination of the two drugs as determined by Western blots. These data suggest that the human pancreatic cell line L3.6 is more effectively killed following treatment with chemotherapeutic agents that cause death through at least two pathways, a caspase-dependent and caspase-independent apoptosis and necrosis.

Cervical cancer with distant metastasis is almost always incurable. The treatment goal is to palliate the patient's symptoms with pain medications and localized radiation therapy. Chemotherapy generally has a limited role, with responses that are short lived. Newer agents investigated as potential therapy include fluorouracil prodrugs. We report on a case where capecitabine was used in metastatic cervical cancer with progression of disease outside the radiation field, following multiple drug regimens including one dose of cisplatin (discontinued due to transient renal toxicity), paclitaxel, and carboplatin and continuous infusion 5-fluorouracil (5-FU) The patient was treated with capecitabine 1100 mg/m2 twice daily for two weeks. After the first week of the cycle, the patient developed grade 2 toxicities consisting of mucositis and hand-foot Syndrome but she continued on therapy through day 14. On day 20 she was hospitalized with grade 4 toxicity, which included febrile neutropenia, urinary tract infection, pancytopenia, mucositis, hand-foot syndrome, and renal failure, all of which have subsequently completely resolved. Restaging demonstrated complete remission. Although the patient suffered toxicity related to capecitabine, 3.5 years post a single cycle of capecitabine, the patient remains in remission, with no evidence of disease reoccurence.