Biomedical subjects

S Wadler

Publications and source records attributed to S Wadler.

At least 19 recordsLinked to original sources

PubMed2000

Long-term swallowing problems after organ preservation therapy with concomitant radiation therapy and intravenous hydroxyurea: initial results.

OBJECTIVE: To evaluate the long-term effects on swallowing function of concomitant continuous infusion hydroxyurea and hyperfractionated radiation therapy used to treat advanced head and neck carcinoma. DESIGN: A prospective evaluation of swallowing function was performed on an inception cohort by analyzing posttreatment videoflouroscopic swallow function studies using radiological descriptors for pharyngeal transport abnormalities and temporal measures of structural movements, as well as by conducting patient interviews to assess alimentation, more than 1 year after tumor treatment (range, 52-124 weeks; median, 70 weeks). SETTING: Academic tertiary care referral medical center. PATIENTS: Ten patients, aged 44 to 71 years, with stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx. MAIN OUTCOME MEASURE: Radiographic and temporal swallow abnormalities, as well as functional status, were documented and compared with published norms and results of earlier swallowing studies when possible. RESULTS: Pharyngeal transport dysfunction and anterior segment abnormalities, manifested by epiglottic dysmotility, vallecular residue, laryngeal penetration, or aspiration, were evident in all 10 patients. Posterior segment abnormalities, such as pharyngeal stasis, constrictor dysmotility and piriform residue were documented in 8 patients. Three patients developed late aspiration, and the majority of patients showed persistent or worsened delay in laryngeal movement compared with their earlier posttreatment evaluations. Also, 3 patients developed a hypopharyngeal stricture, and 6 patients continued to require gastrostomy tube supplementation beyond 1 year. There was no association between site of primary, duration to swallowing evaluation, and severity of dysfunction. CONCLUSION: Prolonged and debilitating functional swallowing abnormalities may occur after this aggressive concomitant chemotherapy and radiotherapy regimen.

Adult↗

PubMed2000

Rheumatoid arthritis exacerbation caused by exogenous interleukin-12.

Interleukin-12 (IL-12) is a pleiotropic cytokine with proinflammatory, immunoregulatory, antitumor, and antimetastatic properties. It plays a crucial role in the development of the Th1 response and subsequent interferon-gamma production and enhancement of cell-mediated cytotoxicity. Recently, IL-12 has been used as an experimental therapy for cancer. Given the multiple immunomodulatory properties of IL-12, there are potential concerns associated with its clinical use. Of special interest are the possible side effects of IL-12 therapy in patients with autoimmune diseases, especially those that are T cell mediated, such as rheumatoid arthritis (RA). We present a case of severe RA exacerbation caused by treatment with IL-12 for metastatic cervical cancer. This is the first reported case of RA flare caused by exogenous IL-12.

Arthritis, Rheumatoid↗

PubMed2000

Downregulation of cyclin D1 alters cdk 4- and cdk 2-specific phosphorylation of retinoblastoma protein.

Progression of cells through the G1 phase of the cell cycle requires the assembly and activation of specific cyclin:cyclin-dependent kinase (cdk) complexes in a tightly regulated, sequential fashion. To more clearly define the temporal events leading to the G1/S transition, sequential changes in the expression of cyclin E and cdks 2, 4, and 6, as well as the phosphorylation of the retinoblastoma protein (pRb), were assayed in RA28 cells, a variant of human colon cancer RKO cells which were modified by transfection of an ecdysone-inducible antisense (AS) CD1 expression system. Induction of cyclin D1 antisense mRNA by the ecdysteroid, ponasterone A, resulted in a 55% decrease in cyclin D1 mRNA and a 58% decrease in CD1 protein levels. There was a 2.4-fold decrease in the ratio of hyperphosphorylated pRb (ppRb) to hypophosphorylated pRb, as well as a 60-75% decrease in cdk 2- and cdk 4-specific phosphorylated pRb proteins. Of interest, cyclin E-dependent phosphorylation (cdk2) decreased 2.5-fold at 3 h despite only a 30% decrease in cyclin E protein level. Levels of cdk 2, cdk 4, and cdk 6 decreased 40-70%, while levels of cyclin A and B were unaffected by induction of CD1 antisense. Induction of a CD1 antisense gene in a human colon cancer cell line resulted in rapid, concomitant changes in CD1 mRNA and protein, cyclin E, cdk2, cdk4, and cdk6, as well as the ratio of ppRb to pRb. In this system, growth regulatory events are tightly regulated and the perturbed expression of a single protein, CD1, rapidly alters expression of multiple regulatory proteins involved in the G1/S transition phase of cell cycle progression.

