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Results for “Pathologic response”

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PubMed2004

The biochemical response of the heart to hypertension and exercise.

Mechanical stress on the heart can lead to crucially different outcomes. Exercise is beneficial because it causes heart muscle cells to enlarge (hypertrophy). Chronic hypertension also causes hypertrophy, but in addition it causes an excessive increase in fibroblasts and extracellular matrix (fibrosis), death of cardiomyocytes and ultimately heart failure. Recent research shows that stimulation of physiological (beneficial) hypertrophy involves several signaling pathways, including those mediated by protein kinase B (also known as Akt) and the extracellular-signal-regulated kinases 1 and 2 (ERK1/2). Hypertension, beta-adrenergic stimulation and agonists such as angiotensin II (Ang II) activate not only ERK1/2 but also p38 and the Jun N-terminal kinase (JNK), leading to pathological heart remodeling. Despite this progress, the mechanisms that activate fibroblasts to cause fibrosis and those that differentiate between exercise and hypertension to produce physiological and pathological responses, respectively, remain to be established.

Animals↗

PubMed2003

Comparison of Calidria chrysotile asbestos to pure tremolite: inhalation biopersistence and histopathology following short-term exposure.

The differences between chrysotile asbestos, a serpentine mineral, and amphibole asbestos have been debated extensively. Many studies have shown that chrysotile is cleared from the lung more rapidly than amphibole. In order to quantify the comparative clearance of chrysotile and the amphibole asbestos tremolite, both fibers were evaluated in an inhalation biopersistence study that followed the European Commission recommended guidelines. In addition, the histopathological response in the lung was evaluated following the short-term exposure. This article presents the results of this study through 90 days after cessation of exposure. Following the termination of the study, a subsequent article will provide the complete results through 12 mo after cessation of exposure. In order to quantify the dynamics and rate by which these fibers are removed from the lung, the biopersistence of a sample of commercial grade chrysotile from the Coalinga mine in New Idria, CA, of the type Calidria RG144 and of a long-fiber tremolite were studied. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 microm has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and the histopathological response. As the long fibers have been shown to have the greatest potential for pathogenicity, the aerosol generation technique was designed to maximize the number of long respirable fibers. The chrysotile samples were specifically chosen to have 200 fibers/cm3 longer than 20 microm in length present in the exposure aerosol. These longer fibers were found to be largely composed of multiple shorter fibrils. The tremolite samples were chosen to have 100 fibers/cm3 longer than 20 microm in length present in the exposure aerosol. Calidria chrysotile fibers clear from the lung more rapidly (T1/2, fibers L > 20 microm = 7 h) than any other commercial fiber tested including synthetic vitreous fibers. With such rapidly clearing fibers, the 5-day exposure would not be expected to result in any pathological change in the lung, and the lungs of animals that inhaled Calidria chrysotile showed no sign of inflammation or pathology and were no different than the lungs of those animals that breathed filtered air. Following this 5-day exposure to tremolite, the tremolite fibers once deposited in the lung parenchyma do not clear and almost immediately result in inflammation and a pathological response in the lung. At the first time point examined, 1 day after cessation of exposure, inflammation was observed and granulomas were already formed. By 14 days postexposure these microgranulomas had turned fibrotic, and by 90 days postexposure the severity of the collagen deposits had increased and interstitial fibrosis was observed in one of the rats. These findings provide an important basis for substantiating both kinetically and pathologically the differences between chrysotile and the amphibole tremolite. As Calidria chrysotile has been certified to have no tremolite fiber, the results of the current study together with the results from toxicological and epidemiological studies indicate that this fiber is not associated with lung disease.

Aerosols↗

PubMed2004

Differential expression of cytokines in UV-B-exposed skin of patients with polymorphous light eruption: correlation with Langerhans cell migration and immunosuppression.

