Biomedical subjects

A Sandler

Publications and source records attributed to A Sandler.

At least 19 recordsLinked to original sources

PubMed2001

Cervical primitive neuroectodermal tumor.

BACKGROUND: Primitive neuroectodermal tumors (PNETs) are rare and potentially aggressive malignancies. CASE: A 24-year-old woman in her eighth week of pregnancy presented with a cervical mass. Tissue biopsy demonstrated poorly differentiated carcinosarcoma with neuroendocrine features. Immunohistochemical studies confirmed the diagnosis of PNET. Treatment included alternating courses of cyclophosphamide, adriamycin, vincristine (CAV) and ifosfamide, etoposide (IE). A radical hysterectomy with bilateral ovarian transposition and periaortic lymphadenectomy was performed with postoperative chemotherapy and radiotherapy. The patient remains disease free 2 years from therapy. CONCLUSION: This is a rare case of cervical PNET occurring in a pregnant patient. A review of the literature indicates that cervical PNET is distinguishable from uterine PNET. This tumor affects younger women and may have a different histogenesis. Pregnancy should not delay diagnosis of this potentially aggressive tumor.

Adult↗

PubMed2001

When should diclofenac be given in ambulatory surgery: preoperatively or postoperatively?

STUDY OBJECTIVE: To determine the optimum time of administration of diclofenac in patients undergoing ambulatory knee arthroscopy: either preoperatively or postoperatively. DESIGN: Randomized, double-blind study. SETTING: Ambulatory surgical unit in a tertiary referral hospital. PATIENTS: 127 ASA physical status I and II patients undergoing ambulatory knee arthroscopy. INTERVENTIONS: Patients were randomized into three groups. The Preop group received 50 mg of potassium diclofenac orally 1 hour preoperatively and a placebo 30 minutes postoperatively. The Pre+postop group received 25 mg of potassium diclofenac 1 hour preoperatively and 25 mg diclofenac 30 minutes postoperatively. The Postop group received a placebo 1 hour before surgery and 50 mg of potassium diclofenac 30 minutes postoperatively. MEASUREMENTS AND MAIN RESULTS: The Postop group received a placebo 1 hour preoperatively and 50 mg of potassium diclofenac 30 min postoperatively. Postoperatively, patients used intravenous patient-controlled analgesia (PCA) with fentanyl. Total fentanyl consumption was recorded. During the recovery period, pain was assessed using a visual analog scale (VAS) at 30-minute intervals. Pain was assessed in both legs at rest, on flexion, and extension of the knee. There were no significant differences in pain scores either at rest or on movement of the operative knee among the Preop, Pre+postop, and Postop groups. The consumption of fentanyl via PCA showed no significant differences among the groups. CONCLUSIONS: There is no difference in pain relief whether diclofenac is given preoperatively or postoperatively in patients undergoing unilateral ambulatory knee arthroscopy. Preoperative and postoperative treatment with diclofenac potassium is equally effective.

Adult↗

PubMed2001

Altretamine for the treatment of metastatic renal cell carcinoma. A Hoosier Oncology Group trial.

Thirty patients with advanced renal cell carcinoma were treated on a phase 11 trial with altretamine. Altretamine was administered orally at a dosage of 260 mg/m2 days 1 through 14 with cycles repeated every 28 days. Nausea and vomiting were the most common toxicities. Ten percent (3 of 30) experienced Grade 3 gait abnormalities. None of the thirty evaluable patients achieved a complete or partial response. In summary, altretamine did not show antitumor activity in the treatment of advanced renal cell carcinoma.

Adult↗

PubMed2001

The survivin:fas ratio in pediatric renal tumors.

