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PubMedDate not supplied

Disruption of oxygen-regulated responses underlies pathological changes in the placentas of women who smoke or who are passively exposed to smoke during pregnancy.

Previously, we showed that maternal smoking harms human placental development by changing the balance between cytotrophoblast (CTB) proliferation and differentiation. To understand the mechanisms involved, we studied the effects of maternal smoking and in vitro exposure of CTBs to nicotine and on CTB expression of molecules that govern cellular responses to oxygen tension: the von Hippel-Lindau tumor suppressor protein (pVHL), the hypoxia-inducible transcription factors (HIFs), and the vascular endothelial growth factors (VEGFs). We previously reported that hypoxia upregulates CTB pVHL expression (1). Here we show that in vitro exposure of CTBs to nicotine has the same effect. Maternal smoking also dysregulated CTB expression of all three molecules. Remarkably, we found that passive exposure to cigarette smoke had many of the same effects as active smoking, a graphic demonstration of the ill effects of cigarette smoke, even secondhand, on placental development. Together, these findings explain, in part, how smoking damages the placenta by altering expression of key mediators of placental development.

Abortion, Induced↗

PubMed1984

Effects of nutrition on disease and life span. I. Immune responses, cardiovascular pathology, and life span in MRL mice.

Mice of the autoimmune, lymphoproliferative strain MRL/lpr and the congenic, nonlymphoproliferative strain MRL/n were fed one of six diets from weaning on-ward. These mice were sacrificed at 3 or 5 months of age. Low fat diets resulted in lower cholesterol and higher triglyceride levels than did cholesterol-containing high-fat diets. Caloric restriction of MRL/lpr mice was associated with an increased plaque-forming cell response to trinitrophenylated polyacrylamide beads, less lymphoproliferation, and less severe glomerulonephritis. Diet did not affect the incidence of autoimmune vasculitis in MRL/lpr mice sacrificed at 5 months. MRL/lpr mice fed a low-fat, calorically restricted diet from 5 months of age to death lived longer than mice which were fed ad libitum a cholesterol-containing, high-fat diet. At death, MRL/lpr mice fed the former diet had the autoimmune vasculitis which had been evident in mice killed at 5 months, whereas mice fed the latter diet, in addition to the vasculitis, had a high incidence of atherosclerotic lesions of intrarenal and aortic branch arteries.

Animal Nutritional Physiological Phenomena↗

PubMed2003

Expression of cell cycle regulatory proteins in breast carcinomas before and after preoperative chemotherapy.

Molecular markers predicting response to preoperative chemotherapy would be of major clinical relevance in breast cancer. Therefore, we studied the relationship between the expression of cell cycle regulatory proteins and clinical outcome in breast cancer patients receiving preoperative chemotherapy. Expression of p2lWaf1, p27KiP1, p53, cyclin D3 and Ki-67 was determined in breast carcinomas by means of immunohistochemistry both prior and after preoperative chemotherapy. Expression data were compared with both clinical parameters and response to preoperative chemotherapy with either cyclophosphamide/methotrexate/5-fluorouracil (CMF, n = 29) or epirubicin/docetaxel (ED, n = 36). In paired samples before and after preoperative chemotherapy, the percentage of p21Waf1, p27Kip1, p53 and cyclin D3 positive nuclei of tumor cells in postchemotherapy specimens was significantly higher than the percentage in prechemotherapy samples but no change in Ki-67 expression was observed. High Ki-67 expression (p = 0.02), negative estrogen receptor status (p = 0.01) and negative progesterone receptor status (p = 0.04) were associated with complete pathologic response to chemotherapy, whereas the other markers did not predict response. In conclusion, expression levels of p21Waf1, p27Kip1, p53 and cyclin D3 significantly increased after preoperative chemotherapy in breast carcinomas but only high Ki-67 expression, negative estrogen receptor status and negative progesterone receptor status were associated with complete pathologic response to preoperative chemotherapy.

Adult↗

PubMed2000

[Study on therapeutic mechanism of anti-rheumatism action of herba siegesbeckiae].

