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Biomedical subjects

S S Frankel

Publications and source records attributed to S S Frankel.

31 records · Page 2Linked to original sources
PubMed1996

Lymphoid changes of the nasopharyngeal and palatine tonsils that are indicative of human immunodeficiency virus infection. A clinicopathologic study of 12 cases.

We report 12 cases in which the histomorphologic changes of the nasopharyngeal tonsils (adenoids) or palatine tonsils suggest infection with the human immunodeficiency virus (HIV). The patients included 10 men and two women, aged 20 to 42 years (median, 33 years). The clinical presentation included airway obstruction, pharyngitis, fever, and a tonsillar or adenoidal mass lesion. Histologic evaluation of the excised adenoids or tonsils in 10 of the cases demonstrated a spectrum of changes including florid follicular hyperplasia, follicle lysis, attenuated mantle zone, and the presence of multinucleated giant cells (MGC). The latter characteristically localized adjacent to the surface or tonsillar crypt epithelium. Two of the 12 cases showed marked lymphoid depletion with absent germinal centers, plasmacytosis, and stromal vascular proliferation. Immunohistochemical evaluation for HIV p24 core protein showed reactivity in 10 of 12 cases localized to follicular dendritic cell network (FDC), the MGC, scattered interfollicular lymphoid cells, and cells identified within the surface or crypt epithelium. Localization of viral RNA by in situ hybridization paralleled the HIV p24 immunohistochemical findings. Additional significant findings included the presence of both CD-68 and S-100 protein in the MGC and the presence of S-100 protein in dendritic cells. Other than HIV, no microorganisms were identified. At the time of presentation, eight patients were not known to be a risk for HIV infection, nor were they known to be HIV infected or suffering from AIDS. In these patients, HIV infection was suspected on the basis of the histologic changes seen in the resected tonsillar and adenoidal tissue. Serologic evaluation (by enzyme-linked immunosorbent assay), confirmed the presence of HIV infection. Our findings suggest the possibility of HIV dissemination through the upper aero-digestive tract mucosa via target cells, such as intraepithelial dendritic cells, submucosal macrophages, and T-lymphocytes. Subsequent presentation of viral antigens to the tonsillar and adenoidal lymphoid tissues results in enlargement of these structures that clinically may simulate a neoplastic proliferation but causes histomorphologic changes that are highly suspicious for HIV infection even in asymptomatic HIV-positive patients.

Adenoids↗
PubMed1996

Ultrastructure of normal armadillo epidermis.

In view of the importance of the nine-banded armadillo (Dasypus novemcinctus) in leprosy research, we studied the ultrastructure of the normal epidermis of this species. The three basic cell types of human epidermis were identified in armadillo skin: keratinocytes, melanocytes, and Langerhans' cells. The role of Langerhans' cells in the human cell-mediated immune system and the description of changes in the number and structure of Langerhans' cells in human leprosy make detailed observations of these cells in the armadillo highly relevant. Clear cells with ultrastructural features typical of Langerhans' cells were observed in normal armadillo epidermis in all areas of skin sampled (abdomen, chin, ear, and thigh), but are fewer than in human skin. These baseline findings are valuable for further studies on Langerhans' cells and the cell-mediated immune function in armadillos with naturally acquired or experimental leprosy.

Animals↗
PubMed1990

Simultaneous pulmonary and renal malignancy.

Simultaneous primary malignancy of the lung and kidney has been rarely recognized during life. Three patients with synchronous primary pulmonary and renal cancer are described. The pulmonary tumors were asymptomatic and were discovered on plain chest roentgenography. The renal tumors, also asymptomatic, were incidentally discovered on CT, performed for staging. Although one patient was treated with interleukin-2 for a presumed solitary pulmonary metastasis from renal carcinoma, in all three patients, both the kidney and lung tumors were eventually removed either concurrently or sequentially. Prior autopsy case series are reviewed. In the elderly, synchronous asymptomatic pulmonary and renal malignancy is not surprising, and it should be approached as a distinct clinical problem. With the use of chest roentgenography for screening high risk populations and CT for staging, simultaneous primary pulmonary and renal malignancy will probably be recognized increasingly.

