Reproductive health and endocrine disruption in women with breast cancer: a pilot study.

PURPOSE: The purpose of this study was to assess whether incorporation of an original reproductive health assessment and algorithm into breast cancer care helps providers appropriately manage patient reproductive health goals and to follow laboratory markers for fertility and correlate these with menstruation. METHODS: This prospective observational pilot study was set in an urban, public hospital. Newly diagnosed premenopausal breast cancer patients between 18 and 49 years old were recruited for this study prior to chemotherapy initiation. As the intervention, these patients received a reproductive health assessment and care per the study algorithm at 3-month intervals for 24 months. Blood samples were also collected at the same time intervals. The main outcome measures were to assess if the reproductive health management was consistent with patient goals and to track any follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) level changes throughout treatment and post-treatment period. RESULTS: Two patients were pregnant at study initiation. They received obstetric consultations, opted to continue pregnancies, and postpone treatment; both delivered at term without complications. One woman desired future childbearing and received fertility preservation counseling. All women received family planning consultations and received/continued effective contraceptive methods. Seventy-three percent used long-term contraception, 18 % remained abstinent, and 9 % used condoms. During chemotherapy, FSH rose to menopausal levels in 82 % of patients and TSH rose significantly in 9 %. While 82 % of women experienced amenorrhea, 44 % of these women resumed menstruation after chemotherapy. CONCLUSIONS: The assessment and algorithm were useful in managing patients' reproductive health needs. Chemotherapy-induced endocrine disruption impacted reproductive health.

Lack of a role of glutathione in cellular nonenzymatic activation of BMS-181174, a novel analogue of mitomycin C.

Recent studies, using a cell-free system, have suggested that thiol-dependent nonenzymatic bioactivation may be responsible for the superior antitumor activity of the mitomycin C analogue BMS-181174 [N-7-[2-(4-nitrophenyldithio)ethyl]mitomycin C] when compared to the parent compound. If operational in tumor cells, this pathway could have enormous clinical implications since tumor cell resistance to a variety of anticancer agents is often associated with increased glutathione (GSH) levels and BMS-181174 may be used to reverse this mechanism of resistance. The present study was undertaken to determine the role of GSH in cellular activation of BMS-181174 using a pair of well-characterized human bladder cancer cells (J82 and SCaBER) as a model. A 20-h pretreatment of J82 and SCaBER cells with a nontoxic concentration of D,L-buthionine-S,R-sulfoximine (BSO) caused about 80-88% reduction in cellular GSH levels. Surprisingly, the sensitivity of both cells to BMS-181174 was increased, not reduced, by BSO-induced GSH depletion. On the other hand, the cytotoxicity of BMS-181174 was significantly reduced in both cells by a 4-h pretreatment with 1 mM GSH. Like BSO, a 4-h pretreatment with another thiol compound (cysteine) resulted in a statistically significant sensitization of both cells to BMS-181174. Cellular GSH levels were not affected in either of the cell lines by pretreatment with GSH or cysteine. In conclusion, the results or the present study argue against a role of GSH in cellular nonenzymatic activation of BMS-181174 in J82 and SCaBER cells.

Biochemical mechanism of cross-resistance to paclitaxel in a mitomycin c-resistant human bladder cancer cell line.

9-fold more resistant to mitomycin C (MMC) than parental cells (J82/WT). The IC(50) values for paclitaxel in J82/WT and J82/MMC-2 cell lines were 0.7+/-0.03 and 2.8+/-0.7 microM, respectively (P<0. 05). Thus, the J82/MMC-2 cell line exhibited 4-fold cross-resistance to paclitaxel compared with J82/WT. Intracellular accumulation of [(3)H]paclitaxel was comparable in J82/WT and J82/MMC-2 cell lines. There were no qualitative or quantitative differences between the J82/WT and J82/MMC-2 cell lines in terms of their alpha-tubulin and beta-tubulin contents. Paclitaxel-induced apoptosis could not be detected in either cell line over a wide range of drug concentrations. These results indicate that cross-resistance to paclitaxel in the J82/MMC-2 cell line is not linked to reduced drug accumulation, increased drug efflux, alterations in tubulin content or reduced paclitaxel-induced apoptosis. Paclitaxel-induced DNA strand breakage, however, determined by alkaline elution, was markedly lower in the J82/MMC-2 cell line than in J82/WT. These results suggest that paclitaxel cross-resistance in J82/MMC-2 may be attributed to reduced paclitaxel-induced DNA strand breakage. The precise mechanism of reduced paclitaxel-induced DNA strand breakage in J82/MMC-2 cell line relative to J82/WT cells, however, remains to be elucidated.

