Biomedical subjects

S Litwin

Publications and source records attributed to S Litwin.

At least 37 records · Page 2Linked to original sources

PubMed1996

Combination paclitaxel (1-hour) and carboplatin (AUC 7.5) in advanced non-small cell lung cancer: a phase II study by the Fox Chase Cancer Center Network.

We have previously reported a 62% response rate and 54% 1-year survival rate for patients with advanced non-small cell lung cancer (NSCLC) treated with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion in combination with carboplatin, using area under the concentration-time curve dosing (FCCC 93-024). Myelosuppression proved dose limiting, but was substantially reduced by the routine use of granulocyte colony-stimulating factor during the second and subsequent cycles. Antitumor activity has been reported with minimal myelosuppression, with paclitaxel 135 and 200 mg/m2 given every 3 weeks by 1-hour infusion to patients with NSCLC. In November 1994, we initiated a phase II trial of paclitaxel 175 mg/m2 given over 1 hour, with carboplatin dosed to a fixed, targeted area under the concentration-time curve of 7.5 every 3 weeks. In the absence of grade 4 myelosuppression, paclitaxel was escalated on an intrapatient basis by 35 mg/m2 per cycle to a maximum dose of 280 mg/m2 by cycle 4. Granulocyte colony-stimulating factor was not routinely used. Eligibility stipulated advanced, measurable, chemotherapy-naive NSCLC. Of 47 patients accrued, 39 (83%) had Eastern Cooperative Oncology Group performance status 1. The median age was 64 years; 40 patients were evaluable for toxicity. Of the first 20 evaluable patients accrued (cohort A), myelosuppression was tolerable. Cumulative peripheral sensory neuropathy grade > or = 1 in 15 (75%) patients and grade 3 in six (30%), however, generally occurring at paclitaxel doses greater than 215 mg/m2, obligated removal from study of at least three patients, despite the absence of disease progression, and proved to be dose-limiting. Consequently, the protocol was revised: the starting dose of paclitaxel was reduced to 135 mg/m2, with intrapatient dose escalation of 40 mg/m2 per cycle to a maximum dose of 215 mg/m2, thus recapitulating the original dosing schema used in FCCC 93-024. To date, 25 patients have been enrolled in this second cohort (cohort B) and treatment has been better tolerated. Of 21 evaluable patients, 13 (62%) have experienced peripheral sensory neuropathy, but only one (5%) has been grade 3. Myelosuppression also has been less pronounced, with 33% grade 4 granulocytopenia and 13% grade > or = 3 thrombocytopenia in cohort B compared with 70% and 50%, respectively, in cohort A. Of the first 22 patients accrued to cohort A, 12 (55%) had major objective responses. Median event-free survival is 23 weeks and median survival is 47 weeks. Of 15 evaluable patients in cohort B, five (33%) have had major objective responses. It is too early to report survival data. In conclusion, paclitaxel by 1-hour infusion in combination with carboplatin at a fixed targeted area under the concentration-time curve of 7.5 is an active regimen in advanced NSCLC. Neurotoxicity, rather than myelosuppression, is dose and protocol limiting at paclitaxel doses exceeding 215 mg/m2.

Adult↗

PubMed1996

Telomerase activity in human laryngeal squamous cell carcinomas.

The activation of telomerase has been shown to be an important step during tumorigenesis in a variety of malignancies and is associated with characteristics of cellular immortality, such as indefinite proliferative potential. We studied telomerase activity in a series of human laryngeal carcinomas. Thirty-six tumors from 35 patients were studied using a sensitive PCR-based technique, the telomeric repeat amplification protocol assay. Telomerase activity was present in 32 tumors (89%), and the level of activity correlated with the stage of disease. In two of four telomerase-negative tumors, we found evidence of an inhibitor of telomerase activity. In many cases, samples of mucosa surrounding the tumor were also studied, and telomerase could be detected in 16 of 21 patients. For this reason, we proceeded to perform a topographical analysis that demonstrated a pattern of telomerase activity suggestive of a spread of telomerase-positive cells. In conclusion, these data indicate that telomerase activation is important for laryngeal carcinogenesis and that telomerase assay might be a valuable addition to determine the spread of the disease.