BACKGROUND: Disturbances in UV-induced Langerhans cell migration and T helper (T(H)) 2 cell responses could be early steps in the pathogenesis of PLE. OBJECTIVE: To establish whether UV-B exposure induces aberrant cytokine expression in the uninvolved skin of patients with polymorphous light eruption (PLE). DESIGN: Immunohistochemical staining and comparison of microscopic sections of skin irradiated with 6 times the minimal dose of UV-B causing erythema and the unirradiated skin of patients with PLE and of healthy individuals. SETTING: University Medical Center (Dutch National Center for Photodermatoses). Patients Patients with PLE (n = 6) with clinically proven pathological responses to UV-B exposure and normal erythemal sensitivity. Healthy volunteers (n = 5) were recruited among students and hospital staff. MAIN OUTCOME MEASURES: Expression of cytokines related to Langerhans cell migration (interleukin [IL] 1, IL-18,and tumor necrosis factor [TNF] alpha); T(H)2 responses (IL-4 and IL-10); and T(H)1 responses (IL-6, IL-12, and interferon gamma). Double staining was performed for elastase (neutrophils), tryptase (mast cells), and CD36 (macrophages). RESULTS: The number of cells expressing IL-1beta and TNF-alpha was reduced in the UV-B-exposed skin of patients with PLE compared with the skin of healthy individuals (P<.05 for TNF-alpha). No differences were observed in the expression of T(H)1-related cytokines but fewer cells expressing IL-4 infiltrated the epidermis of patients with PLE 24 hours after irradiation (P =.03). After UV exposure TNF-alpha, IL-4, and, to a lesser extent, IL-10 were predominantly expressed by neutrophils. CONCLUSIONS: The reduced expression of TNF-alpha, IL-4, and IL-10 in the UV-B-irradiated skin of patients with PLE appears largely attributable to a lack of neutrophils, and is indicative of reduced Langerhans cell migration and reduced T(H)2 skewing. An impairment of these mechanisms underlying UV-B-induced immunosuppression may be important in the pathogenesis of PLE.

Adult↗

PubMed2003

Automated quantification of apoptosis after neoadjuvant chemotherapy for breast cancer: early assessment predicts clinical response.

PURPOSE: A large body of evidence implicates apoptosis in the effects of cancer chemotherapeutic agents on tumor cells in vitro and tumor xenografts in vivo, but the predictive value of apoptosis as an early marker for clinical response in cancer patients remains unclear. EXPERIMENTAL DESIGN: We developed an automated, laser scanning cytometer-based method to quantify the percentage of tumor cells containing DNA fragmentation characteristic of apoptosis in tumor sections. We measured levels of apoptosis in a panel of 15 matched, 18-gauge core breast cancer biopsies obtained before and 48 h after neoadjuvant therapy with docetaxel plus doxorubicin or paclitaxel as part of two prospective clinical trials. RESULTS: The results revealed a strongly significant (P = 0.0023) association between chemotherapy-induced apoptosis and pathological response. CONCLUSIONS: If the results can be validated in a larger patient cohort, the method could be used to "tailor" therapy to optimize benefit in a patient-specific fashion.

Apoptosis↗

PubMed1979

The understanding and teaching of reaction to pain.

Pain is both the commonest and one of the most enigmatic symptoms in medicine. Its subjective nature renders management difficult and its conceptualization is complex. Reaction to pain cannot be easily generalized; group differences are postulated, based on sex, age, culture, psychiatric diagnosis and personality variables. Early developmental aspects of pain and discussed in animal studies and case reports but little systematic data exist. Experimental findings show the influence on pain response of cognitive and emotional factors. Clinically, the variables determining perception, reporting and reaction to pain are numerous and harder to study scientifically. Acute and chronic pain should be distinguished: the latter is more complicated, leading of ten to diagnostic problems and management stalemates. Discovering the relationship of pain to emotional phenomena, as cause or effect, is difficult, though essential to effective treatment. Various frames of reference apply: e.g., individual medical, familial, and "workmen's compensation" models. Reaction by family, lawyer, or work commission involves potential secondary gain and may reinforce or discourage pathological responses by the patient. The potential of pain for symbolic meaning and its acceptance as a "legitimate" medical symptom renders it ideal for both expression and masquerading of intrapsychic and interpersonal conflicts involving anger, punishment, control and dependency. Teaching about pain and its significance is best done in clinical settings such as obstetrical units and multidisciplinary pain clinics. Videotaped modular presentations with discussion provide a satisfactory though less desirable alternative.

Acute Disease↗

PubMed1991

Resectable gastric carcinoma. An evaluation of preoperative and postoperative chemotherapy.