OBJECTIVE: To explore the mechanism of anti-rheumatism action of the active fraction of Herba Siegesbeckiae (AFHS). METHODS: Adjuvant arthritis model of rat was made to observe the effect of AFHS on lymphocyte proliferation, interluekin-1 (IL-1) and IL-2 activity, pathologic section of ankle joint, and analgesic effect of AFHS in model rat. RESULTS: AFHS could reduce the inflammatory pathologic response of ankle joint, it functions well as analgesics, the analgesic rate being 65%, AFHS could also improve T-lymphocyte proliferation, improve IL-2 activity and inhibit IL-1 activity, as compared with the control group, the difference was significant (P < 0.01). CONCLUSION: Through regulating the immune function of organism, AFHS could improve the local pathologic response so as to antagonise against rheumatism, therefore, it is a good anti-rheumatism herbal medicine.

Animals↗

PubMed1988

Morphological alterations of the glomerular (visceral) epithelium in response to pathological and experimental situations.

The glomerular (visceral) layer of Bowman's capsule is comprised of a unique population of cells which have been termed "podocytes." Arising from these cells are large major processes and numerous smaller foot processes which completely surround underlying glomerular capillary loops. Podocyte foot processes interdigitate with each other and are separated by spaces (filtration slits) which are designed to facilitate flow of a large amount of filtrate across the glomerular wall. Podocytes exhibit dramatic morphological changes in response to the nephrotic syndrome and some forms of acute renal failure and may play an important role in the pathophysiology of these conditions. In vitro and in vivo studies have shown that a reduction in the sialic acid component of a thick anionic surface coat plays a major role in the morphological changes that these cells exhibit in the nephrotic syndrome. Also, it has been shown that filamentous actin concentrated mainly within podocyte foot processes are the contractile elements responsible for altering the shapes of these processes. There is evidence to suggest that by altering the shapes of their foot processes, podocytes in the normal kidney are able to alter the number of fully patent filtration slits and thereby actively regulate the rate of solute efflux across the glomerular wall. In vitro and in vivo studies have indicated that cytoplasmic microtubules are probably not involved in alterations of the podocyte foot processes but do appear important in maintaining the morphological integrity of podocyte cell bodies and their major processes. In the present paper, the morphological changes which glomerular podocytes exhibit in response to the nephrotic syndrome, various forms of acute renal failure, and during in vitro incubation are discussed along with studies of the possible roles of cytoplasmic microtubules, microtubules, and the glomerular anionic surface coat in these changes.

Acute Kidney Injury↗

PubMed1998

Management of the clinically positive neck in organ preservation for advanced head and neck cancer.

BACKGROUND: To investigate clinicopathologic predictive criteria for the optimal management of neck metastases in patients with advanced head and neck cancers treated with combined chemoradiotherapy. METHODS: Prospective study, 48 patients. Mean length follow-up, 23 months. RESULTS: Neck stage predicted neck response to chemoradiotherapy; N3 necks showed more partial responses (P = 0.04), and N1 necks showed more complete responses (P = 0.12). Primary tumor site strongly predicted the pathologic response found on neck dissection in patients with a clinical partial response (cPR) following chemoradiotherapy. There was no difference in survival between patients with a clinical complete response (cCR) after chemoradiotherapy, and patients with a pathologic complete response (pCR) after neck dissection (P = 0.20); however, when grouped together, these patients survived longer than did patients with a pPR at neck dissection (P = 0.06). CONCLUSIONS: Clinical response to induction chemotherapy is a poor predictor of ultimate neck control. Induction chemotherapy followed by chemoradiotherapy, and planned neck dissection for patients with persistent cervical lymphadenopathy, provides good regional control.

Adult↗

PubMed2000

[Head shaking test and low-frequency rotation-acceleration test: comparison of sensitivity and specificity].