Carcinoma, Squamous Cell↗

PubMed1995

Glutathione S-transferase activity and glutathione S-transferase mu expression in subjects with risk for colorectal cancer.

The glutathione S-transferases (alpha, mu, and pi), a family of Phase II detoxication enzymes, play a critical role in protecting the colon mucosa by catalyzing the conjugation of dietary carcinogens with glutathione. We investigated the efficacy of using the glutathione S-transferase (GST) activity of blood lymphocytes and GST-mu expression as biomarkers of risk for colorectal cancer. GST activity was measured in the blood lymphocytes of control individuals (n = 67) and in the blood lymphocytes (n = 60) and colon tissue (n = 34) of individuals at increased risk for colon cancer. Total GST activity was determined spectrophotometrically with the use of 1-chloro-2,4-dinitrobenzene as a substrate. The ability to express the um subclass of GST was determined with the use of an ELISA. Although interindividual variability in the GST activity of blood lymphocytes was greater than 8-fold (range, 16.7-146.8 nmol/min/mg), the GST activity of blood lymphocytes and colon tissue within an individual was constant over time and was unrelated to sex, age, or race. The GST activity of blood lymphocytes from high-risk individuals was significantly lower than that of blood lymphocytes from control individuals (P < or = 0.004). No association was observed between the frequency of GST-mu phenotype and risk for colorectal cancer. Blood lymphocytes from high-risk individuals unable to express GST-mu had lower levels of GST activity than did those from control subjects with the GST-mu null phenotype; however, this difference was significant in male subjects only (P < or = 0.006). Analysis of paired samples of blood lymphocytes and colon tissue indicated a strong correlation between the GST activity of the two tissue types (Spearman's rank correlation, r = 0.87; P < or = 0.0001). The GST activity of blood lymphocytes may be used to identify high-risk individuals with decreased protection from this Phase II detoxication enzyme who may benefit from clinical trials evaluating GST modulators as chemopreventive agents for colorectal cancer. The GST activity of blood lymphocytes may also be used in colorectal cancer chemoprevention trials to monitor the responsiveness of colon tissue to regimens that modify Phase II detoxication enzymes.

Adult↗

PubMed1995

A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas.

BACKGROUND: We hypothesized that delivering adjuvant radiotherapy (RT) preoperatively with chemotherapy might enhance local control of the cancer and patient tolerance for the intervention. METHODS: Thirty-four patients with localized pancreatic cancer (24 head, 8 head and body, 2 body and tail) were treated during the past 6 years with an intramural protocol consisting of 5-fluorouracil (1,000 mg/m2 on days 2 to 5 and 29 to 32) and mitomycin-C (10 mg/m2 on day 2) given with preoperative external beam RT (median 5,040 cGy). Nine patients did not have surgery: 1 refused, 1 died of cholangitis, and 7 were noted to have distant (5) or unresectable local cancer (2) after RT. Of the 25 patients who underwent celiotomy, 11 had liver (8) or peritoneal (3) metastases and 3 had palliative pancreatectomies (2 with liver metastasectomy and 1 with hepatic artery and portal vein replacement). The remaining 11 patients (44% of the cohort with surgery, 32% of all patients) had potentially curative (PC) resections (5 total pancreatectomy, 5 Whipple, 1 distal pancreatectomy). Median tumor diameter by computed tomographic scan was 3.75 cm (range 3 to 5) for the 11 patients who received PC resections and 4.5 cm (range 3 to 7.5) for all patients. Of the 11 patients with PC resections, 8 had evidence of superior mesenteric, portal or splenic venous involvement and 4 had been deemed unresectable at previous celiotomies. RESULTS: One patient developed respiratory failure and one died postoperatively, yielding a 9% rate of major morbidity and mortality. Median follow-up of the surviving patients with curative resection is 33 months (range 14 to 70). Their median survival from the time of tissue diagnosis is 45 months with a median disease-free survival of 27 months. The product limit estimate of 5-year survival is 40% (95% confidence bounds +29%, -30%). One patient had a microscopically positive resection margin, which was a falsely negative frozen section margin at the pancreatic neck. Two patients had positive regional lymph nodes. Five patients have been diagnosed with recurrent cancer. Only 1 has had a local/regional component to the recurrence. CONCLUSIONS: Preoperative RT and chemotherapy followed by resection is well tolerated and safe for patients with locally advanced pancreatic cancer. This approach provides tumor free resection margins and offers prolonged survival to patients with truly localized pancreatic cancer.