Patients with locoregional gastric carcinoma often die because of the low rates of curative resection and frequent appearance of distant metastases (mainly peritoneal and hepatic). To evaluate the feasibility of preoperative and postoperative chemotherapy, 25 consecutive previously untreated patients with potentially resectable locoregional gastric carcinoma received two preoperative and three postoperative courses of etoposide, 5-fluorouracil, and cisplatin (EFP). Ninety-eight courses (median, five courses; range, two to five courses) were administered. Six patients had major responses to EFP. Eighteen patients (72%) had curative resections, and three specimens (12%) contained only microscopic carcinoma. At a median follow-up of 25 months, the median survival of 25 patients was 15 months (range, 4 to 32+ months). Peritoneal carcinomatosis was the most common indication of failure. One patient died of postoperative complications, but there were no deaths due to chemotherapy. EFP-induced toxic reactions were moderate. Preoperative and postoperative chemotherapy for locoregional gastric carcinoma is feasible, and additional studies to develop regimens that could result in 5% to 10% complete pathologic responses may be warranted.

Adenocarcinoma↗

PubMed2004

Photodynamic therapy of multiple nonmelanoma skin cancers with verteporfin and red light-emitting diodes: two-year results evaluating tumor response and cosmetic outcomes.

BACKGROUND: Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge. OBJECTIVE: To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers. DESIGN: Open-label, randomized, multicenter, dose-ranging phase 2 study conducted at 4 North American university-based dermatology clinics. PATIENTS: Fifty-four patients with 421 multiple nonmelanoma skin cancers including superficial and nodular basal cell carcinoma and squamous cell carcinoma in situ (Bowen disease). METHODS: A single intravenous infusion of 14 mg/m(2) of verteporfin followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm(2) of red light (688 +/- 10 nm) from a light-emitting diode panel. MAIN OUTCOME MEASURES: Pathologic response of treated sites was assessed at 6 months. Clinical and cosmetic responses were assessed and graded at 6 weeks, 3 months, and 6 months after verteporfin PDT, with optional follow-up visits at 12, 18, and 24 months. RESULTS: The histopathologic response, defined as absence of tumor on biopsy specimens 6 months after verteporfin PDT, ranged from 69% at 60 J/cm(2) to 93% at 180 J/cm(2). At 24 months of follow-up (276 tumors in 31 patients), the clinical complete response rate ranged from 51% at 60 J/cm(2) to 95% at 180 J/cm(2). No significant systemic adverse events were observed; most events occurred at the treated tumor sites and included events such as pain. Overall, 65% (95% confidence interval, 58%-71%) of tumors were judged to have good to excellent cosmesis at 24 months. CONCLUSION: A single course of verteporfin PDT showed treatment benefit for patients with multiple nonmelanoma skin cancers.

Adult↗

PubMed2006

Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region.

PURPOSE: Epidermal growth factor receptor (EGFR) has been associated with radioresistance in solid tumors. Recently a polymorphism in the Sp1 recognition site of the EGFR promoter region was identified. The present study investigated the predictive value of this polymorphism for the outcome of chemoradiation in locally advanced rectal cancer. METHODS AND MATERIALS: The study included 77 patients with locally advanced T3 rectal tumors. Treatment consisted of preoperative radiation therapy at a total tumor dose of 65 Gy and concomitant chemotherapy with Uftoral. Blood samples from 63 patients were evaluated for Sp1 -216 G/T polymorphism by polymerase chain reaction analysis. Forty-eight primary tumor biopsies were available for EGFR immunostaining. Patients underwent surgery 8 weeks after treatment. Pathologic response evaluation was performed according to the tumor regression grade (TRG) system. RESULTS: Forty-nine percent had major response (TRG1-2) and 51% moderate response (TRG 3-4) to chemoradiation. The rates of major response were 34% (10/29) in GG homozygote patients compared with 65% (22/34) in patients with T containing variants (p=0.023). Fifty-eight percent of biopsies were positive for EGFR expression (28/48). The major response rates with regard to EGFR immunostaining were not significantly different. EGFR-positive tumors were found in 83% of the GG homozygote patients compared with 38% of patients with TT or GT variants (p=0.008). CONCLUSIONS: There was a significant correlation between EGFR Sp1 -216 G/T polymorphism and treatment response to chemoradiation in locally advanced rectal cancer. Further investigations of a second set of patient and other treatment schedules are warranted.

