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PubMed2002

Docetaxel plus epidoxorubicin as neoadjuvant treatment in patients with large operable or locally advanced carcinoma of the breast: a single-center, phase II study.

BACKGROUND: The objective of this study was to test the activity and toxicity of epirubicin plus docetaxel as primary chemotherapy for women with large, operable (T2; > 3 cm) or locally advanced (Stage III) breast carcinoma, including patients with inflammatory breast carcinoma. METHODS: In this single-center, open-label, single-stage, Phase II trial, epirubicin (75 mg/m(2); intravenous bolus) followed by docetaxel (80 mg/m(2); 1-hour intravenous infusion) was administered on Day 1 of each cycle for four cycles. RESULTS: Nine of 30 patients (30%) had inflammatory breast carcinoma. Twenty-three patients (76.7%; 95% confidence interval, 57.7-90.1) had a clinical objective response that was complete in 6 patients (20%). Twenty-seven patients (90%) underwent surgery that was conservative in 5 patients (16.7%). Pathologic response evaluation revealed four complete responses (13.3%; 95% confidence interval, 3.8-30.7). Grade 4 neutropenia was recorded in 80.0% of patients, and febrile neutropenia was recorded in one-third of patients. Anemia and thrombocytopenia were never severe. Other side effects were diarrhea (26.6%), oral mucositis (43.3%), and emesis (26.6%). CONCLUSIONS: Neoadjuvant chemotherapy with epirubicin plus docetaxel was a feasible treatment and was active in an unfavorable series of patients with locally advanced breast carcinoma, including patients with inflammatory breast carcinoma.

Adult↗

PubMed2005

Survival in cervix cancer patients treated with radiotherapy followed by radical surgery.

AIM: To determine the incidence and predictive value of residual disease in the hysterectomy specimens of cervical cancer patients treated with primary radiotherapy, with or without chemotherapy, followed by surgery and to determine whether pathologically confirmed residual disease is a surrogate marker of outcome. METHODS: The medical records of patients treated for stage IB/II carcinoma of the cervix in a single institution between 1985 and 2000 were retrospectively analysed into two different groups, depending on whether they had received radiotherapy or concurrent chemo-radiotherapy. Six to 8 weeks after irradiation, all patients underwent radical or extrafascial hysterectomy and pelvic and para-aortic lymphadenectomy. RESULTS: A total of 403 patients were included in the study (360 in the radiotherapy only group and 43 in the chemo-radiotherapy group). One hundred and seventy-eight patients had residual disease on hysterectomy specimens in the radiotherapy group. Considering only the stages IB2 and II, 126 (52%) and 16 (37%) patients had residual disease on hysterectomy specimens in the radiotherapy group and in the chemo-radiotherapy group, respectively (P=0.08). Residual disease was associated with pelvic and para-aortic nodal metastases. The 5-year local control and overall survival rates were 88 and 86%, respectively, in the patients with complete pathologic response and 73 and 62%, respectively, in the patients with residual disease (P<0.001). In multivariate analysis, FIGO stage, residual disease, and pathologic nodal involvement were independent predictive factors of both local recurrence and overall survival. CONCLUSION: Pathologically confirmed residual disease on hysterectomy specimen is an independent and strong predictive factor of both local recurrence and overall survival.

Adult↗

PubMed1978

Visual evoked responses in multiple sclerosis: comparison of two methods for pattern reversal.

Visual evoked responses have been elicited by reversal of a black and white checkerboard pattern and also by a display of light-emitting diodes (LED) generating a reversal of a pattern of illuminated red circular areas. In a control group the LED display produced responses of lower amplitude and shorter latency compared to responses to checkerboard stimulation. In patients with a definite or probable diagnosis of multiple sclerosis the stimulators were equally effective in evoking pathological responses; in patients with a possible but less certain diagnosis abnormal responses were found in a higher percentage when the LED stimulus was used. Differences in stimulus field size and in stimulus colour are discussed as possible reasons for this result.