BACKGROUND/PURPOSE: Apoptosis factors inducing or preventing cell death may govern the behavior of certain tumors. Fas is a pro-apoptotic receptor that induces cell death when bound by its ligand and is expressed at greater levels in pediatric renal tumors of good prognosis. Survivin is a novel inhibitor of apoptosis that is expressed in a cell cycle-dependent manner and is abundantly expressed in several tumors of unfavorable histology. This study evaluates the expression of survivin, as well as the prognostic value of the survivin:fas ratio in various types and stages of pediatric renal tumors. METHODS: Multiple apoptosis mRNA species were quantified by Rnase protection assay (RPA) in 32 pediatric renal tumors and adjacent normal kidney specimens before chemotherapy: Wilms' tumor (WT), n = 9; clear cell sarcoma (CCS), n = 4; rhabdoid tumor of the kidney (RTK), n = 5; mesoblastic nephroma (MN), n = 3 and normal kidney, n = 11. Western Blot and immunocytochemistry were used to confirm survivin protein expression in a selective specimen survey. Follow-up data were obtained on patient outcomes, and antiapoptotic to proapoptotic ratios were calculated and correlated with clinical recurrence of disease. RESULTS: Pediatric renal tumors express greater levels of both pro- and antiapoptotic factors than normal kidney. Survivin and fas appeared to be expressed differentially in the tumor specimens sampled. Five of 10 (50%) tumors that went on to recur expressed survivin, whereas survivin was present in only 2 of 11 (18%) nonrecurrent tumors. Conversely, only 2 of 10 (20%) tumors that recurred were fas positive, whereas 5 of 11 (45%) tumors that did not recur expressed fas. The mean survivin:fas ratio was significantly greater in the 10 tumors that went on to recur after treatment (4 RTK, 3 CCS, 3 WT), than in tumors not recurring (2.16+/-1.4 v 1.0+/-1.07; P =.01, Kruskal-Wallis test). The positive predictive value of tumor recurrence was 85.7% (CI: 42.1%, 99.6%) and the negative predictive value was 71.4% (CI: 41.9%, 91.6%) when a cutoff ratio of 1.6 was considered. CONCLUSIONS: The survivin:fas mRNA ratio is of prognostic value in its ability to predict recurrent disease in children undergoing treatment for pediatric renal tumors. In this series, a ratio of greater than 1.6 predicted recurrent disease with a high probability irrespective of clinical stage or pathologic type. Determining the survivin:fas ratio may guide treatment, follow-up and counseling of patients with pediatric renal tumors.

Apoptosis↗

PubMed2001

Nonanatomic hepatic resection with a pledgetted suturing technique.

BACKGROUND/PURPOSE: Anatomic hepatic resection is dependent on the segmental infrastructure of the liver, whereas nonanatomic resection is independent of structural planes and is often fraught with excessive bleeding. The authors describe their experience with a novel technique using pledgetted suturing for extensive liver resection in patients with benign or malignant hepatic tumors. METHODS: Four children, (mean age, 24.7 +/- 12.5 months) underwent liver resection for the following hepatic lesions: hepatoblastoma, invasive Wilms' tumor, Caroli's disease, and infantile hemangioendothelioma. In the child with hepatoblastoma, the lesion was considered unresectable by segmental anatomy. A surgical technique was designed in which nonabsorbable 2-0 Teflon felt pledgetted sutures were placed through the liver parenchyma in a nonanatomic resection plane. The mattress sutures were sequentially tied until the resection plane was defined. The resection was sharply completed with a scalpel along the line of pledgetted sutures, independent of hepatic segmental anatomy. RESULTS: Complete surgical resections of the hepatic lesions were obtained in all cases. Estimated blood loss was minimal with a mean of 5.3 +/- 0.9 mL/kg. No patient received a blood transfusion as a result of the hepatic resection. There were no postoperative hepatic complications resulting from the resection. The child with hepatoblastoma had a delayed recovery, resulting in reexploration that ruled out a subphrenic abscess. CONCLUSIONS: The pledgetted suturing technique for hepatic resection is relatively bloodless, safe, easy to perform, and may enable a complete surgical resection of otherwise unresectable lesions. We advocate this technique when approaching a large hepatic lesion that would entail a difficult or incomplete anatomic resection in infants. J Pediatr Surg 36:209-212.

Child, Preschool↗

PubMed2001

Multistaged extrathoracic esophageal elongation procedure for long gap esophageal atresia: Experience with 12 patients.