Aged↗

PubMed1980

Characteristics and effect of antiinflammatory drugs on adriamycin-induced inflammation in the mouse paw.

A subplantar injection of 5--100 micrograms adriamycin in the mouse hind paw produced a biphasic inflammatory response. The first phase peaked at 2 h while the second, more severe phase peaked at four to five days. The magnitude of inflammation was dose related. Administration of [EH]adriamycin revealed that 78% of the drug was lost from the paw within one day. The loss of the remaining drug followed a biphasic decay curve. The first-phase half-life was 1.2 days, and the second-phase half-life was 16.0 days. Vascular permeability, as measured by the leakage of intravenously administered [125I]albumin, was increased between day 4 and day 8. Pathologically, the paw had mild edema and hemorrhage by 4 h after adriamycin injection. The most severe pathological response was seen at 5 days with diffuse inflammation characterized by edema of the dermis, cellular debris, and mononuclear inflammatory cells. By 10 days the inflammatory response was still present but the edema was milder. The antihistamine diphenhydramine, an H1-blocker, inhibited the first phase of inflammation at the highest dose tested but had no effect on the second phase of inflammation. The antihistamine metiamide, an H2-blocker; the antiserotonin drug, p-chlorophenylalanine; and the antiinflammatory drugs, aspirin, hydrocortisone, and ibuprofen failed to antagonize adriamycin-induced inflammation at 2 h or 5 days after adriamycin injection. Indomethacin reduced the inflammation after 5 days but only at toxic dose levels.

Animals↗

PubMed2025

HMGA2 links morphological evolution and microenvironment dynamics to systemic therapy response in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits significant heterogeneity due to morphological changes and tumor microenvironment dynamics, influencing systemic therapy responses. While the role of high-mobility group AT-hook 2 (HMGA2) in tumor progression has been implicated in other cancers, its significance in ccRCC remains unclear. This study investigates the role of HMGA2 in these processes and its clinical impact. METHODS: Spatial transcriptomics (ST) was performed on primary ccRCC samples to investigate expression trajectories associated with HMGA2 expression and morphological evolution. In metastatic ccRCC cohorts treated with systemic therapy, immunohistochemistry and bulk RNA sequencing data were analyzed to evaluate molecular and clinical features in relation to HMGA2. Single-cell RNA sequencing (scRNA-seq) data were used to explore immune cell populations and their interactions. Based on these findings, multiplex immunohistochemistry (mIHC) assessed spatial distribution, cell-cell interactions, and pathological responses of key immune populations. RESULTS: HMGA2 expression was associated with aggressive morphological patterns, such as solid sheets and rhabdoid/sarcomatoid. ST revealed a progressive increase in HMGA2 expression along the morphological trajectory, marked by a shift from clear to eosinophilic cytoplasm, with eccentric nuclei and prominent nucleoli, and loss of vascular architecture. HMGA2-high tumors exhibited aggressive phenotypes driven by cell cycle, epithelial-mesenchymal transition, and inflammatory signaling pathways. Clinically, patients with high HMGA2 had worse progression-free survival but responded better to immune checkpoint inhibitor combination (Combo-ICI) therapy than to tyrosine kinase inhibitor monotherapy. To assess the immune landscape, scRNA-seq data revealed that HMGA2-high tumors were enriched with progenitor exhausted CD8+ T cells (Tpex), along with increased frequencies of conventional dendritic cell type 1 (cDC1) and inflammatory cDC type 2, which were found to interact with Tpex via ICAM-1. mIHC confirmed that Tpex were enriched among Combo-ICI responders in HMGA2-high tumors, with higher densities and closer proximity to ICAM-1+ cDC1. CONCLUSIONS: These findings suggest that dynamic HMGA2 expression contributes to morphological evolution and modulates immune responses through enhanced Tpex-cDCs engagement, serving as a potential marker for systemic therapy response in ccRCC. However, additional experimental studies are required to validate these mechanisms.

Humans↗

PubMed1995

Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance.