In studying the vestibular-oculomotor reflex (VOR) in patients with equilibrium disorders, both active and passive methods are used and at different stimulation frequencies, particularly to evaluate vestibular compensation. The present study compares the sensitivity and specificity of the low-frequency pendular test and the HST in normal subjects and in subjects suffering from various vestibular pathologies but showing no signs of spontaneous nystagmus, even under optimal evaluation conditions (infrared videonystagmoscopy). These spontaneous nystagmus-free subjects underwent a routine study including: case history, infrared videonystagmoscopy (HST with 2 Hz stimulation) and ENG recording (saccadic movement, smooth pursuit, OKN, VOR, VOR-fix during pendular stimulation at 0.05 Hz and VOR after Fitzgerald-Hallpike heat stimulation). On the basis of the results the subjects were classified as follows: normal (N): case history free of any equilibrium disorders and all tests negative (122 cases; 8.1%); peripheral vestibular pathology (P): case history of equilibrium disorders and labyrinthine predominance (LP) in excess of 20% upon caloric testing (716 cases; 47.6%); central pathology (C): case history of equilibrium disorders and at least 3 pathological results from among the following tests: saccadic movement, smooth pursuit, OKN, VOR-fix (226 cases; 15.0%); mixed pathology (M): with both signs of P and C (440 cases; 29.3%). The pendular test showed signs of directional dominance (DP) higher than 10% (normal limit) in 7 cases of N (5.7%), 308 P (43.0%), 33 C (14.6%) and 162 M (36.8%). DP was higher than 10% in 55.2% of the P and M cases with onset less than 1 month before, in 42.8% of those with onset within the year and in 37.2% of those with onset more than a year before. A pathological response to the HST was observed (characterized by a series of at least 3 nystagmus shakes after a maximum latency of 15 seconds) in 0 N (0.0%), 378 P (52.8%), 4 C (1.8%) and 247 M (56.1%). The nystagmus seen was nearly always monophasic (92.5%), biphasic nystagmus was only seen in only a few cases (7.5%); moreover it was predominantly horizontal in nature (94.9%) while it was vertical in only a few of the C cases (5.1%). The HST proved pathological in 46.5% of those pathologies with onset less than 1 month before, in 55.8% of those with onset within the year and in 54.4% of those with onset more than a year before. In 213 of the cases presenting pathological response to the HST there was agreement between VOR DP at the pendular test and the direction of the nystagmus evoked by the HST: 138 P (74.6%), 0 C (0.0%), 75 M (68.2%): moreover there was no agreement in 83 cases. When the DP was lower than 10% at the pendular test, the HST proved pathological in 213 P (52.2%), 3 C (1.6%), 150 M (53.9%). Both tests gave negative results in 112 N (91.8%), 163 P (22.8%), 186 C (82.3%), 123 M (27.9%). In cases of peripheral vestibular deficit (P and M) the sensitivity of the rotoacceleration test was 40.7%, specificity 88.5%. The sensitivity of the HST was 54.1%, specificity 98.8%. The sensitivity of the association using both tests was 75.2%, specificity 85.7%.

Biophysical Phenomena↗

PubMed1995

Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study.

PURPOSE: We report a prospective randomized trial in women with advanced ovarian cancer to evaluate the importance of chemotherapy dose-intensity on survival, progression-free survival (PFS), and response. PATIENTS AND METHODS: A total of 485 patients with epithelial ovarian cancer and residual masses more than 1 cm following surgery (stage III presentation) or any stage IV presentation were randomly assigned to receive either standard therapy (cyclophosphamide 500 mg/m2 and cisplatin 50 mg/m2 intravenously every 3 weeks for eight courses) or intense therapy (cyclophosphamide 1,000 mg/m2 and cisplatin 100 mg/m2 intravenously every 3 weeks for four courses). Dose modification was rigidly controlled to maintain intensity. Clinical and pathologic responses were assessed, when appropriate, as well as PFS interval and survival. RESULTS: A total of 458 patients met all eligibility criteria and were assessed for survival and PFS. The dose-intensive group received the same total dose of cyclophosphamide and cisplatin, but 1.97 times greater dose-intensity than the standard group. Clinical and pathologic response rates; response duration, and survival were similar in both groups of patients. Hematologic, gastrointestinal, febrile episodes, septic events, and renal toxicities were significantly more common and severe in the dose-intensive group. CONCLUSION: A doubling of the dose-intensity in the treatment of bulky ovarian epithelial cancers led to no discernible improvement in patient outcome and was associated with more severe toxicity. This study provides no evidence to support the hypothesis that modest increases in dose-intensity without increasing total dose are associated with significant improvement in overall survival or PFS.