Characterization of a human bladder cancer cell line selected for resistance to BMY 25067, a novel analogue of mitomycin C.

This study describes characteristics of a human bladder cancer cell line, SCaBER/R, selected for resistance to a mitomycin C (MMC) analogue BMY 25067. The SCaBER/R cell line was isolated by repeated 24 h exposures of the parental cells to 0.09 microM BMY 25067 (IC90, 24 h drug exposure) over a period of about 180 days. Approximately 2.2-fold higher concentration of BMY 25067 was required to kill 50% of the SCaBER/R cell line compared with parental cells (p < 0.001). The IC20 and IC90 values for BMY 25067 were also significantly higher in the SCaBER/R cell line than in SCaBER. Unlike most MMC resistant cell lines, the SCaBER/R cell line displayed a marked cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and lacked cross-resistance to cisplatin, doxorubicin or VP-16. The SCaBER/R cell line also displayed a marked cross-resistance to the parent drug (MMC) and BMY 25282, another analogue of MMC. NADPH cytochrome P450 reductase activity, an enzyme implicated in bio-reductive activation of MMC, did not differ significantly in these cells. DT-diaphorase activity, another MMC activation enzyme, was significantly lower in the SCaBER/R cell line when compared to the SCaBER cells. These results suggest that relatively lower sensitivity of SCaBER/R cell line to MMC and BMY 25067 may result from impaired drug activation. Cellular levels of glutathione (GSH) and GSH-transferase (GST), which have been suggested to affect the cytotoxicity of MMC, were comparable in SCaBER and SCaBER/R cell lines. BMY 25067 induced DNA interstrand cross-links (DNA-ISC) could not be detected in either of the cell lines even at drug concentrations which produced a significant cell kill. These findings suggest that (a) cellular resistance to BMY 25067 in the SCaBER/R cell line may be due to impaired drug activation, and (b) the nature of the cytotoxic produced by BMY 25067 may be different from that of MMC.

Mechanism of differential efficacy of garlic organosulfides in preventing benzo(a)pyrene-induced cancer in mice.

The mechanism of differential efficacies of diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), dipropyl sulfide (DPS) and dipropyl disulfide (DPDS) in preventing benzo(a)pyrene (BP)-induced cancer in mice has been investigated by determining their effects on the enzymes of BP activation/inactivation pathways. With the exception of DATS, treatment of mice with other organosulfides (OSCs) caused a small but significant increase (37-44%) in hepatic ethoxyresorufin O-deethylase (EROD) activity. However, the forestomach EROD activity did not differ significantly between control and treated groups. Only DAS treatment caused a modest but statistically significant reduction (about 25%) in pulmonary EROD activity. These results suggest that while reduction of EROD activity may, at least in part, contribute to the DAS-mediated inhibition of BP-induced lung cancer, anticarcinogenic effects of OSCs against BP-induced forestomach carcinogenesis seems to be independent of this mechanism. Treatment of mice with DAS, DADS and DATS resulted in a significant increase, as compared with control, in both hepatic (3.0-, 3.2- and 4.4-fold, respectively) and forestomach (1.5-, 2.7- and 2.7-fold, respectively) glutathione transferase (GST) activity toward anti-7beta,8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE), which is the ultimate carcinogen of BP. The pulmonary GST activity was not increased by any of the OSCs. Even though epoxide hydrolase (EH) activity was differentially altered by these OSCs, a correlation between chemopreventive efficacy of OSCs and their effects on EH activity was not apparent. The results of the present study suggest that differences in the ability of OSCs to modulate GST activity toward anti-BPDE may, at least in part, account for their differential chemopreventive efficacy against BP-induced cancer in mice.

Gender-related differences in susceptibility of A/J mouse to benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis.