PURPOSE: This study evaluates the multistaged extrathoracic esophageal elongation procedure performed on 12 babies with long gap esophageal atresia over 15 years. METHODS: Eight babies had pure esophageal atresia, 2 had proximal tracheoesophageal fistula (TEF), and 2 had distal TEF. The gaps ranged between 2 and 7 vertebral bodies. Proximal esophagostomy, TEF ligation, and gastrostomy were performed initially. The proximal esophagus is elongated 2 to 3 cm each time by translocating the esophagostomy distally along the anterior chest wall at 2- to 3-month intervals. Sham-fed milk is collected in an ostomy bag and refed via the gastrostomy. The definitive esophageal reconstruction is performed at 5 to 24 months of age. RESULTS: Only one elongation was required in 4 babies, 2 were needed in 5, 3 in 2, and 5 in 1 patient. All patients tolerated sham feeding well. After esophageal restoration, 3 patients had minor leakage. All (12 of 12) patients had anastomotic stenosis requiring multiple dilatations, of which, 3 needed resection of stricture. Eleven patients had gastroesophageal reflux that required fundoplication. Follow-up was possible in 11 patients for 4 months to 14 years after esophageal restoration. Seven early patients are eating normally. CONCLUSION: Multistaged extrathoracic esophageal elongation is effective in stretching the proximal esophagus to bridge 2 to 7 vertebral bodies.

Child, Preschool↗

PubMed2001

The inhibitor of apoptosis protein survivin is associated with high-risk behavior of neuroblastoma.

BACKGROUND/PURPOSE: Apoptotic factors inducing or preventing cell death may intrinsically govern the behavior of some tumors. Survivin is a recently described member of the inhibitor of apoptosis protein (IAP) family, that is expressed in a cell cycle-dependent manner and is found in tumors of unfavorable histology. This study examines the presence of several apoptotic factors, including survivin, in neuroblastoma (NB) tumors. Clues to survivin's function in NB are provided by examining its association with behavior and cell dynamics in tumors and cell lines. METHODS: Expression of a panel of apoptosis factors were quantified in 15 NB and related tumors before chemotherapy and in 3 NB cell lines (NB7, NB10, and NB16). Survivin and other apoptotic factors, as well N-myc amplification in primary tumors was correlated with recurrent disease and outcome. Proliferation rate, apoptosis assays, cell cycle analysis, and drug- or immune-mediated cell death were assessed in cell lines and evaluated in the context of differential survivin and apoptosis gene expression. RESULTS: All 7 tumors that went on to recur expressed survivin, whereas expression was absent in all 8 tumors that went into remission. N-myc was amplified in 4 (57.1%) of the 7 recurrent tumors. Of the 8 tumors that were cured, Fas was expressed in 3 (38%), TRAIL-R1 in 6 (75%) and tumor necrosis factor (TNF)-R1 in 8 (100%), whereas these pro-apoptotic receptors were present in only 1 (14%), 1 (14%), and 4 (57%) of the 7 tumors that went on to recur, respectively. Of the 3 cell lines, NB10 expressed the least survivin, displayed the lowest proliferation index, and had the fewest number of cells in the G2/M (mitotic) phase of the cell cycle. Furthermore, NB10 also was most sensitive to TNF-related apoptosis-inducing ligand (TRAIL) or etoposide-induced cell death. CONCLUSIONS: In primary NB tumors, survivin expression was associated with tumors of high risk and unfavorable prognosis, whereas pro-apoptotic receptor expression was more abundant in tumors of favorable prognosis. In this small series, survivin expression appeared to be more predictive of recurrent disease than N-myc amplification. In cell lines, survivin expression was cell cycle dependent, and its expression was associated with greater proliferation rates and greater resistance to drug- or immune-mediated cell death. Survivin expression may become a useful prognostic marker in NB and could be a potential target for the treatment of this tumor. J Pediatr Surg 36:1785-1791.

Apoptosis↗

PubMed2001

Treatment of metastatic non-small-cell lung cancer.

The management of advanced NSCLC remains a daunting challenge; however, new tools are available for treating this malignancy, and continued progress is likely. The future is bright, with a myriad of opportunities to exploit our ever-expanding knowledge of tumor biology. What is perhaps most needed, however, is development of new methods to prevent children and young adults from ever taking up the use of tobacco. In addition, clinicians need new techniques to assist those who are already addicted to escape from tobacco's death grip. Sadly, most users of tobacco still fail to recognize the dangers of their habit. This needs to change.

