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Biomedical subjects

R R Paladugu

Publications and source records attributed to R R Paladugu.

At least 19 recordsLinked to original sources
PubMed1990

Effects of 5-azacytidine in Syrian golden hamsters: toxicity, tumorigenicity, and differential modulation of bronchial carcinogenesis.

5-Azacytidine (AZC) was studied in a lung cancer model in outbred and syngeneic (F1D) hamsters wherein benzol[a]pyrene (BP) from sustained release implants (SRI) induces preneoplastic mucosal changes which progress to bronchogenic cancer. In pilot studies to evaluate AZC toxicity, a dose schedule of 5 mg/kg biweekly was found suitable and was then used for long-term administration in all subsequent studies. Three groups of outbred hamsters were studied: BP SRi alone (n = 60), BP SRI + AZC (n = 60), and AZC alone (n = 54). AZC treatment was begun 3-5 days after SRI placement. Sixty-one days after the start of the experiment, seven or eight hamsters were sacrificed from each group. Later sacrifices were at 3-week intervals in groups receiving BP SRI and at 6-week intervals in the AZC only group. Four groups of F1D syngeneic hamsters were studied: BP SRI alone (n = 50); BP + AZC starting 3-5 days after SRI placement and continuing until death (n = 52); BP + AZC from 3 to 5 days until 75 days after SRI placement (n = 49); BP + AZC starting 80 days after SRI placement and continuing until death (n = 52). Hamsters (n = 9-14) from each group were sacrificed at 120, 150, 180, and 220 days after SRI implantation. AZC alone was not carcinogenic under these conditions. Both outbred and F1D hamsters treated with early or continuous AZC had slower rates of neoplastic change from BP SRI than did animals receiving BP SRIs alone or BP + late AZC. The incidence of epidermoid cancer were the same for all regimens, but the tumors in those receiving AZC early in carcinogenesis were smaller than in those receiving late or no AZC. The incidences of nonepidermoid cancer were lower in those receiving AZC during early carcinogenesis, and larger tumors were noted in the absence of AZC. Thus, within the study period in this unique hamster lung cancer model, AZC given early in carcinogenesis inhibited only the later (promotional) phase of BP epidermoid carcinogenesis, but inhibited all phases of nonsquamous cancer development induced by BP. This differential modulation of bronchial carcinogenesis, which occurs from AZC given during preneoplastic stages, may prove useful for delineating molecular mechanisms underlying specific phenotypic types of bronchogenic cancers.

Animals↗
PubMed1987

Differential susceptibility to bronchial carcinogenesis in syngeneic hamsters.

Previous studies of chemical carcinogenesis in the lung of Syrian golden hamsters have utilized outbred (nonsyngeneic) animals. Using the endobronchial sustained release implant technique, which causes focally originating cancers in outbred hamsters, we studied the course of bronchial carcinogenesis in two varieties of syngeneic Syrian golden hamsters, the LSH and the F1D strains (BIO 15.16 male X BIO 87.20 female). With either 10% benzo(a)pyrene or 10% methylcholanthrene sustained release implants the time course of epithelial transition from normal to neoplastic was the same for F1D hamsters as previously described for outbred hamsters. Using 10% benzo(a)pyrene sustained release implants the incidence of cancers as a function of time was significantly lower (P less than 0.001) in LSH hamsters as compared to outbred and F1D animals. Of 19 tumors transplanted into syngeneic F1D hamsters, 16 have been successfully propagated by serial transplantation. We conclude that (a) F1D hamsters are comparable to outbred animals in the response of their bronchial epithelium to endobronchial benzo(a)pyrene and methylcholanthrene, (b) there are significant differences in susceptibility to bronchial chemical carcinogenesis among hamster strains, thereby giving opportunity to study potential genetic control mechanisms during bronchial carcinogenesis, and (c) F1D hamsters are suitable for studies of lung cancer biology using tumor transplantation methods.

Animals↗
PubMed1986

Carcinogenesis in heterotopic respiratory epithelium in canine subcutaneous bronchial autografts.