Adult↗

PubMed1997

High-dose therapy with carboplatin and paclitaxel in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer deaths in the United States. The combination of more active agents like vinorelbine and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) with cisplatin has led to improved survival for patients with advanced metastatic disease. The ability to escalate the dose of cisplatin-based regimens is limited by nonhematologic toxicities and is especially difficult in the population of patients with advanced NSCLC. However, the development of new agents with significant activity against NSCLC as well as new strategies for high-dose therapy have made it possible to examine the potential of dose-intense therapy in this population. A phase I trial performed at the University of North Carolina was designed to evaluate paclitaxel 250 mg/m2 given over 24 hours plus escalating doses of carboplatin starting at an area under the concentration-time curve (AUC) dose of 8 supported by peripheral blood stem cells and filgrastim in the treatment of advanced NSCLC. The AUC dose of carboplatin was escalated in increments of 2. The maximum tolerated dose of carboplatin combined with paclitaxel 250 mg/m2 administered over 24 hours was defined at an AUC of 18. In this study, six of seven patients with advanced NSCLC had major responses. This regimen is currently being tested in patients with locally advanced NSCLC by the Cancer and Leukemia Group B: patients receive two cycles of induction therapy with paclitaxel 250 mg/m2 over 3 hours followed by carboplatin at an AUC of 18 supported by peripheral blood stem cells and filgrastim. Depending on response to induction therapy, patients then receive surgical resection, thoracic radiation therapy, or both. This phase II trial will examine clinical and pathologic responses and the toxicity of this high-dose regimen in patients with locally advanced NSCLC. Ultimately, phase III trials will be needed to establish the role of this approach in NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1983

Clinical and pathological evaluation of response to chemotherapy in patients with esophageal carcinoma.

Pretreatment clinical staging, radiographic response to chemotherapy, and posttreatment pathological staging were assessed in 39 patients with epidermoid carcinoma of the esophagus. Thirty patients received combined modality therapy with cisplatin, vindesine, and bleomycin followed by surgery; nine patients were treated with the same chemotherapy with or without radiation therapy. Using barium esophagrams as the measure of response, radiographic objective regressions were quantitated and considered as complete (CR), partial (PR), and minor or no radiographic response. Sixty percent of patients had CR or PR. However, surgical or endoscopic restaging showed residual microscopic or macroscopic disease in nine patients, with complete radiographic regression. Downstaging of the primary tumor following chemotherapy (pretreatment clinical staging as compared to posttreatment pathological staging) was common. Chemotherapy-induced objective regressions in esophageal carcinoma can be achieved frequently and can be quantitated, using serial barium esophagrams. Complete radiographic regressions should be confirmed by repeat endoscopy or surgery. Downstaging of the primary tumor is commonly noted in responding patients, but it is too soon to determine whether or not this will effect their long-term prognosis.

Antineoplastic Agents↗

PubMed2002

Preoperative chemoradiation in patients with resectable rectal cancer: results on tumor response.

BACKGROUND: There is no consensus about the role of preoperative radiotherapy (RT) and chemotherapy (CT) in patients with resectable cancer of the distal rectum. This study analyzed the local clinical and pathologic response in patients receiving preoperative RT/CT for rectal cancer. METHODS: Thirty-two consecutive patients with a palpable adenocarcinoma of the rectum received preoperative RT (45 Gy in 25 fractions over 5 weeks) plus continuous chemotherapy with doxifluridine and leucovorin or 5-fluorouracil by continuous intravenous infusion during RT. Surgery was performed 8 weeks later. The Wilcoxon and chi(2) tests were used for data analysis. RESULTS: Twelve patients had mild gastrointestinal toxicity, only one of whom required interruption of therapy. The tumor shrank to 57.8% of its original size, and at the echoendoscopy (u) there was a 58.7% decrease of the maximum diameter (P <.001). Downstaging from uT3 and uT2 to <uT3 and <uT2, respectively, occurred in 41.6% of patients (P =.0020). Total and major regression of the tumor at the histopathologic examination occurred in 12.5% and 50% of patients. CONCLUSIONS: Local response to preoperative RT/CT was highly satisfactory and allowed conservative surgery in 81% of patients. Optimization of the combined therapy could achieve even better results.

Adenocarcinoma↗

PubMed2002

[Misdiagnosis of corticomedullary mixed pathological changes in adrenals: report of 4 cases].

Pathological changes usually occur independently in the adrenal cortex and medulla because of their distinct embryonic origins, and changes involving both the cortex and medulla are rare. We report 4 cases of corticomedullary mixed pathological changes adrenal glands. CT scanning of the adrenal glands showed unilateral abnormalities in all the 4 cases, 3 of which were diagnosed as aldosteronism and the other pheochromocytoma before surgery. Unilateral adrenalectomy was performed in the 4 patients 3 being cured and discharged. The other 1 had recurrence 18 months postoperatively with suspected pathological changes on the other side. Subsequent pathological examination confirmed the suspicion in both the cortex and medulla of the other adrenal gland. In cases with clinical presentations as simultaneous onset of aldosteronism and catecholamine responses, pathological changes in both the cortex and medulla of the adrenal glands should be considered. Perioperative management of such cases should be the same as that in cases of catecholamine responses, and the diagnosis relies on histopathological examination.