Animals↗

PubMed2001

Facial diplegia as the presenting manifestation of acute lymphoblastic leukemia.

A 36-year-old man with recent onset of unilateral peripheral 7th nerve paresis presented ten days later with involvement of the other side of his face. Physical examination was otherwise normal, and since blood tests and imaging were also normal, he was considered to have bilateral Bell's palsy. However, unexpected headaches and worsening of the paresis led to a gallium-67 scan which revealed uptake in the mediastinum. A repeat lumbar puncture revealed cells which were identified as lymphoblasts. T-cell acute lymphoblastic leukemia (T-ALL) was diagnosed, although the peripheral blood smear was normal. The differential diagnosis of bilateral 7th nerve palsy and of mononuclear cerebrospinal fluid pleocytosis is discussed, as well as this rare central nervous system presentation of acute leukemia.

Adult↗

PubMed2000

The modified Puestow procedure for complicated hereditary pancreatitis in children.

PURPOSE: The aim of this study was to evaluate the role of longitudinal pancreaticojejunostomy (modified Puestow procedure) in the treatment of complicated hereditary pancreatitis (HP) in children. METHODS: The authors reviewed their experience with the modified Puestow procedure for complicated HP in patients less than 18 years of age at a single tertiary care facility between 1973 and 1998. Main study outcomes included surgical morbidity and mortality, pre- and postoperative pancreatic function, number of hospitalizations, and percentile ideal body weight (IBW). RESULTS: Twelve patients (6 boys and 6 girls) with a mean age of 9.3 years were identified. Presenting diagnoses were abdominal pain (n = 10), failure to thrive (n = 4), pancreatic pleural effusion (n = 2), and pancreatic ascites (n = 1). Blood loss was greater in patients who underwent distal pancreatectomy to localize the duct (n = 6) than in those who underwent direct transpancreatic duct localization (n = 6; 29.1+/-6.8 v. 8.3+/-3.7 mL/kg; P = .03). Other complications in patients who underwent distal pancreatectomy included splenic devascularization requiring splenectomy (n = 1) and postoperative intraabdominal bleeding with subsequent left subphrenic abscess (n = 1). There was no surgical mortality. Five patients had steatorrhea preoperatively that resolved in 4 patients postoperatively and was well controlled in the fifth. Mean number of hospitalizations for pancreatitis in the 5 years after surgery were markedly less than in the 5 years preceding surgery (0.4+/-0.2 v. 3.5+/-0.5; P = .01, n = 9). Percentile ideal body weight tended to increase within the first postoperative year (24.6+/-6.8 v. 45.0+/-8.3; P = .07, n = 9), and by the third year this trend was clearly significant (27.0+/-7.2 v. 60.9+/-9.5; P = .01, n = 8). CONCLUSIONS: In children with complicated HP, the modified Puestow procedure improves the quality of life by improving pancreatic function, decreasing hospitalizations, and increasing the percentile ideal body weight. Direct pancreatic duct localization during the procedure had a lower morbidity rate than localization via distal pancreatectomy. It is our impression that surgery performed in the early stage of complicated disease may preserve pancreatic function.

Adolescent↗

PubMed2000

Overexpression of Fas-ligand by neuroblastoma: a novel mechanism of tumor-cell killing.