Blotting, Western↗

PubMed2000

Management of cancer treatment-related diarrhea. Issues and therapeutic strategies.

The cancer treatment-related diarrhea caused by acute graft-versus-host disease (GVHD) and chemotherapeutic agents, particularly fluoropyrimidines and irinotecan, significantly affects patient morbidity and mortality. The mechanisms causing cancer treatment-related diarrhea are not fully understood, but histopathologic evidence points to a multifactorial process that causes an absorptive and secretory imbalance in the small bowel. Cancer treatment-related diarrhea could be life-threatening, yet assessment and treatment are not currently standardized. Several clinicians participated in a closed roundtable meeting to review the mechanisms of chemotherapy-induced diarrhea (CID) and GVHD-induced diarrhea, management issues in cancer treatment-induced diarrhea, and pharmacologic approaches to treatment. The meeting produced a proposal for new treatment guidelines and an algorithm, which include the use of octreotide for the management of CID- and GVHD-induced diarrhea. The development of diarrhea assessment guidelines that expand on the current National Cancer Institute criteria and allow for better patient management was also proposed.

Antineoplastic Agents↗

PubMed1999

Quantification of ribonucleotide reductase expression in wild-type and hydroxyurea-resistant cell lines employing in situ reverse transcriptase polymerase chain reaction and a computerized image analysis system.

Ribonucleotide reductase (RR) is the enzyme responsible for converting nucleoside diphosphates to deoxynucleoside diphosphates, ensuring a balanced supply of deoxyribonucleotides for DNA synthesis. Expression of RR is tightly regulated, but it is affected by exogenous agents, such as hydroxyurea (HU), which inactivates the tyrosyl free radical on the small subunit of RR, R2. We have previously employed in situ reverse transcriptase (RT)-PCR to estimate expression of R2 in wild-type and HU-resistant human colon carcinoma cell lines and to correlate altered expression of R2 with changes in cell size and morphology. The current studies were undertaken to render this methodology more quantitative. Both wild-type and resistant cells were grown on partitioned glass slides and analyzed with in situ RT-PCR. Because both wild-type and resistant cells were analyzed under a single cover slip, protease digestion, reverse transcription, PCR, and color development were all performed under identical conditions. Images were analyzed with NIH Image 1.59 software. There was a highly significant correlation between expression of R2 and cell size for both sensitive and resistant cells (P = 0.0001, for both). When cell size was compared either with expression of R2 or cell shape, however, these correlated only in wild-type cells (P = 0.001 and 0.0001, respectively). These data demonstrate that normal cell growth in the unperturbed wild-type cell line was closely linked to expression of R2, whereas in the resistant variants which overexpress R2, these correlations were absent, suggesting that HU resistance is related to loss of linkage between R2 expression and cell growth and confirming previous data relating overexpression of R2 with multiple other changes in the cell growth repertoire. Thus, we have demonstrated for the first time a quantitative application of in situ RT-PCR.

Base Sequence↗

PubMed1999

Pharyngeal transport dysfunction consequent to an organ-sparing protocol.