Adenocarcinoma↗

PubMed1995

Nondisjunction rates and abnormal embryonic development in a mouse cross between heterozygotes carrying a (7, 18) robertsonian translocation chromosome.

Mice bearing Robertsonian translocation chromosomes frequently produce aneuploid gametes. They are therefore excellent tools for studying nondisjunction in mammals. Genotypic analysis of embryos from a mouse cross between two different strains of mice carrying a (7,18) Robertsonian chromosome enabled us to measure the rate of nondisjunction for chromosomes 7 and 18. Embryos (429) were harvested from 76 litters of mice and the parental origin of each chromosome 7 and 18 determined. Genotyping these embryos has allowed us to conclude the following: (1) there were 96 embryos in which at least one nondisjunction event had taken place; (2) the rate of maternal nondisjunction was greater than paternal nondisjunction for teh chromosomes sampled in these mice; (3) a bias against chromosome 7 and 18 nullisomic gametes was observed, reflected in a smaller than expected number of uniparental disomic embryos; (4) nondisjunction events did not seem to occur at random throughout the 76 mouse litters, but were clustered into fewer than would be expected cy chance; and (5) a deficiency of paternal chromosome 18 uniparental disomic embryos was observed along with a higher than normal rate of developmental retardation at 8.5 days post coitum, raising the possibility that this chromosome has at least one imprinted gene.

Aneuploidy↗

PubMed1995

Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis.

PURPOSE: To determine the activity and toxicity of combination paclitaxel (24 hours) and carboplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligibility required measurable disease (stage IV or stage IIIB with malignant pleural effusion), Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, absolute neutrophil count > or = 2,000/microL, platelet count > or = 100,000/microL serum creatinine concentration < or = 1.5 mg/dL, and bilirubin level < or = 2 mg/dL. Paclitaxel was initially administered at a dose of 135 mg/m2/d, followed by carboplatin on day 2 at a targeted area under the concentration-time curve (AUC) of 7.5 using the Calvert formula. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously (SC) on days 3 to 17 was introduced during the second and subsequent cycles. In patients who sustained less than grade 4 myelosuppression, the paclitaxel dose was sequentially escalated 40 mg/m2 per cycle to a maximum of 215 mg/m2. Treatment was repeated at 3-week intervals for six cycles. RESULTS: From June 1993 through February 1994, 54 patients were enrolled; 53 are assessable for toxicity and response. The median age was 62 years (range, 34 to 84). Sixty-nine percent were male, 65% had adenocarcinoma, and 93% had stage IV disease. Two hundred sixty-eight cycles were administered; 32 patients (59%) completed all six cycles. Twenty-five unanticipated hospitalizations occurred during treatment (9.3% of cycles) in 20 patients (37%). Myelosuppression was the principal toxicity; grade 3 or 4 granulocytopenia occurred in 57% of patients after the first cycle, but decreased to 35% during the second cycle after introduction of G-CSF and consistently remained < or = 22% during subsequent cycles. Seven episodes of neutropenic fever occurred, all during the first cycle. Grade 3 or 4 thrombocytopenia and anemia occurred in 47% and 33% of patients, respectively. Eight patients (15%) required platelet transfusions and 16 (30%) required packed RBC support. Neuropathy, myalgias/arthralgias, and thrombocytopenia, although generally mild, were cumulative. The paclitaxel dose was boosted to 215 mg/m2 in > or = 70% of patients who received three or more cycles. At an AUC of 7.5, the median first-cycle carboplatin dose was 424 mg/m2 (range, 273 to 709 mg/m2). The objective response rate was 62%, with five (9%) complete responses and 28 (53%) partial responses. The median progression-free survival time was 28 weeks and the median survival time 53 weeks. The 1-year survival rate is 54%. CONCLUSION: The paclitaxel-carboplatin combination is active in advanced NSCLC and may enhance survival; it merits further investigation in phase III trials.