BACKGROUND/PURPOSE: Binding of Fas ligand (Fas-L) to the membrane-bound Fas receptor incites a series of intracellular events that results in programmed cell death or apoptosis. Although this apoptotic phenomenon plays a key role in down-regulating cytotoxic T cells, the authors have shown previously that pancreatic beta cells (bTC) overexpressing Fas-L paradoxically undergo accelerated rejection that is dependent on a Fas/Fas-L interaction. This study evaluates whether a neuroblastoma (NB) cell line manipulated to overexpress Fas-L undergoes similar destruction and whether tumor-specific protective immunity can be produced. METHODS: The authors transfected NB cells (SK-N-MC) with either mFas-L cloned into a pcDNA3.1/Zeo plasmid vector (NB/Fas-L) or with the vector alone (NB/control). Successful transfection of Fas-L was characterized by reverse transcription polymerase chain reaction (RT-PCR) and the ability of transfectants to induce apoptosis of Fas-sensitive T cells (Jurkat). Expression of Fas and Fas-L in untransfected NB clones was characterized by immunohistochemistry and RNase protection assay (RPA). Apoptosis was measured by FACScan analysis using an Annexin V assay. A total of 3x10(6) NB/control and NB/Fas-L cells were implanted subcutaneously into the hind leg of Balb/C SCID mice. Tumor-specific protective immunity was also tested in this model by inoculating mice with NB/Fas-L before implanting NB/control cells. RESULTS: Zeocin resistance and RT-PCR confirmed successful transfection of Fas-L into NB cells. Fas Ligand transfectants induced apoptosis in 17.6%+/-2.9% of Fas-sensitive T cells, whereas controls induced apoptosis in only 2.8%+/-1.2% (P = .01, n = 3). Although Fas appears to be constitutively expressed by NB in low amounts, introduction of Fas-L into NB cells did not induce suicide or affect tumor cell growth in vitro. In vivo, NB cells expressing Fas-L failed to grow in SCID mice (n = 3), whereas controls grew rapidly in all animals until death (n = 3). NB/control cells implanted into the opposite leg of mice that rejected initial NB/Fas-L transfectants also grew rapidly (n = 3) implying no protective immunity. CONCLUSIONS: Overexpression of Fas-L in NB clones targets such cells for rapid destruction even in immune compromised hosts, suggesting potential utility of Fas-L in combating NB. In this SCID mouse model, the observed effect is probably neutrophil mediated and does not provide tumor-specific protective immunity.

Animals↗

PubMed2000

Differential apoptosis gene expression in pediatric tumors of the kidney.

BACKGROUND/PURPOSE: Apoptosis, or programmed cell death, is essential in maintaining normal homeostasis of tissues. The process of apoptosis is controlled by numerous pro- and antiapoptotic factors. Variations in expression of such factors may account for some variations in tumor behavior. This study evaluates the expression of apoptotic mRNA species in pediatric renal tumors to determine whether a pattern of differential apoptosis gene expression correlates with tumor grade and type. METHODS: Twenty-five frozen tissue specimens were obtained from patients undergoing biopsy or resection of pediatric renal tumors before chemotherapy: Wilms' tumor stage II (WT-II, n = 4); Wilms' tumor stage III/IV (WT-III/IV, n = 4); clear cell sarcoma of the kidney stage III (CCSK, n = 2); rhabdoid tumor of the kidney stage III/IV (RTK, n = 4); and normal kidney (NK, n = 11). An RNase Protection Assay (RPA) was performed for 19 pro- and antiapoptotic mRNA species to detect and quantify expression (percentage of GAPDH expressed). Expression of specific mRNAs of interest were confirmed by Western Blot (WB). RESULTS: The expression of apoptotic mRNA species varied markedly between tumors. WT-II expressed greater amounts of proapoptotic receptor mRNA than CCSK or RTK. (Fas, 17.0+/-2.7% v. 2.5+/-0.5% v. 3.3+/-0.9%; P<.02; DR5, 77.0+/-8.8% v. 13.5+/-0.5% v. 27.0+/-4.8; P<.001; TNF-R, 71.3+/-17.0% v. 21.0+/-4.0% v. 29.0+/-5.0%; P<.07, respectively). Surprisingly, antiapoptotic factors (e.g., bcl-2 and bcl-xl) were not overexpressed in poor prognostic tumors (CCSK, RTK) compared with those with good prognosis (WT). Expression of TRAIL (a ligand for DR4 and DR5) was significantly lower in CCSK and RTK than in normal kidney (9.5+/-1.5% v. 56.1+/-10.1%; P = .01). CONCLUSIONS: Proapoptotic receptors are expressed at greater levels in good prognostic tumors, and this finding is compatible with their clinical behavior. Knowledge of differential apoptotic gene expression is of potential value in predicting prognosis and treating such tumors with targeted ligands.

Apoptosis↗

PubMed2000

The influence of gemcitabine and cisplatin schedule on response and survival in advanced non-small cell lung cancer.