Adenocarcinoma↗
PubMed1985

Phase I and pharmacologic study of oral ftorafur and X ray therapy in advanced gastrointestinal cancer.

We have treated 15 patients with advanced gastrointestinal carcinoma with a cyclical regimen of combined Ftorafur (N1-((2-furanidyl-))-5-Fluorouracil, a 5-FU pro-drug) and external beam radiation. The Ftorafur (FT) was administered orally in daily doses of between 1.0 and 2.5 g/m2/day in 3 divided doses in a Phase I format. The drug was given daily for 5 days along with conventional X ray treatment portals and daily radiation doses of 250 rad on each of the first 4 days of each treatment cycle. The patients were then rested for a minimum of 10 days or until all significant side effects had passed. The total number of 1,000 rad cycles and radiation dose were dictated by tolerance and by normal organ dose limitations. The most common toxicity in general, and the most common limiting toxicity was nausea and vomiting, in contrast to oral FT alone where diarrhea is more prominent. Stomatitis was seen only once and no other form of serious toxicity was encountered. Two-thirds of the patients responded in subjective terms (pain relief). There was 1 partial response to FT alone (pulmonary metastases outside the treatment field). The sole patient whose treatment field was outside the abdomen (chest portals for esophageal carcinoma) developed pneumonitis which contributed to his death. No other delayed effects were noted. Serum FT levels were related to the ingested dose and in the microgram range while serum 5-FU levels were in the nanogram range indicating slow decomposition of FT into 5-FU. The therapy was reasonably well tolerated at doses of 2.0 g/m2/day or lower with abdominal radiation. FT offers the potential for replacing intra-venous infused 5-FU as a clinical radiosensitizer.

Administration, Oral↗
PubMed1985

Phase I and pharmacologic study of 72-hour infused 5-fluorouracil and hyperfractionated cyclical radiation.

We have studied 21 patients infused for 72 hours with 5-Fluorouracil (5-FU) at progressive doses combined with hyperfractionated radiation. The schedule was chosen as being one capable of inducing 5-FU radiosensitization (RS). All patients were started at a daily 5-FU dose of 40 mg/kg/24 hours; doses were then escalated with each subsequent treatment cycle to limiting toxicity or until taken off study. Patients received between one and six infusion cycles. Every treatment cycle included coincident hyperfractionated radiation to various body areas including the abdomen, chest, and head and neck region. Radiation fractionation was invariant; 1,000 rad were delivered in four equal fractions. Two fractions of 250 rad each were given on days 1 and 2 of each three day 5-FU cycle, i.e. at approximately 0, 8, 24, and 32 hours into the drug infusion. Patients were followed for toxicity; serum 5-FU concentrations were determined using a high pressure liquid chromatographic assay. 5-FU clearances were calculated from the mean serum drug levels and the infused drug dose. The toxicity spectrum was not found to be significantly different from infused drug alone in this dose range save when the head and neck region received coincident irradiation. In that region the two anticipated toxicities combined in what appears to be a synergistic fashion to enhance mucositis. Most toxicities including gastrointestinal and bone marrow appeared dependent on the mean serum 5-FU level as did mucositis itself. 5-FU clearance was found to be non-linear in this dose region but did not appear influenced by radiation to any part of the body. This study shows that 72-hour infused 5-FU can be combined with external beam radiation and will produce reasonably predictable toxicity patterns which depend on the region of the body being irradiated. 5-FU toxicity correlates with mean serum drug level which is itself dependent on 5-FU clearance. Minor variations in 5-FU clearance therefore probably contribute to the natural range found in the dose-response relationship for infused 5-FU toxicities. Future studies should integrate this understanding of 5-FU pharmacokinetics into treatment regimens. The combination of infused 5-FU and coincident radiation appears useful in treating several tumor types, particularly squamous and squamous-like cancers. However, further scheduling and radiation fractionation studies are desirable to optimize 5-FU RS in man and to quantify late effects.

Combined Modality Therapy↗
PubMed1985

Phase I and pharmacologic study of 72-hour infused 5-fluorouracil in man.