Adult↗

PubMed1995

Paclitaxel by 24- or 1-hour infusion n combination with carboplatin in advanced non-small cell lung cancer: the Fox Chase Cancer Center experience.

A phase II trial of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin included 54 chemotherapy-naive patients with advanced non-small cell lung cancer. Eligibility mandated Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate hematologic, renal, and hepatic function. Paclitaxel 135 mg/m2 over 24 hours preceded carboplatin dosed to an area under the concentration-time curve of 7.5. Six planned courses were given every 3 weeks. Granulocyte colony-stimulating factor was introduced during the second and subsequent cycles, and paclitaxel increased 40 mg/m2/cycle (maximum, 215 mg/m2) in patients with absolute neutrophil and platelet nadirs exceeding 500/microL and 50,000/microL, respectively. Grade 3 or 4 neutropenia, observed in 54% of patients during cycle 1, declined to 35% during cycle 2 and to 22% or less during cycles 3 through 6. Neuropathy, myalgias/arthralgias, and thrombocytopenia were mild but cumulative. In 53 evaluable patients, the objective response rate was 62%, with 9% complete remissions and a median response duration of 6 months (range, 1 to 19+ months). At median potential follow-up of 16 months, 9% of patients remain progression free (52+ to 80+ weeks). Median survival is 12.5 months; 1-year survival is 54%. Paclitaxel/carboplatin is highly active in advanced non-small cell lung cancer; granulocyte colony-stimulating factor abrogates neutropenia as the dose-limiting toxicity, but has no effect on the cumulative incidence of thrombocytopenia or treatment delays. One-hour paclitaxel infusion is minimally myelosuppressive, logistically easier, and less costly. A follow-up study combined paclitaxel (175 mg/m2) over 1 hour followed by carboplatin (area under the concentration-time curve, 7.5). In the absence of grade 4 myelosuppression, paclitaxel was increased 35 mg/m2/cycle (maximum, 280 mg/m2). Granulocyte colony-stimulating factor was implemented only after neutropenic fever or grade 4 neutropenia. Of 17 patients entered, 13 are evaluable for toxicity and seven for response. Four patients have sustained a partial response, two a minor response, and one stable disease. The incidence of grade 3 or 4 neutropenia, thrombocytopenia, and anemia in cycle 1 was 38%, 16%, and 0%, respectively, and 72%, 28%, and 28%, respectively, during cycle 2. Major nonhematologic toxicities include myalgias and arthralgias (54%) and fatigue and neuropathy (78%), the latter cumulative and progressive over successive cycles. Preliminary data suggest comparable activity for the 1- and 24 hour paclitaxel infusions in combination with carboplatin. The more severe neuropathy of the 1-hour paclitaxel/carboplatin combination may be related to the paclitaxel dosing schema (175 mg/m2 to as high as 280 mg/m2).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1995

How accurate is size measurement of pancreas cancer masses by computed axial tomography (CT) scanning?

With the advent of preoperative radiotherapy for pancreas cancers, their measurement by imaging is rendered more important, so that outcome data from various treatment programs may be compared. Two radiologists have examined tumor size measurements from 29 patients by CT scans obtained within a week of measurement in the Pathology Department after resection. The radiologists assessed these scans independently from one another and blinded from the pathologic measurement. The largest diameter of their readings was compared to the largest diameter of the tumor measured by the Pathology technician. The correlation between radiologists (P < 3 x 10(-8) was excellent. Correlation between the average of the two radiologic estimates of greatest tumor diameter and actual tissue measurement is excellent for tumors (n = 21) greater than 2 and less than 5 cm in diameter (P < 0.03), but of four specimens measured in the Pathology laboratory as less than 2 cm, all were measured by the radiologists as being at least 1.5 cm larger. Twenty of the 29 cancers (69%) were measured by two radiologists to be within 1 cm of the actual diameter. The nine specimens producing the greatest errors were two with diffuse mucinous tumors throughout the gland (radiologists undercalled by 2.5 cm), one 7 cm mass with a cystic center composed of necrotic cells (overcalled by 2.5 cm, perhaps because of deformity or release of fluid in Pathology), four small masses (1, 1.5, 1.5, and 1.5 cm in diameter), smaller than the normal diameter of the pancreas head, and two tumors with inexplicably inaccurate size estimates.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMed1995

Reconstruction with myocutaneous flaps following resection of locally recurrent rectal cancer.