OBJECTIVE: To investigate the effects of a protocol of concomitant intravenous hydroxyurea and hyperfractionated, accelerated, external-beam radiation therapy on the swallowing mechanism of patients with advanced-stage head and neck cancer. DESIGN: Posttreatment videofluoroscopic swallow function studies, using images of single-bolus swallows of low-density liquid barium, were analyzed in real time, slow motion, and frame by frame using an integrated system that allows objective analysis of video recordings through image processing and digitization (Kay Elemetrics Computerized Swallowing Station). Radiological descriptors were used for pharyngeal transport abnormalities, and temporal measures were obtained of structural movements. SETTING: Academic, tertiary care, referral medical center. PATIENTS: Fifteen consecutive patients with previously untreated, stages III and IV, nonmetastatic squamous cell carcinoma of the head and neck who underwent a phase 1 study of prolonged infusion hydroxyurea therapy in combination with hyperfractionated, accelerated external-beam radiation therapy for their disease. RESULTS: All patients had anterior pharyngeal segment dysfunction, characterized by no epiglottic movement and slowed laryngeal motility (1.011 +/- 0.379 seconds [mean +/- SD). Anterior pharyngeal dysfunction was more severe in patients with primary tumors of the hypopharynx than in those with cancer of the oropharynx. Twelve (80%) of our patients demonstrated posterior pharyngeal segment dysfunction characterized by impaired pharyngeal constrictor motility. All 15 patients displayed pharyngeal stage abnormalities that limited bolus transport and clearance. CONCLUSIONS: Severe pharyngeal physiological abnormalities were present that led to impaired bolus transport and that were frequent and debilitating consequences of this organ-sparing protocol. Long-term follow-up of this group will be required to assess the permanence of the abnormalities.

Adult↗

PubMed1999

A phase II double-blind randomized study of the simultaneous administration of recombinant human interleukin-6 and recombinant human granulocyte colony-stimulating factor following paclitaxel and carboplatin chemotherapy in patients with advanced epithelial ovarian cancer.

PURPOSE: Recombinant human interleukin-6 (rhuIL-6) is a glycosylated cytokine with hematopoietic stimulatory effects. In particular, preclinical studies suggest the agent can stimulate thrombopoiesis, even in conjunction with chemotherapy. We attempted to determine whether higher dose chemotherapy for ovarian cancer was possible given the pharmacologic use of this important growth factor. METHODS: We conducted a randomized, double-blind phase II study of IL-6 plus granulocyte colony-stimulating factor (G-CSF) versus placebo plus G-CSF in combination with a standard chemotherapy regimen. Patients with epithelial ovarian cancer, stages Ic to IV, were eligible. All patients were previously untreated with chemotherapy and had Karnofsky performance status >/=60. rhuIL-6 (Escherichia coli, SDZ ILS 969) 1.0 micrograms/kg or placebo was given subcutaneously on days 2-8 every cycle together with G-CSF 5.0 micrograms/kg subcutaneously days 2-15, following administration of paclitaxel 175 mg/m2 as a 3-h infusion and carboplatin given to a desired AUC of 7.5 on day 1 every 21 days. RESULTS: Fifty patients were entered in this study, although the study was temporarily suspended by the FDA in midstudy over manufacturing concerns. Therefore, 37 patients were evaluable for efficacy of growth factor; 19 patients received placebo plus G-CSF and 18 rhIL-6 plus G-CSF. There was no difference in prognostic variables between these two groups. Platelet nadirs were lower in the first cycle for the placebo group (P = 0.004, Wilcoxon sum-rank test) but not in other cycles. There was no statistically significant difference in cycle treatment delays, carboplatin dose delivered, number of patients with grade 4 thrombocytopenia, or platelet transfusion. Nonetheless, the trend of the data favored IL-6 in all cases. CONCLUSIONS: This study demonstrated a minimal effect (statistically significant in the first cycle only) on thrombopoiesis in women undergoing paclitaxel and carboplatin therapy of ovarian cancer. No clinically significant effect on actual chemotherapy delivery was demonstrated, however. Future studies, if warranted, to ameliorate thrombocytopenia should be carried out with regimens producing even greater thrombocytopenia than the current regimen in the control arm.