Benzo[a]pyrene (BP) is a suspected human carcinogen and is known to produce tumors in the lung and forestomach of mice. Glutathione (GSH) S-transferases (GST) play a major role in the detoxification of the ultimate carcinogen of BP, (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene ((+)-anti-BPDE). Previous studies have shown gender-related differences in the expression of GST isoenzymes in mice. The present study was designed to test the hypothesis whether gender-related differences in the expression of GST isoenzymes can affect the susceptibility of mice to BP-induced lung and forestomach tumorigenesis. The expression of pi class isoenzyme mGSTP1-1, which is highly efficient in the detoxification of (+)-anti-BPDE, was approximately 3.0- and 1.5-fold higher in the liver and forestomach of male A/J mouse, respectively, as compared with the female. The levels of other major GST isoenzymes, mGSTA3-3 (alpha class), mGSTM1-1 (mu class) and mGSTA4-4 (alpha class), were also significantly higher in the liver of the male mouse as compared with the female. While pulmonary mGSTP1-1 expression did not differ significantly between male and female A/J mice, the expression of mGSTA3-3, mGSTM1-1 and mGSTA4-4 was significantly higher (1.4-4.0-fold) in the lung of the male A/J mouse as compared with the female. At lower concentrations of BP (0.5 mg BP/mouse), the tumor incidence/multiplicity was significantly higher in the lung as well as in the forestomach of female mice as compared with male mice. For example, while 30% of the female mice developed pulmonary tumors 26 weeks after the first 0.5 mg BP administration, none of the male mice had tumors in their lungs. At higher doses of BP (1.5 mg BP/mouse), however, this differential was either abolished or relatively less pronounced. Our results suggest that up to a certain threshold of BP exposure the levels of GST isoenzymes may be an important determinant of susceptibility to BP-induced tumorigenesis in mice.

Surgical treatment of peptic ulcer disease.

Elective surgery for peptic ulcer disease has diminished significantly over the past 15 years. However, emergency surgery has not shown a decline. Some series have even reported an increase in hospitalizations and operations for hemorrhage. The appropriate surgical procedure for peptic ulcer disease must be tailored to the specific needs of the individual patient. During emergency operations for hemorrhage from duodenal ulcer, we recommend suture ligature of the bleeding vessel and vagotomy-pyloroplasty for high-risk patients, or vagotomy-antrectomy for the lower-risk patient. Bleeding gastric ulcers should be resected, if possible. For massive hemorrhage from stress ulceration requiring surgery, near-total or total gastrectomy should be performed. Perforated duodenal ulcers are best managed by closure and a definitive ulcer operation, such as vagotomy-pyloroplasty. Perforated gastric ulcers are best excised but may be simply closed if conditions do not favor resection. In these situations, biopsy should be performed. We recommend truncal vagotomy-antrectomy for patients presenting with obstruction. Vagotomy (truncal or proximal gastric) with drainage is an acceptable alternative in this situation. For patients with intractable ulcer disease or for those who are noncompliant, proximal gastric vagotomy is the preferred operation. However, other operations may need to be considered, depending on the specific situation. Recurrent ulceration needs appropriate work-up to determine the possible cause. Although patients with ulcer recurrence initially may be placed on medical treatment, about 50% will require reoperation. The most effective procedure for peptic ulcer disease is truncal vagotomy-antrectomy, which has a recurrence rate of less than 1%. The procedure with the least morbidity and the fewest undesirable side effects is proximal gastric vagotomy. Ulcer recurrence after proximal gastric vagotomy or truncal vagotomy-pyloroplasty is in the range of 10% to 15%.

Operative ultrasound guidance for various surgical procedures.

Although percutaneous ultrasound-guided technique is currently a common practice, the use of ultrasound for the purpose of guidance during surgery has not been widely practiced. Over a period of 10 years, we performed operative ultrasonography in 2,314 operations. In 321 of these operations, operative ultrasound guidance was performed for direct assistance of various surgical procedures, particularly during operations on the brain and spinal cord, liver, pancreas, and kidney. Procedures guided by operative ultrasound were classified into the following categories: intraoperative needle placement for fluid aspiration (n = 38), agent injection (n = 14), catheter introduction (n = 27), biopsy (n = 57), surgical tissue dissection for incision (n = 48), resection (n = 82) of organs, and extraction (n = 55) of stones or foreign bodies. Operative ultrasound guidance facilitates various surgical procedures and is considered a useful modality for reducing operative complications, shortening operating time, performing otherwise impossible procedures, and, at times, developing new surgical operations.