Adrenal Cortex↗

PubMed1995

192 IgG-saporin. 2. Neuropathology in the rat brain.

We have previously shown that an immunotoxin (IT) directed against the p75 component of the nerve growth factor receptor (NGFr) selectively abolished cholinergic neurons in the basal forebrain of the rat following intraventricular administration. We now report the neuropathological responses in the rat brain to the IT, with particular emphasis on the cholinergic basal forebrain (CBF) and other known p75NGFr-positive brain regions. Animals received intraventricular injections of IT and were allowed to survive for various times. Sections through the entire brain were evaluated using (1) hematoxylin and eosin; (2) glial fibrillary acidic protein immunohistochemistry; and (3) Griffonia simplicifolia lectin histochemistry. The only clearly degenerating cells following IT treatment were located in the CBF or in the Purkinje cell layer of the cerebellum. A marked microglial response was demonstrated that was tightly linked both topographically and temporally to the loss of neurons in these areas. The astroglial response was mild in the same regions in which the microglial response was obvious. The other areas of rat brain including the terminal fields of CBF projections showed no consistent reactive cellular responses in IT-treated animals. This study extends and corroborates previous work indicating specificity of IT, demonstrates active neuronal degeneration by conventional pathological methods for the first time, and illustrates the unexpected and novel finding that the predominant pathological response to the IT-induced loss of neurons is microglial. Both the high degree of specificity and the distinctive glial response distinguish the IT model from other experimental models of CBF neurodegeneration.

Animals↗

PubMed2001

A phase II study of gemcitabine and cisplatin combination as induction chemotherapy for untreated locally advanced cervical carcinoma.

BACKGROUND: Cisplatin-based chemoradiation for locally advanced cervical carcinoma is now the standard of care for most patients with cervical carcinoma. However, induction chemotherapy followed by surgery, particularly with newer agents or combinations remains to be explored. This study was undertaken to evaluate the antitumor activity and toxicity of gemcitabine in combination with cisplatin for untreated locally advanced cervical carcinoma. PATIENTS AND METHODS: Open-label, single center, phase II, non-randomized study of neoadjuvant gemcitabine plus cisplatin. Forty-one patients with histologic diagnosis of cervical carcinoma, with no previous treatment and staged as IB2 to IIIB, were treated with three 21-day courses of cisplatin 100 mg/m2 day I and gemcitabine 1000 mg/m2 days 1 and 8, followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated before each course and at the end of chemotherapy. RESULTS: All patients were evaluated for toxicity and 40 for response. The overall objective response rate was 95% (95% confidence interval (CI): 88%-100%) being complete in 3 patients (7.5%) and partial in 35 (87.5%). A complete pathological response was found in 6 (26%) of the 23 patients that underwent surgery. Granulocytopenia grades 3-4 occurred in 13.8% and 3.4% of the courses, respectively, whereas non-hematological toxicity was mild. CONCLUSIONS: Induction chemotherapy with the combination of gemcitabine and cisplatin is highly active for untreated cervical cancer patients and has an acceptable toxicity profile.

Adenocarcinoma↗

PubMed1992

Cell-matrix response in tendon injury.

The healing response after tendon injury is defined by cell matrix adaptive capability. There are distinct macrotraumatic and microtraumatic injury patterns and a spectrum of pathologic responses from inflammation to tissue degeneration, as characterized by the tendinosis phenomenon. Epigenetic and genetic factors govern recovery from tendon injury. The potential for future modulation of injury repair by protein mediators or growth factors appears promising.

Achilles Tendon↗

PubMed1989

[Cis-dichlorodiammineplatinum in osteosarcoma. Osteosarcoma Cooperative Study Group report].

Thirty-two patients with primary osteosarcoma and 18 patients with advanced osteosarcoma were treated by iv or ia infusion of cisplatinum at a dose of 100 mg/m2 every three weeks. The efficacy of the agent for primary osteosarcoma was mainly estimated by X-ray findings and histologic examination. One patient had a partial response, and 7 patients had a minor response. Pathologic evaluation of the extent of the primary tumor necrosis was performed on 27 resected specimens. Eight of 27 cases showed a good response (Ayala III A less than). One of 18 patients with advanced osteosarcoma had a partial response, and 2 a minor response. Nausea and vomiting (88%), liver dysfunction (42%), leukopenia (36%), nephrotoxicity (20%) and auditory disturbance (20%) were the main side effects in 50 patients. However, side effects of cisplatinum were generally reversible. The results suggest that cisplatinum is effective against osteosarcoma and may enhance the therapeutic results in osteosarcoma.