Local or regional recurrence is frequent in patients treated for rectal cancer. Many will die with regional disease in the absence of distant metastases. To achieve cure or palliation, radical surgery resulting in large pelvic defects may be warranted. Myocutaneous flap reconstruction may be used to achieve satisfactory closure. From 1988 to 1993, nine patients (5 female, 4 male) underwent 10 myocutaneous flap reconstructions for large perineal or pelvic defects following surgical extirpation of recurrent rectal cancer at Fox Chase Cancer Center. All nine patients had been previously treated with radiation therapy. Their clinical course was reviewed and quality of life assessed. The mean age at diagnosis of recurrence was 56 years. In six, this was a first, and in three patients a second recurrence. Clinical presentation was most often bleeding, abscess, or perineal pain. Resection was determined by extent of recurrence and included perineal resection, pelvic exenteration, cystectomy, sacrectomy, or coccygectomy. Extent of disease necessitated intraoperative radiation therapy in one case and placement of brachytherapy catheters in four. Bilateral gracilis flaps were used in four, unilateral in three, gluteus maximus in two, and combined gluteal and gracilis flaps in one patient. Six perineal and four combined perineal and vaginal defects were reconstructed. The mean length of surgery was 9.1 hours, and the length of hospitalization averaged 17.5 days. In nine of 10 cases, patients had prehospital level of function at discharge. Acute surgical flap-related complications included three cases of minor wound infection or separation, two of minimal but persistent drainage, and one of vaginal colonization.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Molecular and genetic epidemiology of hepatocellular carcinoma: studies in China and Senegal.

To identify environmental, viral, and genetic factors that may influence the risk of developing hepatocellular carcinoma (HCC), large prospective studies are being conducted in Haimen City, China and Senegal, and a case-control study of genetic variation in the detoxification of aflatoxin-B1 was carried out in Shanghai, China. Analysis of 78 HCCs that have occurred among 51,020 men enrolled in a large prospective study in Haimen City, China showed a strong association of HCC with chronic hepatitis B virus (HBV) infection. There were also significant associations of HCC risk with occupation (farming), history of a clinical episode of hepatitis in adulthood, and a family history of HCC. Study of 52 HCC cases and 116 controls for genetic polymorphisms and HCC risk showed a significant association with epoxide hydrolase (EPHX) mutant alleles (1/2, 2/2) and a borderline association with homozygous deletion of the glutathione-S-transferase mu (GSTM1) gene. There was a multiplicative interaction of these polymorphisms with chronic HBV infection such that HBsAg-positive persons who were GSTM1 null and were EPHX 1/2 or 2/2 had 135 times the risk of HCC as HBsAg-negative persons with the wild type genotypes for GSTM1 and EPHX. The risk of HCC is not uniform among persons with chronic HBV or HCV infections. Studies of genetic, viral, and environmental interactions may permit identification of those individuals at highest risk within groups at increased risk of HCC. Prevention strategies could then be targeted at those individuals.

Aflatoxin B1↗

PubMed1995

Pretreatment p53 protein expression correlates with decreased survival in patients with end-stage head and neck cancer.

Relatively little is known about p53 changes in far-advanced head and neck cancer for several reasons: (a) most patients respond well to initial treatment; (b) most institutions do not encounter large numbers of these patients; (c) recurrent or metastatic disease is often within body cavities inaccessible for analysis; and (d) the variety of treatment regimens and disease sites makes meaningful conclusions difficult to draw in such a heterogeneous group. The purpose of this study was to evaluate the clinical significance of p53 mutations and overexpression in a homogeneous group of patients with end-stage squamous cell carcinoma of the head and neck. Pretreatment tumor specimens from a homogeneous group of 16 patients with end-stage squamous cell carcinoma of the head and neck were obtained. All patients had recurred after surgery and radiation +/- induction chemotherapy, and all met the criteria for enrollment in a Phase II chemotherapy trial consisting of 5-fluorouracil, N-phosphoacetyl-L-aspartate, and recombinant IFN-alpha. Each was analyzed for mutations in exons 5-8 of the p53 gene and protein expression using the p53 polyclonal antibody CM-1. No relationship was found between p53 immunostain or p53 mutations and age, gender, site of primary tumor, or site of disease recurrence. p53 alterations also did not correlate with response to Phase II chemotherapy. p53 immunostain (but not p53 mutations) correlated with a shorter survival (P = 0.0124) after diagnosis with end-stage disease. This suggests that mechanisms other than p53 mutations which alter the half-life of p53 protein may contribute to the outcome of these patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Association between high levels of ornithine decarboxylase activity and favorable prognosis in human colorectal carcinoma.