Short bronchial segments obtained by pneumonectomy were implanted, 9-12 per dog, in the subcutaneous tissues of the back of seven dogs. These subcutaneous bronchial autografts (SBA) became vascularized, and they contained viable, histologically normal respiratory epithelium 4 wk after implantation. From 1-3 mo after implantation, 10% methylcholanthrene in steroid suspension medium was instilled into 21 SBAs, and 10% methylcholanthrene in a silicone polymer sustained release implant was placed in 22 SBAs. Ten SBAs were left carcinogen free as controls. SBA contents were examined cytologically at 3-mo intervals. Biopsies were done from 2-32 mo after carcinogen implantation. Progressive preneoplastic changes were noted in all five dogs which received carcinogen. Curetments of five SBAs after 14-mo exposure to methylcholanthrene yielded 10(4)-10(5) cells from each SBA; 40-70% of the cells obtained were at the same stage of atypical squamous metaplasia. At least one SBA in each dog yielded cancer cells by cytological criteria by 19-29 mo after instillation. Biopsy of a grossly abnormal SBA revealed well-differentiated epidermoid carcinoma at 32 mo. The multiple SBA method provides isolated portions of canine respiratory epithelium for the study of chemical carcinogenesis and for the production of sizable preneoplastic cell populations.

Animals↗
PubMed1986

Endobronchial carcinogenesis in dogs.

A canine model of squamous cell lung cancer has been developed through studies with 110 dogs exposed by 11 focal endobronchial regimens to chemical carcinogens: benzo(a)pyrene, nitrosomethylurea, methylcholanthrene, and dimethylbenzanthracene. A combination of nitrosomethylurea and benzo(a)pyrene caused the first invasive cancer after 5.5 years. Toxic side-effects resulted from either nitrosomethylurea or high-dose dimethylbenzanthracene given by bronchial submucosal injection and from adjuvant immunosuppression with azathioprine and corticosteroids. Four regimens in 58 dogs caused 31 cancers, including five T1-2 N0 M0 cancers, 17 metastasizing carcinomas, and nine carcinomas of lesser stages. The following regimens caused cancers: sequential benzo(a)pyrene, nitrosomethylurea, and yttrium 91; benzo(a)pyrene and topical nitrosomethylurea; low-dose dimethylbenzanthracene; high-dose methylcholanthrene. The most suitable regimen to date has been 30 mg of methylcholanthrene given by submucosal injection every 2 to 3 weeks; this produced cancers at preselected sites within 2 years of first exposure in eight of 10 dogs. The neoplastic continuum has followed a predictable, reproducible sequence that regularly began with epithelial hyperplasia. Squamous metaplasia occurred in 6 to 18 weeks; it was followed by progressive squamous atypia. The interval until invasive cancer developed varied with the regimen employed; it was about 20 months with methylcholanthrene. Serial cytologic specimens, studied by image analysis, revealed progressive increase in mean total cellular deoxyribonucleic acid content from diploid in normal cells to greater than tetraploid in cancer cells (p less than 0.01). We have recently been successful with serial passage of four canine lung cancers from four to twelve transplant generations in nude mice. There is now a predictable large animal model of squamous cell lung carcinoma at preselected site(s) that closely resembles human lung cancer. The preneoplastic period is short enough to be fiscally defensible, but long enough to permit study of the biologic changes during endobronchial carcinogenesis.

Adenocarcinoma↗
PubMed1985

Bronchopulmonary Kulchitzky cell carcinomas. A new classification scheme for typical and atypical carcinoids.