The relationships between the administered dose, clearance, and the toxicity spectrum of 5-fluorouracil (5-FU) administered as 72-hour constant infusion have been studied in 21 patients with advanced cancer. This was done as a pilot study for possible future combination using 5-FU as a radiosensitizer. Individual patients tolerated up to 65 mg/kg/24 hours, but serious toxicity appeared once as low as 35 mg/kg. Limiting toxicity proved to be "mixed" with upper intestinal symptoms (nausea and vomiting), stomatitis, and central nervous system signs all occurring in various patients. Central nervous system effects (both cerebellar and vomiting) proved as troublesome as stomatitis. There was only a general link between the administered dose and the subsequent toxicity grade, but a reasonably quantitative relationship emerged when the serum 5-Fu levels obtained and the degree of patient toxicity were compared. The clearance of 5-FU was confirmed to be nonlinear over the entire dose range studied (25-65 mg/kg/24 hours), consistent with a two-compartment model of drug metabolism. One compartment appears to be systemic (extra-hepatic) metabolism (probably anabolic removal) which is saturated at just below 15 mg/kg/day. Doses above that level lead to drug accumulation. No steady state was reached, contrary to previous reports. At the higher infusion rates, clearance progressively approaches that predicted by the assumption that the second compartment is splanchnic blood flow and catabolism. While 5-FU can be administered as a 72-hour infusion as one possible schedule for use as a single agent or for combined modality studies, CNS effects are quite troublesome in comparison to longer infusions to toxicity.

Drug Evaluation↗
PubMed1985

Relevance of the pharmacology of oral tegafur to its use as a 5-FU pro-drug.

We have studied the pharmacology of iv and oral tegafur (FT) and compared the results with similar studies using continuously infused 5-FU. All patients received daily abdominal irradiation as well as FT. In eight patients receiving 1.0 g/m2 of iv FT, serum FT levels were essentially the same as those in five patients receiving the same dose of oral FT. Oral FT appeared well-absorbed, even with abdominal irradiation. The mean serum FT achieved on a daily basis was a linear function of the oral FT dose between 1.0 and 2.5 g/m2 and was consistently about 1000-fold higher than the resultant 5-FU level. The major FT metabolite, dehydro-FT (DHFT), was persistently present at about ten times the 5-FU level. Because of their long half-lives, both FT and DHFT accumulate during continuous therapy. When the mean serum 5-FU levels with oral FT were compared to those found during continuous 5-FU infusions, we found that oral FT was the equivalent of low-level 5-FU infusion. Oral FT at 1.0 g/m2 was the equivalent of about 11.5 mg/kg/24 hours of 5-FU, increasing to about 17.5 mg/kg of 5-FU for oral FT at 2.5 g/m2. The pharmacologic properties of FT appear to dictate its most useful schedule (continuous oral dosing in multiple doses) and explain why FT alone is not ideal as a 5-FU pro-drug. In addition, insight into the pharmacokinetic limitations of FT also suggests means by which its usage may be improved, including its potential application as a radiosensitizer.

Administration, Oral↗
PubMed1984

Treatment with combined intra-arterial 5-FUdR infusion and whole-liver radiation for colon carcinoma metastatic to the liver. Preliminary results.

Twenty-eight patients with colon carcinoma metastatic to the liver were treated with continuously infused intra-arterial 5-fluorouracil deoxyriboside (5-FUdR) and cyclical whole-liver radiation (2000-3000 rad). Survivorship ranged from 25 days to almost 4 years and was a clear function of the extent of liver dysfunction at the time of initiation of this treatment. Difficulties in establishing the objective complete response rates in patients with minor imaging abnormalities were frequently noted. Both extracorporeal and permanently implanted arterial infusion devices have been employed, the results favoring the internal infusion units. Under ideal circumstances (early treatment, disease limited to the liver, and a permanent indwelling pump), a median survivorship of approximately 2 years can be projected with a significant number of patients rendered free of progressive cancer in the liver for months to years. The dose-limiting feature of this approach is treatment-related to hepatitis, which proved lethal in one of 28 patients thus far treated. Preclinical studies on the original and reduction of drug- and x-ray-induced liver toxicity should have high research priority.