Several studies have documented increased expression of ornithine decarboxylase (ODC) in neoplastic colorectal tissue versus normal-appearing colonic mucosa. The present study was undertaken to determine whether there is an association between the degree of overexpression of ODC in colorectal carcinomas and survival in a series of 74 patients. A high level of tumor ODC expression was found to be significantly associated with greater survival in our patient series. Patients with tumor ODC activities greater than the median and especially in the highest quartile experienced a more favorable outcome than those patients with ODC values below the median or in the lowest quartile (P = 0.03 and 0.02, respectively). The presence of a GTP-activatable isoform of ODC was also significantly associated with a favorable prognosis but only in tumors of the right colon (P = 0.01). There was no association found between ODC activity and tumor grade, tumor size, or patient age, sex, or race. Our results demonstrate that high levels of ODC expression (and presence of a GTP-activatable isoform for right-sided colon tumors) predict a favorable prognosis in human colorectal carcinoma. Knowledge of a patient's ODC status at the time of surgery may be useful in decisions regarding adjuvant therapy. Understanding the mechanism(s) involved should lead to new therapeutic approaches for advanced colorectal carcinoma.

Aged↗

PubMed1994

The mechanism of autoantibody production in an autoimmune MRL/lpr mouse.

Rheumatoid factors (RF) and anti-DNA Abs from MRL/lpr mice have features similar to Abs directed toward foreign Ags, indicating a role of specific activation by Ags during disease. But our previous studies and analogous studies from others concentrated on a limited subset of hybridomas selected on the basis of Ag binding to well characterized target autoantigens. Thus, it has been unclear to what extent clonal expansion is restricted to identifiable autospecificities. To obtain a more complete picture of disease-associated autoantibody production, we designed the following experiment. A large number of B cell hybridomas were generated from the spleen of an MRL/lpr mouse and then analyzed for self-specificity, sequence, and clonal relationship. Surprisingly, we found that clonal expansion was limited to only a few autospecificities, implying a unique property of this response. In addition, we used Southern blotting with heavy and L chain constant region probes to screen both RF and non-RF hybridomas for membership in clones, one of which was first identified among RF hybridomas. We found no non-RF members of this clone. The size and number of mutations of this clone were sufficient for us to conclude that nonspecific (i.e., non-RF) mutant members are rapidly lost. Had an Ag other than IgG2a been driving clonal expansion, we should have seen mutants that retained spectificity for that Ag but that lost specificity for IgG2a. This observation, along with the restriction of clonal expansion to a few autospecificities, provides strong evidence that normal autoantigens themselves drive autoantibody clonal expansion.

Amino Acid Sequence↗

PubMed1994

Is frozen section analysis of reexcision lumpectomy margins worthwhile? Margin analysis in breast reexcisions.