Adolescent↗

PubMed1997

Preliminary results of neoadjuvant paclitaxel and carboplatin in the treatment of early stage non-small cell lung cancer.

The purpose of this study is to determine the feasibility of delivering neoadjuvant paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin to patients with clinical early stage (stage I and II) non-small cell lung cancer. Although neoadjuvant chemotherapy appears to prolong survival in patients with stage IIIA non-small cell lung cancer, several studies have demonstrated an increase in perioperative mortality associated with this approach. This study is designed to address whether three cycles of paclitaxel (200 mg/m2/3 hour, day 1) and carboplatin (area under the concentration-time curve 5, day 2) can be given preoperatively to patients with clinical stage I and II non-small cell lung cancer and to assess the associated toxicities, pathologic response rate, disease-free survival, and overall survival of this group of patients. Thus far, five patients have been enrolled. Three have successfully undergone resection, with no perioperative complications noted. One patient had a pathologic complete remission and two had pathologic partial remissions. Preliminary results indicate that this approach is well tolerated and results in major tumor response.

Adult↗

PubMed2001

Inhibition of the cyclin D1/E2F pathway by PCA-4230, a potent repressor of cellular proliferation.

1. Tight control of cellular growth is essential to ensure normal tissue patterning and prevent pathological responses. Excessive vascular smooth muscle cell (VSMC) proliferation is associated with the pathophysiology of atherosclerosis and restenosis post-angioplasty. Thus, drug targeting of pathological VSMC growth may be a suitable therapeutic intervention in vascular proliferative diseases. 2. In the present study, we investigated the mechanisms underlying VSMC growth arrest induced by the pharmacological agent PCA-4230. Addition of PCA-4230 to cultured VSMCs blocked the induction of cyclin D1 and cyclin A expression normally seen in serum-restimulated cells. Moreover, PCA-4230 inhibited cyclin-dependent kinase 2 (CDK2) activity and abrogated hyperphosphorylation of the retinoblastoma (Rb) gene product. Similarly, PCA-4230-dependent growth arrest of transformed cell lines correlated with reduced level of cyclin D1 protein and inhibition of CDK2 activity. Consistent with these findings, PCA-4230 repressed serum-inducible cyclin A promoter activity, and overexpression of either cyclin D1 or E2F1 efficiently circumvented this inhibitory effect. Importantly, adenovirus-mediated overexpression of E2F1 restored S-phase entry in PCA-4230-treated VSMCs, demonstrating that PCA-4230 represses cyclin A gene expression and VSMC growth via inhibition of the cyclin D1/E2F pathway. 3. Because of its ability to inhibit the growth of human VSMCs and transformed cell lines, future studies are warranted to assess whether PCA-4230 may be a suitable therapeutic intervention for the treatment of hyperproliferative disorders, including cardiovascular disease and cancer.

Animals↗

PubMed1973

Fluid secretory response of bovine Thiry jejunal fistula to enterotoxin of Clostridium perfringens.

The effect of enterotoxin of Clostridium perfringens type A was studied in Thiry fistula of the bovine jejunum. Accumulation of fluid as a pathological response was demonstrable within 30 min after introduction of enterotoxin into the fistula; the fluid volume increased rapidly within the first 2 hr and reached maximum in 7 hr. The enterotoxin was not destroyed by the jejunal fluid; 52% of it was absorbed in 2 to 3 hr, and all of the enterotoxin was taken up within 8 hr postinoculation. The accumulation of fluid by the fistula after 0.5 to 2 hr of exposure to enterotoxin ceased completely within 5 hr.

Animals↗

PubMed2003

Absence of CCR8 does not impair the response to ovalbumin-induced allergic airway disease.

Interaction of chemokines with their specific receptors results in tight control of leukocyte migration and positioning. CCR8 is a chemokine receptor expressed mainly in CD4(+) single-positive thymocytes and Th2 cells. We generated CCR8-deficient mice (CCR8(-/-)) to study the in vivo role of this receptor, and describe in this study the CCR8(-/-) mouse response in OVA-induced allergic airway disease using several models, including an adoptive transfer model and receptor-blocking experiments. All CCR8(-/-) mice developed a pathological response similar to that of wild-type animals with respect to bronchoalveolar lavage cell composition, peripheral blood and bone marrow eosinophilia, lung infiltrates, and Th2 cytokine levels in lung and serum. The results contrast with a recent report using one of the OVA-induced asthma models studied here. Similar immune responses were also observed in CCR8(-/-) and wild-type animals in a different model of ragweed allergen-induced peritoneal eosinophilic inflammation, with an equivalent number of eosinophils and analogous increased levels of Th2 cytokines in peritoneum and peripheral blood. Our results show that allergic diseases course without critical CCR8 participation, and suggest that further work is needed to unravel the in vivo role of CCR8 in Th2-mediated pathologies.