Detection of preoperatively unrecognized multiple pancreatic pseudocysts by intraoperative ultrasonography. Report of two cases.

During two pancreatic operations, intraoperative ultrasonography detected multiple pancreatic pseudocysts that were unrecognized preoperatively. In each operation, a single pseudocyst was detected by preoperative ultrasonography, computed tomography, and intraoperative surgical exploration. In addition, high-resolution ultrasonography used during the operations also identified and precisely localized additional smaller pseudocysts. Also, the use of color Doppler imaging during the operations enabled the delineation of small blood vessels around the pseudocysts. The accurate diagnosis of multiple pseudocysts and the precise anatomic information provided by intraoperative ultrasonography permitted appropriate surgical treatment of the pancreatic pseudocysts which, in turn, might help prevent recurrence of the disease.

Inguinal node metastases.

Twenty-two hundred and thirty-two patients with inguinal node metastases were reviewed. The primary site of malignancy was determined in 2210 (99%) of these patients and was, in order of frequency, skin of the lower extremities, cervix, vulva, skin of the trunk, rectum and anus, ovary and penis. The determinant three-year survival rate for the remaining 22 patients with metastatic disease from an unknown primary site was 50%. The source of the primary (stomach) was discovered in only one of the 22 patients; however, the treatment of choice was superficial groin dissection, and if surgical excision was adequate, radiation therapy did not appear to be necessary to obtain local control.

Carcinoma of the anal gland: case report and review of the literature.

Anal gland cancer is often insidious in its presentation with no evidence of an intraluminal mass. It is frequently slow-growing and often thought to be a perirectal or ischiorectal abscess. Repeated incision and drainage is performed until a biopsy reveals the diagnosis. A very wide resection is then necessary to totally remove the tumor.

Mechanism of increased sensitivity to etoposide in a mitomycin C-resistant human bladder cancer cell line.

The mechanism of increased sensitivity to etoposide (VP-16) in a human bladder cancer cell line (J82/MMC-2), which is >9-fold more resistant to mitomycin C (MMC) compared with parental cells (J82/WT), was investigated. Colony formation assays, following 1 hr drug exposure, revealed that about a 2.2-fold higher concentration of VP-16 was required to kill 50% of the J82/WT cell line compared with J82/MMC-2. The MTT assays, following continuous drug exposure, also showed that the J82/MMC-2 cell line was significantly more sensitive to VP-16 compared with J82/WT. Accumulation of VP-16 was significantly higher in the J82/MMC-2 cell line compared with J82/WT at every drug concentration tested. Likewise, intracellular VP-16 retention was significantly higher in the J82/MMC-2 cell line compared with J82/WT when drug uptake was measured as a function of varying incubation time and at a fixed VP-16 concentration. The efflux of VP-16 from the J82/MMC-2 cell line was equivalent to that from J82/WT. In agreement with the results of drug uptake studies, the levels of VP-16-induced protein-DNA complexes were markedly higher in the J82/MMC-2 cell line compared with J82/WT. The catalytic activity of topoisomerase II (topo II) in 0.35 M NaCl nuclear extract of J82/WT cells was equivalent to that of J82/MMC-2. The levels of topo II mRNA were also comparable in these cells. Our results suggest that the mechanism responsible for the collateral sensitivity of the J82/MMC-2 cell line to VP-16 may be attributable to a relatively higher drug accumulation in this cell line compared with parental cells.

University-based postresidency training programs in surgical oncology.

The issue of postresidency training in surgical oncology engenders much debate, particularly as it impacts on general surgery training. With the goal of enhancing instruction in surgical oncology in the future, a survey was conducted to assess the role of surgical oncology programs and educational activities within university-based surgery training programs. The results of the study demonstrate an increased emphasis on surgical oncology training over the past five years. The findings also indicate that education activity in surgical oncology in all departments of surgery has increased greatly, as demonstrated by an increased number of specific teaching rounds and conferences. The impact of this increased awareness on the future of surgical oncology training is discussed.