Typical and atypical carcinoids constitute less than 5% of lung tumors. They and small cell undifferentiated lung cancers (SCLC) belong to the same family of apudomas arising from bronchopulmonary Kulchitzky cells. To reflect the overlap among these cancers, the authors suggest calling them Kulchitzky cell carcinomas (KCC); to indicate their spectrum of aggressiveness, the authors suggest calling typical carcinoids KCC-I, atypical carcinoids KCC-II, and small cell cancers KCC-III. One hundred fifty-six KCCs were reviewed: 115 were KCC-I and 41 were KCC-II. The ratio of women to men equals 2:1. At time of initial diagnosis, all patients with KCC-I, except one patient, were in Stage I. Among patients with KCC-II, 16 (39%) were in Stages II or III at time of presentation. The incidence of carcinoid syndrome was 1.9%. Treatment was lobectomy in 112 (72%) of patients, the remainder having lesser resections or pneumonectomy in approximately equal distribution. Our data cannot support the use of radical resection in the treatment of KCC because none of the patients died of local recurrence. The mean diameters of KCC-I and -II tumors were 1.5 and 2.8 cm, respectively. Increased mitotic activity and tumor necrosis were reliable criteria for diagnosing KCC-II. Electron microscopic examination did not help in differentiating KCC-I and KCC-II. Thorough sampling of the entire tumor was found to be mandatory for precise diagnosis and for differentiation from KCC-III (SCLC). Measurement of nuclear DNA was done using integrated optical density (IOD) by image analysis. The IODs of KCC-I, -II and -III were 1.36, 1.55 and 1.94, respectively. These significant differences (P less than 0.001) correlated with the aggressiveness of the cancers. Of patients with KCC-I, 1.7% succumbed to KCC; this included one patient reported to have died of KCC-III (SCLC). Of 41 patients with KCC-II, 11 (27%) died of KCC; this includes at least 3 deaths from KCC-III.

Adolescent↗
PubMed1985

Clonal evolution of T-cell prolymphocytic leukemia to a T-large-cell lymphoma. A morphologic and immunologic study.

We describe a patient with T-cell prolymphocytic leukemia who developed a large-cell lymphoma of the T-cell type. The neoplastic cells of the large-cell lymphoma demonstrated the same immunologic phenotype (ER+, Leu-3+, Leu-2-, and HLA ABC+) as the cells of the prolymphocytic leukemia, which indicated a clonal evolution of a T-cell prolymphocytic leukemia into a large-cell lymphoma of the T-cell phenotype.

Aged↗
PubMed1984

Carcinogenesis in canine bistomal heterotopic tracheal grafts.

Successful canine lung cancer models have required repeated focal bronchial carcinogen exposure under general anesthesia. To simplify serial studies of the respiratory mucosa during carcinogenesis, bistomal autologous heterotopic tracheal pedicle grafts have been made. These grafts can readily be returned to the original orthotopic site, and this has been shown to be a method with which to study reversibility of mucosal changes. Polycyclic aromatic hydrocarbons were applied topically to the mucosa three times a week for 21 to 22 months in 21 grafts. Implants of Silastic polymer from which carcinogen was released in sustained-release fashion were then left in the grafts for 4 to 6 weeks. Serial cytological and histological examinations showed development of atypical squamous metaplasia in the graft mucosa. Mucosal papillomatosis was noted in 4 of 7 grafts surgically excised 17 to 18 months after completion of carcinogen exposure. The heterotopic bistomal tracheal graft provides a useful method for studying respiratory epithelial carcinogenesis without repeated general anesthesia.

Animals↗
PubMed1984

Steroid-withdrawal radiation pneumonitis in cancer patients.

Two cancer patients developed steroid-withdrawal radiation pneumonitis. This complication is a recognized risk in the treatment of patients with Hodgkin's disease and other malignant lymphomas, but is under-recognized in patients receiving treatment for carcinoma.

Adenocarcinoma↗
PubMed1983

Glassy cell carcinoma of the cervix. Cytologic and clinicopathologic analysis.

A clinicopathologic analysis of 15 patients with glassy cell carcinoma confirmed that this is a rare disease, having an incidence of 1.2%. It is a rapidly progressive and biologically aggressive disease with early extrapelvic metastasis. The five-year survival and the median survival in our series were 28% and 14 months, respectively. The majority of patients (87%) were understaged, which may have played a role in the poor prognosis. Four of 12 patients (33%) were initially diagnosed as having a benign disease (false-negatives). Defining of cytologic characteristics and differential features of this tumor may facilitate an early and more accurate diagnosis to improve prognosis.