BACKGROUND: The authors performed reexcision lumpectomy on patients with breast cancer with tumor at or close to the resection margin or if the margin status was unknown. Frozen section analysis (FSA) of reexcision lumpectomy margins was performed to allow additional excision of margins or mastectomy, saving the patient another operation or an additional radiation boost. METHODS: The authors reviewed the accuracy of FSA of margins in 107 patients undergoing reexcision lumpectomy between 1987 and 1992. There were 359 frozen sections performed on 156 specimens. Sensitivity and specificity of FSA for each frozen section margin, specimen, and patient were evaluated, as was gross inspection of tumor involvement at the resection margins. The accuracy of each pathologist's use of FSA also was evaluated. RESULTS: FSA sensitivity per frozen section margin, specimen, and patient was 0.90, 0.89, and 0.85, respectively. The specificity of gross inspection was 0.97, 0.96, and 0.96 (sensitivity, 0.44), which was significantly less accurate than that of FSA (P = 0.0015) or permanent section (P = 0.019). There was no significant discordance between FSA and permanent section. Of 19 pathologists doing FSA, 6 evaluated 10 or more specimens. The error rate ranged from 4% to 10% among pathologists with 10 or more readings, whereas 12 of 13 pathologists with fewer readings had no errors. The final pathologist had a 100% error rate, significantly worse (range, P = 0.0085-0.02) than any experienced pathologist. Thirty-four (32%) patients underwent additional excision (24 patients) or mastectomy (10 patients) based on the results of FSA, which saved the patients from undergoing another operation. No one required an additional operation or a mastectomy because of a false FSA result. CONCLUSION: FSA is safe and accurate in evaluating reexcision lumpectomy margins. Gross inspection is not reliable in margin evaluation. FSA saved an additional operation 32% of the time. Obtaining clear margins during one procedure eliminates the necessity of an additional radiation boost and probably will improve cosmesis.

Breast Neoplasms↗

PubMed1994

Deletion and editing of B cells that express antibodies to DNA.

We previously demonstrated that in mice transgenic for genes coding for an anti-ssDNA autoantibody B cells were functionally inactivated but not physically deleted. We have now extended this model by introducing an arginine into the CDR2 of the heavy chain transgene. This change alters the specificity of the Ab from anti-ssDNA to anti-dsDNA and increases the affinity for ssDNA. Mice carrying this transgene displayed a significant reduction of peripheral B cells and anti-dsDNA B cells were not recovered from the spleens. The remaining B cells escape deletion by revising their Ag receptors in several ways: 1) elimination of the transgenic heavy chain gene via intrachromosomal recombination, followed by rearrangement and expression of endogenous VH genes; 2) ongoing rearrangement of endogenous kappa light chain genes to generate a non-dsDNA-binding Ab; and 3) expression of a rare V lambda gene, V lambda x, to generate a non-DNA-binding Ab.

Amino Acid Sequence↗

PubMed1994

Cytogenetic analysis of 63 non-small cell lung carcinomas: recurrent chromosome alterations amid frequent and widespread genomic upheaval.

A detailed cytogenetic analysis of 63 non-small cell lung carcinomas (NSCLCs) was carried out for identification of recurrent chromosomal alterations. Most specimens displayed very complex karyotypes with multiple numerical and structural changes (median number, 31). Losses of chromosomes 9 (65% of cases) and 13 (71%) were the most frequent numerical changes. Loss of the Y was often observed in tumors from males. Gain of chromosome 7 was also frequent (41%). Chromosome arms 1p, 1q, 3p, 3q, 6q, 7q, 8q, 9p, 11q, 17p, and 19q were particularly prone to rearrangement. The chromosome arm most often contributing to losses was 9p (79%). Other arms that were frequently lost included 3p, 6q, 8p, 9q, 13q, 17p, 18q, 19p, 21q, 22q, and the short arm of each acrocentric chromosome. The percentage of cases with loss of 3p was significantly higher in squamous cell carcinomas (94%) than in adenocarcinomas (60%). There was also a statistically significant increase in the proportion of cases with gains of 1q, 7p, and 11q in adenocarcinomas compared to squamous cell carcinomas. Several recurrent isochromosomes and unbalanced exchanges were found. Among these was i(5p), which was observed in nine tumors, eight of which displayed adenomatous features. An i(8q) was identified in six cases, including five adenocarcinomas. Double minutes and/or homogeneously staining regions were seen in seven specimens. These data indicate that numerous chromosome alterations contribute to the pathogenesis of NSCLC and that, amid this widespread genomic disarray, recurrent abnormalities exist that could have biological and clinical implications.

Adult↗

PubMed1994

Morbidity after intraperitoneal insertion of saline-filled tissue expanders for small bowel exclusion from radiotherapy treatment fields: a prospective four year experience with 34 patients.