PURPOSE: Gemcitabine-cisplatin combinations are among the most active for the treatment of non-small cell lung cancer. Previous reports have suggested that the day of cisplatin administration affects both toxicity and drug delivery. We undertook this retrospective analysis to determine whether it also affects response and survival. PATIENTS AND METHODS: This was a retrospective analysis of six studies of gemcitabine and cisplatin. Gemcitabine, 1000-1500 mg/m(2) was administered on days 1, 8, and 15 of a 28 day cycle. In four studies cisplatin 100 mg/m(2) was administered with mannitol diuresis every four weeks on either day 1, day 2 or day 15. In two studies cisplatin 25-30 mg/m(2) was administered on day 1, 8 and 15. Standard prognostic factors including age, gender, stage, performance status, and histologic subtype were analyzed along with day of cisplatin administration. Single variable Cox proportional hazards regressions were performed. This was followed by multiple variable Cox proportional hazards regression, beginning with a full model containing terms for gender, age, performance status and stage. The least statistically significant terms were subsequently dropped from the model to reach a final model with only statistically significant variables. A similar approach was followed to fit a multiple variable logistic regression model to overall response data. RESULTS: Overall response rates were highest (36-46%) in the three studies that administered cisplatin on days 2 or 15, and these studies had the highest 1-year survival rates (52-58%). Survival was better for patients who received cisplatin on day 2 or 15 compared to those treated on either day 1 or weekly on days 1, 8, 15 (P=0.020). In the final model of the Cox regression analysis, survival was better for cisplatin on days 2 or 15 (hazard ratio=0.69, P=0.008) and female gender (hazard ratio=0.72, P=0.036). Only cisplatin delivery on day 2 or day 15 predicted for significantly better response (42 vs. 29%, P=0.036). CONCLUSION: In a 28 day cycle in which gemcitabine is administered day 1, 8 and 15, the best therapeutic index is achieved with cisplatin administration on day 2 or 15.

Adult↗

PubMed2000

Chemotherapy in metastatic non-small-cell lung cancer.

Over the last decade, a group of new agents with differing mechanisms of action have shown great promise in early clinical studies in non-small-cell lung cancer (NSCLC). These include the taxanes docetaxel (Taxotere) and paclitaxel (Taxol); the nucleoside analog gemcitabine (Gemzar); the vinca alkaloid vinorelbine (Navelbine); the topoisomerase-I inhibitor irinotecan (Camptosar, CPT-11); and the bioreductive agent tirapazamine. Cisplatin (Platinol), which has been the "backbone" of combination chemotherapy in patients with NSCLC because of its proven single-agent activity, has been examined in combination with these agents as well as radiation and surgery in numerous trials. This article summarizes trials of these combination therapies in the treatment of NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Phase I/II trial of irinotecan, carboplatin, and paclitaxel in advanced or metastatic NSCLC.

This multicenter study enrolled 73 patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). The study design was based on the hypothesis that the non-overlapping toxicities of a 3-drug combination of irinotecan (Camptosar, CPT-11), carboplatin (Paraplatin), and paclitaxel (Taxol) would allow them to be dosed at recommended or standard doses, respectively. Of the 32 patients in phase I portion of the trial, six received irinotecan 40 mg/m2 plus carboplatin at an area-under-curve (AUC) of 6 and paclitaxel 225 mg/m2 on an every-3-week schedule (regimen A). Due to the unexpectedly severe toxicity associated with this regimen, the carboplatin and paclitaxel doses were reduced, while the irinotecan doses were escalated from 40 to 80 to 125 mg and reduced to 100 mg/m2 (regimen B). In the phase II portion of the trial, irinotecan was dosed at 100 mg/m2 because 3 of 8 patients who received the 125 mg/m2 dose in phase I experienced first-course grade 3/4 toxicities. However, the toxicity of regimen B proved unacceptably severe in phase II; 13 of the 40 patients (35%) experienced grade 3/4 neutropenia and 30% suffered febrile or septic neutropenia. The unconfirmed objective response rate in phase I was 64.5%; median time to progression and median survival were 7.1 months and 11.6 months, respectively, and 1-year survival was 46.9%. The unconfirmed objective response rate in phase II was 60.6%, including one complete response (CR) and 19 partial responses (PRs); one CR and 16 PRs were subsequently confirmed. The efficacy and toxicity of this triple combination strongly suggest significant pharmacokinetic and/or pharmacodynamic interactions, warranting continued clinical investigation.