Adenocarcinoma↗

PubMed1999

Antisense therapeutics in oncology: points to consider in their clinical evaluation.

Novel therapeutics in oncology stem from a rational design of drugs targeting selective pathways that stimulate and maintain tumor cell growth. Many of these agents are cytostatic in action and also have a limited toxicity profile. However, some can be cytotoxic if they successfully modulate molecular pathways of apoptosis, such as bcl-2. This article discusses points to consider in the design of one class of cytostatic agents, antisense therapy. Our purpose is to stimulate designs that answer the question specifically with regard to proof-of-concept, and the concepts proposed should be viewed as ideas in development rather than firm recommendations.

Apoptosis↗

PubMed1999

Phase I-II study of 5-fluorouracil, recombinant interferon alpha2a, and cisplatin in combination with external beam radiation therapy followed by surgery in patients with locally advanced carcinoma of the esophagus.

Multimodality therapy has been demonstrated to be superior to external beam radiation therapy and possibly surgery alone for the treatment of carcinoma of the esophagus. The combination of 5-fluorouracil (5-FU), cisplatin, and recombinant interferon alpha2a (IFN) has yielded 65% response rates in metastatic and regionally advanced carcinoma of the esophagus. A phase I-II study was performed to assess the feasibility of combining 5-FU, IFN, and cisplatin with external beam radiation therapy followed by surgery in potentially resectable patients. Eligibility included biopsy-proven stage II-III squamous cell or adenocarcinoma of the esophagus with no prior therapy. External beam radiation therapy was administered concurrently with chemotherapy beginning on day 1, 5 days per week, twice a day with 1.5 Gy/fraction to a total dose of 45 Gy. 5-FU was administered at 750 mg/m2 on days 1, 8, 15, 22, and 29 after the administration of IFN and cisplatin. IFN was given at a dose of 6 million units subcutaneously three times per week beginning on day 1. Dose levels I, II, and III of cisplatin were 25, 30, and 35 mg/m2 administered on days 1, 8, 15, 22, and 29. The sequence of administration was IFN followed by cisplatin followed immediately by 5-FU. Dose escalation between patient cohorts occurred if 0/3 or < or = 1/6 patients had dose-limiting toxicity, i.e., grade II-III toxicity attributable to cisplatin. A phase II trial was planned using the maximum tolerated dose of cisplatin determined from the phase I trial. Patients who successfully completed therapy underwent thoracic exploration to resect residual disease. Twelve patients were enrolled; all were eligible. The demographics of the population were median age, 60 years (range, 44-77); nine male and three female patients; nine squamous cell carcinoma, one adenocarcinoma, and two adenosquamous histology; stage II:III, 2:10. Grade 3-4 toxicities included granulocytopenia (12 patients), thrombocytopenia (six), anemia (three), infection (six), diarrhea (two), mucositis (two), and renal and hepatic toxicities (one). Five patients had a clinical complete response, among whom four underwent surgery. At surgery, one patient had no evidence of residual disease and three patients had microscopic disease only. Two patients had progressive disease and five could not complete the therapy because of toxicities. Two patients are alive and disease free at 25 and 23 months, respectively. This regimen, though active, demonstrated an unfavorable toxicity profile and cannot be recommended for further study.

Adenocarcinoma↗

PubMed1999

Krukenberg tumors: can management be improved?