Adoptive Transfer↗

PubMed1989

An alternative pathogenetic pathway for oral submucous fibrosis (OSMF).

Oral submucous fibrosis is a potent pre-cancerous condition which occurs almost exclusively in Indians but cases have been reported from several countries. The definite aetiology of OSMF is still unknown and there is no known treatment for it. Chilles, tobacco use, vitamin deficiencies and betel quid chewing have been implicated. Ramanathan is of the view that OSMF seems to be the Asian version of sideropenic dysphagia. He suggests that OSMF appears to be an altered oral mucosa following prolonged period of chronic deficiency of iron and/or vitamin "B" complex especially folic acid. This changed state of the oral mucosa subsequently appears to develop more easily a hypersensitivity to oral irritants such as spices especially chillies and to the betel quid. We hold that the hypersensitivity caused by local irritants and the resultant persistent juxta epithelial inflammatory response noted in OSMF (in a host system already primed by an intrinsic genetic defect) act as the initiating factor leading to a defective inflammatory--reparative response, culminating in fibrotic healing. The role of iron and "B"complex together with others may be contributory (promotor) to this pre-existing pathologic response of the lamina propria.

Anemia↗

PubMed2005

Doppler ultrasonography for the assessment of tumor necrosis after percutaneous ethanol injection prior to liver transplantation as adjuvant therapy of hepatocellular carcinoma.

INTRODUCTION: Percutaneous ethanol injection (PEI) is considered to be a curative treatment for hepatocellular carcinoma (HCC). The imaging technique of choice for the assessment of local response after PEI has not been well defined, but helical computerized tomography (hCT) has been recommended. The aim of this study was to assess the accuracy of Doppler ultrasonography (US) for evaluation of tumor necrosis after PEI. PATIENTS AND METHODS: Twenty-one patients with single HCC listed for liver transplantation underwent multisession US-guided PEI. Liver Doppler US was done at the 4th week after PEI. Complete response was defined as the absence of any intratumoral Doppler signal. The liver was analyzed in transplant recipients during the follow-up. Complete pathological response was defined as necrosis > or = 90% of total tumor volume. Histological and sonographic findings were compared. RESULTS: Twelve patients underwent transplantation (9 men, mean age 60 +/- 5.2 years). Nine of these (75%) showed a complete ultrasonographic response. In the explanted liver, complete necrosis was present in 6 nodules, and incomplete necrosis was seen in the remaining 6 cases. In comparison with histology, Doppler US showed values of sensitivity, specificity, positive predictive values, and negative predictive values of 50%, 100%, 100%, and 60%, respectively. Overall accuracy was 75%. CONCLUSIONS: In our series, Doppler US showed low sensitivity but high specificity in the assessment of HCC necrosis after PEI. The ultrasonographic finding of complete response requires hCT for confirmation, but the presence in Doppler US of neoplastic viable tissue is enough to indicate a further cycle of PEI.

Administration, Cutaneous↗

PubMed1997

Preoperative 5-fluorouracil and radiation therapy for locally advanced breast cancer.

BACKGROUND: Fifteen percent of breast cancer patients present with large tumors involving skin or chest wall. Often, surgery with primary wound closure is impossible. We used neoadjuvant chemoradiation in locally advanced breast cancer patients, in hopes of increasing resectability. METHODS: Eligible patients had locally advanced breast cancer deemed unresectable with primary wound closure. Patients received 8 weeks of infusional 5-fluorouracil (5-FU) 200 mg/m2 per day and radiation therapy to 50 Gy. Patients rendered resectable underwent modified radical mastectomy (MRM) followed up by chemotherapy. RESULTS: Of 30 evaluable patients, 73% had an objective clinical response. All were able to undergo MRM with primary wound closure; 63% had residual disease, 20% had minimal microscopic disease, and 17% had complete pathologic response. Treatment-related toxicity was minimal. Surgical morbidity was not increased. CONCLUSIONS: Infusional 5-FU with concomitant radiotherapy is well tolerated and effective at producing shrinkage in the majority of patients, converting inoperable breast cancer to easily resectable disease.

Adult↗