Adult↗

PubMed2000

Extensive small-cell lung cancer: a treatment overview.

New cases of lung cancer will be diagnosed in an estimated 164,100 Americans in 2000, and approximately 25% or 41,000 of those cases will be small-cell lung cancer (SCLC). Despite initial sensitivity to chemotherapy, only 10% of all patients with SCLC achieve significant long-term survival. Studies have yet to demonstrate a significant survival advantage for maintenance chemotherapy. In addition, it appears that chemotherapy is effective for only four to six cycles in the treatment of SCLC, and there is no defined role for dose escalation. In extensive disease, no chemotherapy combination has exhibited a definitive survival advantage although it appears that single-agent etoposide (VePesid, VP-16) may be inferior to combination intravenous chemotherapy. Several new agents with significant activity in SCLC await further study.

Antineoplastic Agents↗

PubMed1999

Overexpression of Fas ligand does not confer immune privilege to a pancreatic beta tumor cell line (betaTC-3).

BACKGROUND: Fas ligand (Fas-L) is thought to provide immune privilege to specific tissues and tumors by inducing an apoptotic signal of cytotoxic T cells expressing its Fas receptor. Purpose. The purpose of this work was to evaluate whether an immortalized insulin-secreting cell line (betaTC-3) gains immune privilege by inducing overexpression of Fas-L. METHODS: A lipofection technique was used to transfect a betaTC-3 tumor cell line with a plasmid (pcDNA3.1/Zeo) carrying the Fas-L gene and a zeocin resistance gene. Insertion of Fas-L into betaTC was characterized by reverse transcription polymerase chain reaction (RT-PCR) and the ability of transfectants (betaTC-3/Fas-L) to induce apoptosis of Fas-sensitive T cells. Transfectants and control cells were tested for insulin secretion following which 1 x 10(6) insulin-secreting betaTC-3 and betaTC-3/Fas-L cells were subcutaneously implanted into syngeneic, allogeneic, and Fas mutant (lpr) syngeneic mice. Survival of the insulin-secreting cells was then determined by monitoring serum glucose levels in recipients. RESULTS: Successful transfection of vector resistance gene was achieved in the transfected betaTC-3 cells, which was confirmed by zeocin resistance. RT-PCR in resistant Fas-L clones confirmed the transcription of Fas-L, which was absent in controls. Fas-L transfectants induced 20 +/- 4.2% apoptosis of Fas-sensitive T cells, while controls induced 3.47 +/- 2.3% by flow cytometry (P = 0.04, n = 3). Insulin secretion was equivalent in both betaTC-3 and betaTC-3/Fas-L cells. Syngeneic mice implanted with control betaTC-3 cells died within 3 weeks from hypoglycemia due to overgrowth of betaTC-3 tumor. Implanted Fas-L transfected betaTC-3 cells were killed and had no effect on glycemic status except in Fas mutant hosts, where tumors formed in two of three mice. CONCLUSIONS: Despite the ability of transfected betaTC-3 cells to induce apoptosis of T cells in vitro, expression of Fas-L provided no immune privilege to these cells in vivo, but paradoxically induced killing of betaTC-3 cells even in syngeneic hosts.

Animals↗

PubMed1999

High-resolution holocene environmental changes in the thar desert, northwestern india

Sediments from Lunkaransar dry lake in northwestern India reveal regional water table and lake level fluctuations over decades to centuries during the Holocene that are attributed to changes in the southwestern Indian monsoon rains. The lake levels were very shallow and fluctuated often in the early Holocene and then rose abruptly around 6300 carbon-14 years before the present (14C yr B.P.). The lake completely desiccated around 4800 (14)C yr B.P. The end of this 1500-year wet period coincided with a period of intense dune destabilization. The major Harrapan-Indus civilization began and flourished in this region 1000 years after desiccation of the lake during arid climate and was not synchronous with the lacustral phase.

Journal Article↗