OBJECTIVE: The Montefiore Medical Center experience with women with gastrointestinal (GI) cancer was reviewed to: (1) evaluate clinical parameters in patients with Krukenberg tumor (GI cancer metastatic to the ovaries) and (2) evaluate oophorectomy in GI cancer patients. METHODS: (1) Charts of all female patients admitted between 1985 and 1996 with gastric or colon cancer were reviewed. RESULTS: The frequency of Krukenberg tumor was 7/1,021 (0.7%). The median age at presentation was 39.5 years (range 35-80); 5 were premenopausal, 2 of whom were postpartum. Krukenberg tumor was significantly more common in the premenopausal patients with gastric cancer (p = 0.002), colon cancer (p = 0.001), and in both sites combined (p < 0.001). Our rate of pregnancy-associated Krukenberg tumors (28.6%) was significantly higher (p < 0.05) than that found in 4 of 5 large studies. The average survival of our 7 patients was 12.3 months (range 4 days to 26 months), with secondary debulking and chemotherapy offering 1 patient the longest longevity. Only 19/788 (2.4%) women had oophorectomy during their colon cancer surgery revealing 2 (10.5%) Krukenberg tumors, 6 (31.6%) benign solid or cystic ovarian tumors, and 11 (57.9%) normal or atrophic ovaries. CONCLUSIONS: Krukenberg tumors are rare. There is no uniformity of data reported in the literature. Krukenberg tumors were more common in premenopausal women with gastric or colon cancer compared to postmenopausal women. Our rate of pregnancy-associated Krukenberg tumors appeared to be higher compared to other studies. Prophylactic oophorectomy in pre- and postmenopausal women should be considered at the time of GI cancer surgery, and requires further study. A national registry combined with prospective, multisite studies are needed to gather data and evaluate treatment.

Adult↗

PubMed1999

Phase II/pharmacodynamic trial of dose-intensive, weekly parenteral hydroxyurea and fluorouracil administered with interferon alfa-2a in patients with refractory malignancies of the gastrointestinal tract.

PURPOSE: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools. PATIENTS AND METHODS: A single-institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m(2) intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m(2) as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-alpha2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripheral-blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay. RESULTS: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of patients > or = 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytopenia (22%). Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting in 10% of patients. Patients > or = 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7%) complete responders and 11 (37%) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. CONCLUSION: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-alpha2a modulation was well-tolerated with activity in gastric cancer. Patients > or = 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.

Adult↗

PubMed1999

Activity and pharmacodynamics of 21-Day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy. New York Gynecologic Oncology Group.

PURPOSE: Twenty-one-day topotecan infusion was administered as second-line therapy in patients with previously treated ovarian cancer (based on our prior favorable phase I experience) to determine its activity, time to progression, and pharmacodynamics. PATIENTS AND METHODS: Ovarian cancer patients with measurable lesions and one prior platinum-containing regimen were eligible. Topotecan 0.4 mg/m(2)/d 21-day continuous ambulatory intravenous infusion, with appropriate dose modifications for toxicity, was administered every 28 days. Weekly blood levels of topotecan and topoisomerase-1 (topo-1) levels in peripheral-blood mononuclear cells (PBMCs) were determined for pharmacodynamic correlation. RESULTS: Twenty-four patients were entered onto the study (six cisplatin-refractory, five relapsing within < 6 months and 13 relapsing > 6 months after platinum-based therapy). A total of 128 cycles of topotecan (median, four cycles per patient; range, one to 12 cycles) were administered. The major toxicity was neutropenia (29% grade 3 in all cycles and 4% grade 4). One episode of grade 4 thrombocytopenia (4%) occurred. Fifty-two percent of the patients had anemia that required transfusions. Eight of 23 patients with measurable disease (35%; 95% confidence interval [CI], 15% to 54%) had partial responses (PRs) lasting longer than 1 month. Two of these patients had minor residual computed tomographic changes but had clinical complete remissions that lasted up to 53 weeks while they were not undergoing further therapy. One patient with nonmeasurable disease had a PR (by CA-125 criteria) that lasted 6 months, for an overall response rate of 38% in nine of 24 patients (95% CI, 18% to 57%). The median time to progression was 26 weeks. Pharmacodynamic analysis demonstrated a statistically significant decrease in free PBMC topo-1 level at weeks 2 and 3 of drug administration. There was a strong statistical correlation between the decrease in free topo-1 levels and increasing area under the curve (AUC) for topotecan. This was confirmed in a pharmacodynamic model. CONCLUSION: Twenty-one-day infusion is a well-tolerated method of administering topotecan. Pharmacodynamic studies demonstrate correlations between (1) the week of infusion and the PBMC topo-1 level, (2) the AUC of topotecan and the decrease in topo-1 levels, and (3) the change in topo-1 level and the neutrophil nadir. The objective response rate of 35% to 38% (95% CI, 15% to 57%) in this small multicenter study is at the upper level for topotecan therapy in previously treated ovarian cancer. Prolonged topotecan administration therefore warrants further investigation in larger, randomized studies comparing this 21-day schedule with the once-daily-for-5-days schedule.