Adenocarcinoma↗
PubMed1983

Acral lentiginous melanoma. A clinicopathologic study of 36 patients.

Acral lentiginous melanoma (ALM) is a distinct variant of malignant melanoma with a predilection for the soles, palms, and nail beds. This melanoma has characteristic histologic features, and its biologic behavior is similar to that of nodular melanoma. It occurs predominantly in the sixth, seventh, and eighth decades of life, with a peak incidence in the seventh decade for males and in the sixth decade for females. Diagnosis of ALM during the radial growth phase is often difficult, and it may not be recognized initially, but treatment in this phase offers an excellent prognosis. There is a high incidence of regressive changes and desmoplasia in ALM; these changes, together with the anatomic peculiarities of nail beds, palms, and soles as compared with other skin areas, make it difficult to determine the Clark's level and to measure the depth of invasion. Wide local excision with lymph node dissection is recommended for subungual melanomas measuring more than 1.00 mm and for lesions showing severe regression. Volar melanomas less than 1.00 mm deep and those in the radial growth phase with minimal invasion require only wide local excision. Amputation of digits and lymph node dissection are recommended for subungual melanomas, if the melanomas exhibit the vertical growth phase. If there is only radial growth without regressive changes, wide local excision is adequate. Patients with metastasis to lymph nodes at the time of diagnosis usually have shorter survival times than do those without lymph node involvement (P = 0.027).

Adolescent↗
PubMed1983

Biologic behavior of thin malignant melanomas with regressive changes.

Thin cutaneous malignant melanomas are defined as lesions measuring less than 0.76 mm in maximal thickness. Eight of the 36 thin lesions that we studied metastasized within two to 120 months. Of the 11 lesions with regressive features, five (45.5%) metastasized. Of 25 lesions without regression, only three (12%) metastasized. Thin melanomas with regressive changes need to be reported as a separate category because of their propensity to metastasize. Conventional prognostic guidelines for treatment of thin melanomas are not applicable to this type of lesion. Clinicians need to be cognizant that regressive changes are serious warning signals when they occur in thin melanomas.

Adult↗
PubMed1982

Carcinoma of the larynx with mucosubstance production and neuroendocrine differentiation: an ultrastructural and immunohistochemical study.

Primary neuroendocrine tumors of the larynx appear to be extremely rare. We report a case of well-differentiated neuroendocrine carcinoma arising in the larynx of a 61-year-old white woman. This case was initially diagnosed as a lymph node metastasis in the neck from an unknown primary carcinoma. Extensive workup subsequently revealed that the larynx was the primary site of the tumor. An electron microscopic study of both the primary and metastatic tumors showed numerous neurosecretory-type granules. Immunohistochemical studies revealed positive immunoreactivity against calcitonin, somatostatin, and ACTH. However, the tumor also displayed focal exocrine differentiation and mucosubstance production. The patient underwent a supraglottic laryngectomy and radical neck dissection and was free of tumor 22 months postoperatively.

Adrenocorticotropic Hormone↗
PubMed1981

A clinically relevant canine lung cancer model.

Research on early human lung cancer is difficult; we have sought a canine correlate. Regimens included endobronchial submucosal injections and topical focal applications of benzo[a]pyrene, nitrosomethylurea, dimethylbenzanthracene, and methylcholanthrene, singly or in combinations. Sustained-release discs were placed into lung parenchyma or sutured into major bronchi. Tracheal segments were isolated as cervical pedicle grafts. Gross and histological evolution was reproducible. Columnar and basal hyperplasia and squamous metaplasia were early changes. Atypia occurred within 6 weeks and was found in all dogs within 16 to 18 weeks. Invasive cancers occurred within 8 to 65 months. No tracheal graft developed cancer. Of 15 dogs with parenchymal sustained-release implants, 1 to date has developed cancer in 8 months. Four endobronchial regimens have produced 16 cancers in 56 lungs at risk for 18 to 65 months. No cancers developed in 23 lungs at risk from eight other regimens. Of 10 dogs at risk for unilateral endobronchial cancer, 5 have had cancer. Of 23 dogs with both lungs at risk, 9 developed cancer. We have shown focal carcinogenesis with well-defined pathogenesis and an extended preneoplastic period at predictable sites in a lung cancer model.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Malignant lymphoma with primary manifestation in the gonad: a clinicopathologic study of 38 patients.