UNLABELLED: When prolonged small bowel exclusion (SBE) from external radiotherapy (RT) fields or immediate exclusion of bowel from brachytherapy sources is required for a patient without adequate omentum, there are no simple proven methods available for accomplishing these goals. We report a prospective study of SBE by intraperitoneal, saline-filled tissue expanders (TE). Thirty-four patients had exclusion of small bowel from either external radiotherapy (RT) ports (20), afterloading catheter treatment fields (5), both (5), or from intracavitary implants (4). Twenty-seven TEs were placed in the pelvis and 7 in the iliolumbar fossa. TE volume ranged from 400-1500 cc (median 550 cc). Patients had rectal (n = 15), colon (6), endometrial (4), anal (3), and vaginal (1) cancers and sarcomas (5). Fifteen patients had recurrent neoplasms, 13 of which were in previously irradiated fields. Nine patients had colorectostomies directly behind the TE, and 12 had other bowel (6) or ureteral (3) anastomoses or bladder repairs (3) adjacent to the TE. RESULTS: TEs remained in the patients from 6 to 173 days (median 95). Morbidity included three early TE withdrawals before RT was begun, one for a prolonged ileus, one for a perineal wound dehiscence, and one for an unrelated small bowel obstruction. Two patients (5.9%) early in the series had post-withdrawal complications (non-lethal small bowel fistulas requiring reoperation), although in a recent cohort of patients no post-withdrawal complications occurred using a different placement technique (0/17 vs. 2/14, P = 0.2). The patient injury complication rate was 4/34 (11.8%). None of these limited or delayed RT, but RT was limited to less than that planned in one other by TE deflation (total complication rate 14.7%). There were no clinical infections involving the prostheses, even though one patient had an abdominal wound dehiscence, 3 had pelvic abscesses, and 2 had exposure of the TE through the vagina (1 planned, 1 at dehisced vaginal cuff) after TE placement. We noted no acute and one possible late RT complication in these patients (18 months median follow-up, range 3-43 months). Small bowel was displaced from > 95 per cent of the RT treatment volume in 70 per cent and from > 75 per cent of the treatment volume in 89 per cent of 27 evaluable patients treated with external RT. CONCLUSION: Intraperitoneal placement of a saline-filled tissue expander is a simple, safe and effective means of small bowel exclusion from RT portals.

Adult↗

PubMed1993

Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A Phase II Study.

BACKGROUND: Low resectability rate and high locoregional recurrence are major factors contributing to the failure of surgical treatment for localized pancreatic adenocarcinoma. A Phase II study involving preoperative 5-fluorouracil (5-FU) and mitomycin C and radiation therapy was evaluated. METHODS: Thirty-one patients with biopsy-proven carcinoma (24, head of pancreas; 2, body; 5 duodenum) were treated with preoperative radiation therapy, 5040 cGy (180 cGy/fraction, 5 days/week), concurrent with 5-FU, 1000 mg/m2/day continuous infusion (days 2-5, 28-32) and mitomycin C 10 mg/m2 bolus (day 2). Ten patients had previous laparotomy or bypass surgery and were deemed unresectable; 21 had percutaneous, endoscopic retrograde choleangiopancreatic, or transhepatic stent biopsies. RESULTS: Toxicity included neutropenic fever (2 patients), biliary sepsis (2 patients), and nausea and vomiting requiring total parenteral nutrition. One patient died of biliary sepsis before completion of chemoradiation and 11 patients showed evidence of metastatic disease (clinical or occult). Resectability rate was 38% (10/26) for pancreatic carcinoma and 80% (4/5) for duodenal carcinoma. Pathology of the resected specimens revealed extensive necrosis and hyalinization with clear margins in all cases. Lymph node metastases were found in one case of pancreatic carcinoma. The four resected duodenal carcinomas contained no residual tumor in the specimens. At a median follow-up of 29 months, the median survival time for those with pancreatic carcinoma was not yet reached in the resection group and was 8 months in the nonresection group. The corresponding actuarial 5-year survival rates were 58% and 0%, respectively. CONCLUSIONS: Neoadjuvant chemoradiation therapy was given safely to patients with pancreatic and duodenal carcinoma. It facilitated complete resection in 38% of patients with pancreatic carcinoma and 80% of those with duodenal carcinoma. A significant downstaging of positive margins and regional lymph nodes occurs as a result of preoperative chemoradiation.

Adenocarcinoma↗