Adult↗

PubMed1999

Interferons as biomodulators of fluoropyrimidines in the treatment of colorectal cancer.

Interferons (IFN)-alpha, -beta, and -gamma enhance the activity of 5-fluorouracil (5-FU) in vitro and in vivo. Various mechanisms have been identified to account for this modulation. First, IFN induces the enzyme thymidine phosphorylase, thereby enhancing the conversion of 5-FU to its active metabolite, 5-fluorodeoxyuridine monophosphate (FdUMP), leading to increased depletion of thymidine triphosphate pools and increased DNA fragmentation. Second, IFN treatment leads to abrogation of an 5-FU-associated increase in the enzyme thymidylate synthase (TS), thus increasing tumor sensitivity to 5-FU. Finally, IFN augments plasma 5-FU levels. Single-institution studies of 5-FU in combination with IFN-alpha showed high response rates; however, randomized trials demonstrated equivalent survival to 5-FU alone or in combination with leucovorin (LV). Randomized trials of 5-FU double-modulated by both IFN-alpha and LV showed no response or survival advantage compared with 5-FU/LV, and greater toxicity. The randomized trials are all limited by inconsistent schedules of administration of IFN-alpha. The combination of 5-FU and IFN-beta has shown promising results in single-arm and small randomized trials. A large randomized trial, requiring a standardized schedule of administration of IFN-beta, has been initiated.

Animals↗

PubMed1998

Management of Krukenberg tumors: an 11-year experience and review of the literature.