This study is based on 38 patients, each of whom had a malignant lymphoma in which the gonad was the site of the main tumor mass at the time of diagnosis. Histiocytic lymphoma was the predominant type in the 27 male patients; in the 11 female patients, poorly differentiated lymphocytic lymphoma was the most frequent type (36%). All of the neoplasms in the males were diffuse, whereas two of the females had neoplasms that were nodular and diffuse. A striking feature was the high frequency of vascular invasion (41%) in the testicular lymphomas, which was reflected in a high incidence (86%) of noncontiguous lung involvement at autopsy, suggesting hematogenous spread. Clinically occult disease is probably responsible for the short interval between the discovery of a gonadal mass and the appearance of generalized disease. A poor prognosis may be expected if there is evidence of generalized disease within one year after diagnosis. Only 2 patients had disseminated disease after a year, whereas all those who died of disseminated disease manifested it within six months after diagnosis. Disease-freee survival times in excess of 60 months in 3 patients who were treated only by orchiectomy or oophorectomy indicate that the gonads may be the primary site of a malignant lymphoma.

Adolescent↗
PubMed1980

Induction of lung cancers in preselected, localized sites in the dog.

Cancers were induced in 10 dogs in preselected sites within the lung. These 10 animals were among 89 dogs enrolled in 10 protocols with different carcinogens, doses, and techniques over 6 years. The 10 dogs that developed cancers were included in five of these protocols; 4 of the cancers were included in one of the protocols. The administered carcinogens included the aromatic hydrocarbons benzo[a]pyrene (BP), N-methyl-N-nitrosourea (MNU), 7, 12-dimethylbenz[a]anthracene (DMBA), 3-methylcholanthrene (MCA), and yttrium-91 (91Y) beta radiation. The techniques of application included intrabronchial and intrapulmonary sustained-release implants of DMBA and 91Y, serial intrabronchial submucosal injections of BP, DMBA and MCA, or topical application of MNU. The intervals from the first application of a carcinogen to the diagnosis of malignant disease ranged from 8 to 56 months. Of the tumors induced, 9 were centrally located squamous cell carcinomas and 1 was a peripherally located carcinosarcoma. Four of the dogs were killed or died with stage 3 disease. The remaining 6 dogs are alive and are being evaluated serially; all 6 are in stage 1.

Animals↗
PubMed1979

Bone marrow transplantation for acute leukemia using a histocompatible paternal donor.

A bone marrow transplantation from an HLA-identical, MLC nonreactive paternal donor has been performed in a patient with acute lymphoblastic leukemia resistant to drug treatment. Prompt engraftment was documented; however, the patient died of interstitial pneumonitis due to cytomegalovirus 65 days after transplant. Clinical manifestation of graft-versus-host reaction was mild. Recurrence or persistence of leukemia was found at the time of death using cytogenetic markers and determination of the leukemic marker enzyme terminal deoxynucleotidyl transferase.

Bone Marrow↗
PubMed1978

Bone marrow transplantation between mixed leukocyte culture reactive siblings.

Bone marrow transplantation from an HLA identical MLC reactive sibling has been performed in a patient with acute myelogenous leukemia resistant to drug treatment. Prompt engraftment was documented; however, the patient died of septicemia 34 days after transplant. Clinical manifestation of graft vs. host reaction was mild but was moderately strong expressed at autopsy tissue samples. Recurrence of persistence of leukemia was found at the time of death.

Adult↗