Adult↗
PubMed1984

Phase I and II trial of five-day infused 5-fluorouracil and radiation in advanced cancer of the head and neck.

Eighteen patients with advanced epithelial cancers of the head and neck region were studied for their tolerance and response to combined cycles of 120-hour infused 5-fluorouracil (5-FU) and external-beam radiation therapy. 5-FU infusions were given under conditions where radiosensitization would be expected at the higher infusion doses. Coincident radiation treatments were given as four sequential daily fractions of 250 rad each administered during days 1 through 4 of each five-day infusion cycle. The patients were rested for at least nine days after each cycle or longer until toxicity was resolved. The regimen was then repeated in each patient for a total of five treatment cycles. Thereafter therapy was consolidated, usually by boost radiation without drug. In sequential patient subsets the infusion load was progressively escalated in a phase I format. The complete response rate for stage IV patients was 75% with survival benefit compared to prior results. 5-FU dose-dependent combined modality loco-regional toxicity was demonstrated without significant enhancement of systemic toxicity of any form; 5-FU dose-dependent enhanced responsiveness and survival benefit is also suggested. Further scheduling and response studies of 5-FU under radiosensitizing conditions appear warranted.

Combined Modality Therapy↗
PubMed1983

Phase I-II study of 120-hour infused 5-FU and split-course radiation therapy in localized non-small cell lung cancer.

Thirty patients with locally advanced nonresectable non-small cell bronchogenic carcinoma were studied for tolerance and response to 120-hour continuously infused 5-FU (IFU) combined with chest x-ray therapy. The IFU was escalated in patient groups from 20 to 35 mg/kg/24 hours. Radiation was also escalated in patient subsets from 200 to 400 rads/fraction using a split-course technique to a total dose of 5000 rads. Tolerance was exceeded by IFU doses of 35 mg/kg/day. The complete response rate was ten of 28 patients (36%); a complete response was associated with a significantly prolonged survival. Radiosensitization of lung cancer by IFU appears clinically feasible in man.

Aged↗
PubMed1982

Clearance of continuously infused 5-fluorouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases.

The steady-state apparent total body clearances (TBC) of continuously infused 5-fluorouracil (5-FU) were determined in 16 adult male patients who were receiving combined 5-FU-radiation therapy. Seven patients (group A) had Stage III adenocarcinoma or epidermoid lung carcinomas; none had known metastases. Five patients had gastrointestinal carcinomas (group B), without known hepatic metastases. Four had gastrointestinal carcinomas with evidence of hepatic metastases (group C). TBCs were calculated from infusion rates and serum 5-FU concentration data. The means (standard errors) of the TBCs were: group A, 4.49 (0.53); group B, 6.51 (0.53); group C, 2.96 (0.91) L/kg/h. The difference among the means was found to be significant (p less than 0.002) by one-way ANOVA. Differences among the groups were then examined using 95 percent confidence intervals: group A was not different from group B or group C; however, groups B and C differed from each other. Patients with hepatic metastases have 5-FU TBCs about half that of those found in patients without hepatic involvement. Clinically, patients in group C attained the higher serum 5-FU concentrations known to be radiosensitizing more frequently than patients in the other two groups; differences in toxicity were not evident. This suggests that administration of an agent that can compete with 5-FU for hepatic metabolism to patients with rapid clearance might improve the therapeutic efficacy of 5-FU.

Adult↗
PubMedDate not supplied

Conservative management without alkylating agents of squamous cell anal cancer using cyclical 5-FU alone and x-ray therapy.

We have treated 11 patients with squamous cell anal carcinoma using a regimen of repeated cycles of 120-hour infused 5-FU (25 mg/kg/24 hours) and x-rays. Total radiation doses were between 3000 (palliative) and 4750 (curative) rads. Unlike all other equivalent combined-modality studies, no alkylating agent or drug other than 5-FU was used. With follow-up between 1 and 4 years, there has been only one local recurrence (coincident with terminal disseminated disease in a stage III patient treated palliatively). All other patients have maintained local control. Inclusion of alkylating agents (eg, mitomycin) in this approach can be questioned if the patient is willing to accept somewhat greater acute but reversible toxic effects.

Alkylating Agents↗