Purposes: The Montefiore Medical Center (MMC) experience with Krukenberg tumors (gastrointestinal cancer metastatic to the ovary) was reviewed 1) in order to determine whether it could be used to make clinical management recommendations, eg, differences in treatment based on menopausal status, secondary debulking, prophylactic oophorectomy; 2) to compare the MMC experience to the reported literature, since one of our patients survived 1912 months beyond the generally accepted mean of this rare tumor.Methods: 1) Prospective study from January 1985-April 1996 of 5 patients followed at MMC with a diagnosis of gastrointestinal (GI) cancer metastatic to the ovary; 2) retrospective chart review of all female patients admitted to MMC with a diagnosis of GI cancer during the same time period; 3) computerized literature review from 1966 to 1996.Results: Five patients were followed prospectively. Retrospective chart review identified 1,016 female patients admitted with gastric (231) or colon (785) cancer, 2 additional cases of Krukenberg tumor were identified. Of the 7 patients with Krukenberg tumors the primary tumor was colon in 5 and gastric in 2. The average age at presentation was 49.3 years (range 35-80); 5 were premenopausal, 2 were postmenopausal, and 2 (28.6%) were postpartum. The average survival of these 7 patients was 12.3 months (range 4 days to 26 months). The 5 patients who had ovarian metastases removed at first laparotomy survived an average of 10.8 months. The 1 patient who had a secondary debulking survived longest (26 months). The 1 patient who had no surgery lived 6 months. These numbers are not statistically significant, but do suggest that further study is warranted. Including the prospectively studied patients, 1,021 patients were evaluated. Seven of 1,021 (0.7%) had Krukenberg tumors. Two of 11 (18.2%) premenopausal gastric cancer patients had a Krukenberg tumor, whereas none of the 222 postmenopausal gastric cancer patients did. Similarly, 3 of 41 (7.3%) premenopausal colon cancer patients had a Krukenberg tumor compared to 2 of 747 (0.3%) postmenopausal colon cancer patients. This difference in menopausal status is significant by Fisher's Exact test (P <.001). Nineteen patients underwent oophorectomy at the time of primary colon cancer surgery: 11 had normal or atrophic ovaries, 2 thecomas, 4 simple cysts, and 2 Krukenberg tumors. Three of 19 (15.8%) were premenopausal.Conclusions: Review of the literature has identified a number of diagnostic and management issues that appear to impact on survival. These include timing of definitive diagnosis of Krukenberg tumors, ie, before, after, or at the same time as diagnosis of the GI primary tumor; menopausal status; concurrent pregnancy; role of debulking; prophylactic oophorectomy. The prognosis worsens when the primary tumor is identified after the metastasis to the ovary is discovered. Krukenberg tumor is more common in premenopausal women than in postmenopausal women. The number of patients with Krukenberg tumors discovered postpartum in our study was significantly increased compared to the other series in the literature. The number of patients who received prophylactic oophorectomy or secondary debulking in our study was inadequate to draw conclusions regarding a benefit of these procedures. However, a benefit may be suggested for debulking, as survival appears to be increased. More importantly, there may be a role for prophylactic oophorectomies in both pre- and postmenopausal patients, as this would eliminate the need for a repeat laparotomy. A randomized trial is needed to evaluate the role of prophylactic oophorectomy and debulking. Since the clinical and pathologic details in the literature vary widely, it is extremely difficult to compare studies, particularly the treatment and survival of patients with Krukenberg tumors. Reports should include age, site of GI primary, time from diagnosis of primary to ovarian metastasis, and overall survival as well as survival from the time of diagnosis and treatment of the Krukenberg. We wish to alert the clinician that persistent GI symptoms always warrant investigation. Pelvic inflammatory disease, pregnancy, and postpartum endometritis may mask the GI symptoms. Delays in diagnosis should be avoided. During surgery, the gynecologic surgeon must do a complete upper abdominal exploration, and the general surgeon must do a complete pelvic evaluation. Since Krukenberg tumors are rare, a national registry should be started to gather information on these patients; this might lead to better diagnosis and treatment.

Journal Article↗

PubMed1998

Effects of perturbations of pools of deoxyribonucleoside triphosphates on expression of ribonucleotide reductase, a G1/S transition state enzyme, in p53-mutated cells.

Effects of drug treatment with antimetabolites on a human colon cancer cell line, SW480, were studied. Cells were treated with 10 microM of 5-fluorouracil (5FU), an inhibitor of pyrimidine synthesis, or 1000 microM of hydroxyurea (HU), an inhibitor of both purine and pyrimidine syntheses, or the combination. Recombinant alpha-2a-interferon (IFN), 500 U/mL, also was employed, as this augments the effects of both antimetabolites in vitro and in vivo. The predominant effect of this combination was to block cells in early S phase as measured by 5-bromo-2'-deoxyuridine (BrdUrd) incorporation. By 24 hr, 86% of the cells had accumulated in S phase, but failed to progress to G2/M. This was accompanied by an early, rapid decline in all four deoxyribonucleoside triphosphates (dNTPs) by 38-86% at 4-24 hr. Despite these effects, expression of the G1/S transition state enzyme, ribonucleotide reductase (RR), increased at 24 hr as measured by a 3 to 5-fold increase in mRNA levels for the M2 subunit, in the absence of a measurable effect on protein levels. The rise in levels of RR mRNA and the continued progression of cells into S phase were associated with a synergistic inhibition of cell cycle proliferation resulting from treatment with the three-drug combination. This suggests that in the presence of antimetabolite-induced depletion of dNTPs, SW480 cells, which lack a normal p53 gene, will proceed into S phase, and that this is associated with a rise in expression of the G1/S transition state enzyme, RR. Cells arrested in S phase by a p53-independent mechanism will undergo a synergistic enhancement of cell death.

Cell Cycle↗

PubMed1998

Close or positive margins after surgical resection for the head and neck cancer patient: the addition of brachytherapy improves local control.