Previous studies in vivo have shown that IL-10 infusion can prevent lethal endotoxic shock. Mice deficient in the production of IL-10 (IL10T) were used to investigate the regulatory role of IL-10 in the responses to LPS in three experimental systems. In a model of acute endotoxic shock, it was found that the lethal dose of LPS for IL10T mice was 20-fold lower than that for wild type (wt) mice suggesting that endogenous IL-10 determines the amount of LPS which can be tolerated without death. The high mortality rate of IL10T mice challenged with modest doses of LPS was correlated to the uncontrolled production of TNF as treatment with anti-TNF antibody (Ab) resulted in 70% survival. Additional studies suggested that IL-10 mediates protection by controlling the early effectors of endotoxic shock (e.g., TNF alpha) and that it is incapable of directly antagonizing the production and/or actions of late appearing effector molecules (e.g., nitric oxide). We also found that IL10T mice were extremely vulnerable to a generalized Shwartzman reaction where prior exposure to a small amount of LPS primes the host for a lethal response to a subsequent sublethal dose. The priming LPS dose for IL10T mice was 100-fold lower than that required to prime wt mice implying that IL-10 is important for suppressing sensitization. In agreement with this assumption, IL-10 infusion was found to block the sensitization step. Interestingly, IL-10 was not the main effector of endotoxin tolerance as IL10T mice could be tolerized to LPS. Furthermore, IL-10 infusion could not substitute for the desensitizing dose of LPS. These results show that IL-10 is a critical component of the host's natural defense against the development of pathologic responses to LPS although it is not responsible for LPS-induced tolerance.

Animals↗

PubMed1999

Preoperative treatment of advanced skin carcinoma with cisplatin and bleomycin.

In advanced skin carcinomas of the head and neck region, the tumor may be unresectable or curative resection or radiation may either fail or produce poor functional and cosmetic results. The goal of this study was to test the ability of preoperative chemotherapy to decrease the extent of needed resection and tumor response. Five patients, three with squamous cell carcinoma and two with basal cell carcinoma, were treated before surgery with three cycles of cisplatin 20 mg/m2 daily for 4 days and bleomycin 20 mg/day for 4 days by continuous infusion every 3 weeks. All patients had advanced cancer in the head and neck region, one had unresectable tumor, two had xeroderma pigmentosum, and one was a 13-year-old child. The history of prior treatments was as follows: radiation therapy (n = 3), systemic chemotherapy (n = 1), surgery (n = 1), and no treatment (n = 1). One patient had complete clinical but not pathologic response, three had partial response, and one had progressive disease. The extent of resection after chemotherapy was dramatically reduced in the patient with a complete response and minimally changed in the patients with partials responses and progressive disease. All patients who underwent surgery became tumor free. Preventable toxicity was symptomatic hypomagnesemia in one patient, reversible elevation of creatinine in one patient, and mild nausea and vomiting in three patients. With this report, the total number of patients with nonmelanoma skin cancer who were treated with cisplatin is 68, and their overall response is 80%. Only 16 reported patients were treated with preoperative chemotherapy, and study of this treatment approach to advanced skin cancer should be pursued.

Adolescent↗

PubMed1999

Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer.

PURPOSE: The objective of this prospective study was to assess the feasibility, toxicity, and efficacy of an intensive trimodality approach in stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-four patients with NSCLC and biopsy-proven N2 nodes (IIIA; n = 25) or N3 nodes or T4 lesions (IIIB; n = 29) were administered two initial cycles of ifosfamide, carboplatin, and etoposide; subsequent radiotherapy (45 Gy, twice-daily 1.5 Gy) with concurrent carboplatin and vindesine; and surgery if the patient's disease was resectable or conventional radiotherapy (16 Gy, 2 Gy/d) if the patient's disease was not resectable or incompletely resectable. RESULTS: Thirty-seven patients (69%) responded to preoperative induction. Forty of 54 patients (74%) had disease that was resectable, with 34 (63%) complete resections (R0). A substantial pathologic response (tumor regression [TR] > 90%) was achieved in 27 of 54 patients (50%) and is revealed as an independent predictor for long-term survival after surgery. Five treatment-related deaths (9%) occurred. With a median follow-up period of 44 months, calculated survival rates at 3 years were 35% for patients with stage IIIA disease, 26% for patients with stage IIIB disease, and 56% for patients with R0 disease and TR > 90%. CONCLUSION: This trimodality approach is feasible and results in encouraging 3-year survival rates in prognostically unfavorable patients with stage III NSCLC. Patients experiencing a 90% degree of pathologic TR were most likely to achieve long-term survival.