PURPOSE: Microscopically positive or close margins after surgical resection results in an approximately 21-26% local failure rate despite excellent postoperative external radiation therapy. We sought to demonstrate improved local control in head and neck cancer patients who had a resection with curative intent, and had unexpected, microscopically positive or close surgical margins. METHODS AND MATERIALS: Twenty-nine patients with microscopically close or positive margins after curative surgery were given definitive, adjuvant external radiation therapy and 125I brachytherapy. All 29 patients had squamous cell cancer and tonsil was the most common subsite within the head and neck region. After external radiation therapy and thorough discussions with the attending surgeon and pathologists, the slides, gross specimens, and appropriate radiographs were reviewed and a target volume was determined. The target volume was the region of the margin in question and varied in size based on the surgery and pathologic results. Once the target volume was identified the patient was taken back to the operating room for insertion of 125I seeds. Activity implanted (range 2.9-21.5 millicuries) was designed to administer a cumulative lifetime dose of 120-160 Gy. RESULTS: Twenty-nine patients were followed for a median of 26 months (range 5-86 months). Two-year actuarial local control was 92%. CONCLUSION: 125I, after external radiation therapy, is an excellent method to improve local control in the subset of patients with unexpectedly unsatisfactory margins.

Brachytherapy↗

PubMed1998

Phase I study of paclitaxel (taxol) and granulocyte colony stimulating factor (G-CSF) in patients with unresectable malignancy.

A phase I trial of a 24-hour infusion of paclitaxel was conducted to identify the maximum tolerated dose of paclitaxel with granulocyte colony-stimulating factor (G-CSF) in patients with unresectable malignancy previously untreated with chemotherapy. Nineteen patients with metastatic melanoma or non-small cell lung cancer were treated with paclitaxel administered at 250, 300, 400 mg/m2 every 3 weeks. G-CSF, 5 microg/kg was given as a daily subcutaneous injection 24 hours after the completion of the infusion. Dose limiting myelosuppression and peripheral neuropathy was observed at 400 mg/m2 and 350 mg/m2. Paclitaxel can be safely administered as a 24-hour infusion at 300 mg/m2 with G-CSF. Further studies of paclitaxel and G-CSF are recommended to determine a dose-response relationship in sensitive tumors.

Adult↗

PubMed1998

A phase I clinical trial of prolonged infusion of hydroxyurea in combination with hyperfractionated, accelerated, external radiation therapy in patients with advanced squamous cell cancer of the head and neck.

BACKGROUND: Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was initiated to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of HU in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck. METHODS: Patients were required to have histologically-documented and radiographically-staged locally advanced SCC of the hypopharynx (AJC stages II, III or IV), oropharynx (AJC stage IV), or oral cavity (AJC stage IV) not amenable to reasonable surgical resection. Eligible patients had adequate bone marrow, hepatic, and renal function and had to give informed consent. Concomitant, hyperfractionated, accelerated radiation therapy (CHRT) consisted of 1.2 Gy BID (6 hour minimum interfraction interval) on weekdays and 1.2 Gy delivered daily on the weekends to a total tumor dose of 74.4 Gy. Continuous infusion hydroxyurea (CHU) was administered at 0.25-0.375 mg/m2/min as a continuous intravenous infusion daily for 5 days with weekends days off for the duration of the radiation therapy. The dose of HU was increased by 0.125 mg/m2/min between dose levels until DLT was reached in 2/6 patients. If the primary had a complete clinical response and biopsies were negative, planned neck dissections were performed. RESULTS: Fifteen patients were enrolled and are evaluable. The initial dose level, 0.25 mg/m2/min was tolerated by 3/3 patients. At 0.375 mg/m2/min, 3/6 patients experienced grade 3-4 infections, with one patient having a non-fatal, subendocardial infarction. At 0.313 mg/m2/min, no patient experienced DLT. CONCLUSION: The MTD for CHU-CHRT was 0.313 mg/m2/min. The toxicities were primarily mucosal and a phase II study is in progress.

Adult↗