Adult↗

PubMed2006

Current understanding of the mechanisms of gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease (GERD) covers a broad range of signs and symptoms arising from the orad movement of gastric contents into the oesophagus, oropharynx, larynx or airway. Most commonly, contact with and damage to the oesophageal epithelium by acidic refluxate causes micro or macroscopic defects leading to the symptom of heartburn. However, GERD can also give rise to extra-oesophageal manifestations such as pharyngitis, laryngitis, asthma and other disorders, identifiable as acid-mediated events by a favorable response to acid suppression. Only one-third of individuals with heartburn have endoscopic evidence of erosive oesophagitis; the remainder have endoscopy-negative or non-erosive reflux disease (NERD). Improved investigative technologies are increasing our understanding of the pathophysiology of NERD. For example, although a number of microscopic abnormalities have been identified, oesophageal damage in NERD has been shown to be characterized by the presence of 'dilated intercellular spaces' within oesophageal stratified squamous epithelium. Dilated intercellular spaces that reflect damage to the intercellular junctions enable levels of acidity that would be considered innocuous when present in the oesophageal lumen to initiate pathological responses within oesophageal nociceptors when present within the intercellular spaces. This effectively gives rise to the symptom of heartburn. Excessive acidity within the intercellular spaces in NERD also presages its evolution to erosive disease, the latter through inflammation-mediated disruption of the antireflux and luminal clearance mechanisms. Support for this scenario is evident by the ability of effective acid control with proton pump inhibitors both to control symptoms, and lead to resolution of dilated intercellular spaces in patients with both erosive and non-erosive disease. This article examines these concepts and how they shape our current understanding of GERD.

Esophagus↗

PubMedDate not supplied

Type III radical hysterectomy after induction chemotherapy for patients with locally advanced cervical carcinoma.

Neoadjuvant chemotherapy followed by surgery is a promising approach in locally advanced cervical carcinoma. The aim of this study was to evaluate the feasibility, technical aspects, and clinical results of surgery after induction chemotherapy in this patient population. Forty-one untreated cervical carcinoma patients staged as IB2 to IIIB received three 21-day courses of cisplatin 100mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 followed by surgery or concomitant chemoradiation. The response to chemotherapy, operability, surgical/pathological findings, disease-free period, and survival of the surgically treated patients were evaluated. All 41 patients were evaluated for toxicity and 40 were evaluated for response. The overall objective response rate was 95% (95% confidence interval 88%-100%), and was complete in three patients (7.5%) and partial in 35 (87.5%). Granulocytopenia grades 3/4 occurred in 13.8% and 3.4% of the courses, respectively, whereas nonhematological toxicity was mild. Twenty-three patients underwent type III radical hysterectomy. Mean duration of surgery was 3.8 h (range 2:30-5:20), median estimated blood loss was 670 ml and median hospital stay was 5.2 days. Intraoperative complications occurred in one case (venous injury). In all but one case the resection margins were negative. Four patients (17%) had positive nodes (one node each); six (26%) had complete pathologic response, three (13%) had microscopic; and 14 (60%) macroscopic residual disease. At 24 months of maximum follow-up (median 20), the disease-free and overall survival rates were 59% and 91%, respectively. Induction chemotherapy with cisplatin/gemcitabine produced a high response rate and did not increase the difficulty of surgery. Operating time, blood loss, intraoperative complications, and hospital stay were all within the range observed for type III hysterectomy in early stage patients. We therefore conclude that type III radical hysterectomy is feasible in locally advanced cervical cancer patients who respond to chemotherapy.

Adolescent↗

PubMed2005

Sphingosine kinase activity and sphingosine-1 phosphate production in rat pancreatic islets and INS-1 cells: response to cytokines.

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid with the potential to mobilize Ca2+, to inhibit apoptosis, and to promote mitogenesis. Sphingosine kinase (SPHK) and S1P were characterized in INS-1 insulinoma cells and isolated rat islets of Langerhans. SPHK activity increased in INS-1 cell homogenates treated with interleukin-1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha), and responses were additive. IL-1beta or TNF-alpha increased islet SPHK activity within 15 min to 1 h; activity remained elevated after 8 h. SPHK2 was the predominant active isoform in INS-1 cells; little or no SPHK1 activity was detected. Cytokines increased endogenous S1P biosynthesis in 32P(i)-prelabeled INS-1 cells, and cycloheximide inhibited the response after 8 h, suggesting that protein synthesis mediated the response. There was no [32P]S1P release from cells. Compared with basal values, IL-1beta and TNF-alpha induced increases in SPHK1a mRNA levels relative to 18S ribosomal RNA in INS-1 cells within 1 h; relative SPHK2 mRNA levels were unchanged after cytokine treatment. IL-1beta, but not TNF-alpha, induced relative SPHK1a mRNA expression levels within 1 h in islets, whereas SPHK2 mRNA levels were unchanged. Thus, IL-1beta and TNF-alpha induced an early and sustained increase in SPHK activity in INS-1 cells and isolated islets, suggesting that S1P plays a role in the pathological response of pancreatic beta-cells to cytokines.

Animals↗

PubMed1996

Surgically documented responses to paclitaxel and cisplatin in patients with primary peritoneal carcinoma.

Intra-abdominal carcinomatosis indistinguishable from ovarian cancer may occur after removal of the ovaries or in association with surface ovarian involvement. Because its histologic pattern and behavior approximate those of ovarian cancer, this entity, known as primary peritoneal carcinoma, has been treated in a similar fashion--cytoreductive surgery followed by systemic chemotherapy. This review was undertaken to assess the efficacy of combination chemotherapy with paclitaxel and cisplatin, the current front-line chemotherapeutic regimen for ovarian cancer, in patients with primary peritoneal carcinoma. Sixteen patients diagnosed between January 1989 and July 1994 with primary peritoneal carcinoma were treated at the Hospital of the University of Pennsylvania. The records of the three patients whose initial chemotherapeutic regimen included paclitaxel and cisplatin were reviewed. An additional case from the Robert Wood Johnson Medical Center, Camden, New Jersey, was included. Pathologic review of all cases was conducted at the time of clinical management and again as part of this study. Reassessment laparotomy was performed in all patients after the completion of chemotherapy. Complete clinical information was available on all patients. All four patients presented with intra-abdominal carcinomatosis, and large volume (> 1 cm) residual disease was present following initial cytoreduction. Following chemotherapy, second-look laparotomy documented one complete pathologic response and three partial (>50% tumor volume reduction), but marked, responses. Combination chemotherapy with paclitaxel and cisplatin produces surgically documented responses in patients with primary peritoneal carcinoma.

Antineoplastic Agents↗

PubMed2001

Pulmonary pathology in patients with AIDS: an autopsy study from Mumbai.

OBJECTIVE: Although India has a high prevalence of HIV/AIDS, the associated pathologies responsible for morbidity have not been evaluated previously in a representative study. Hence, an autopsy study was carried out to analyse the spectrum of pulmonary lesions in patients with HIV/AIDS. METHODS: A retrospective and prospective autopsy study was carried out during 1988-2000 at Mumbai, India. Lungs from 143 adults, with at least 10 sections from each case, were examined using routine and special stains. RESULTS: The risk factors for 97 men (68%) and 38 women (27%) included: heterosexual sex with multiple partners (135 cases, 95%); blood transfusions (three cases; 2%); sex between men (two cases; 1%); and unknown risk factors (three cases, 2%). Pulmonary pathology was observed in 126 (88%) cases. The lesions identified were tuberculosis (85 cases, 59%), bacterial pneumonia (26 cases, 18%), cytomegalovirus (CMV) infection (10 cases, 7%), cryptococcosis (eight cases, 6%), Pneumocystis carinii pneumonia (seven cases, 5%), aspergillosis (four cases, 3%), toxoplasmosis (two cases, 1%), Kaposi's sarcoma (one case, 1%), squamous cell carcinoma (one case, 1%). Two or more infections were observed in 18 (13%) cases. CONCLUSIONS: Pulmonary diseases and risk factors among patients with AIDS in India differ from those reported in industrialized countries. Tuberculosis was the most frequently observed pulmonary infection, followed by bacterial pneumonia and CMV pneumonitis. In contrast with industrialized countries, PCP remains less common in our patients. The information on opportunistic infections obtained in this study will be useful for managing HIV/AIDS cases at district level hospitals where diagnosing specific HIV-associated diseases is not always possible.

AIDS-Related Opportunistic Infections↗