Adult↗

PubMed2005

[Health reasons for work disability among municipal transport drivers].

BACKGROUND: The health condition of public transport drivers is one of the factors playing a role in assuring safety of passengers taking use of this kind of transportation means. Therefore, the assessment of pathologies occurring in this occupational group is essential from the prevention point of view. Drivers employed in the municipal transport system are at particular risk. The aim of the study was to define health reasons of work disability among bus and tram drivers in general and to indicate pathologies responsible for disabilities in particular. MATERIALS AND METHODS: The study covered 940 drivers (including 788 men and 152 women) employed in a municipal transportation enterprise during the years 1996-2000. Bus (30%) and tram (22%) drivers as well as transport service workers (48%), aged over 45 years, but under the retirement age, were eligible for the study. The analysis of temporary work disability during a five-year period was based on sickness absence, sickness absence rate and the average duration of sickness absence. RESULTS: The analysis revealed that diseases of the circulatory system form the major group of pathologies responsible for total sickness absence among bus drivers (43%), tram drivers (27%) and transport service workers (27%). These disease are also a leading cause of earlier retirement. They mostly include ischemic heart disease in bus drivers and hypertension in tram drivers. Cancers (pleura, kidney and eye) were responsible for 9% of sickness absence in the group of male tram drivers, whereas endocrine, nutritional and metabolic diseases and immunity disorders (diabetes, disorders of thyroid gland) in 16% of female tram drivers. Diseases of the musculoskeletal system were major causes of sickness absence among female tram drivers (24%), whereas malignant and benign neoplasms of breast and uterine myoma in 24% of female transport service workers. CONCLUSIONS: The results of the analysis are in agreement with the literature findings and provide explicit evidence that employment in the municipal transport system is the risk factor responsible for the development of serious diseases such as musculoskeletal disorders and neoplasms. Bearing this in mind, this occupational group (bus and tram drivers) should be covered by specially designed prevention programs to protect them against these pathologies, turning special attention to health promotion at and outside workplace.

Aged↗

PubMed2006

Preoperative tegafur suppositories for resectable rectal cancer: phase II trial.

PURPOSE: Preoperative radiochemotherapy for rectal cancer causes a high rate of moderate-to-severe toxicities and is associated with only moderate survival benefits. A simpler, safer, and more convenient treatment would be preferable. Preoperative tegafur suppositories (1,500 mg/day) for at least 14 days were piloted. METHODS: A total of 129 patients with resectable rectal cancer were enrolled. The primary end points were pathologic response, adverse events, rate of sphincter-sparing surgery, recurrence, and survival. RESULTS: The total dose of tegafur ranged from 21 to 78 (mean, 32) g. The anal sphincter was preserved in 60.5 percent with microscopic no residual tumor (R0). The overall morbidity rate was 32 percent. Wound infection occurred in 13.2 percent of cases and anastomotic leakage in 9 percent of cases. Pathologic responses were observed in 70 percent of patients, with a complete necrosis occurring in 3.9 percent, two-thirds or more necrosis in 6.2 percent, one-third or more but less than two-thirds necrosis in 18.6 percent, and less than one-third necrosis in 41.9 percent. The mean total dose that patients showing complete or two-thirds or more necrosis received was 42.8 +/- 6.4 g (P = 0.01) compared with 31.6 +/- 1.2 g administered to patients showing less than two-thirds necrosis. Adverse events were observed in 15.6 percent of patients overall, and Grade III or IV events were observed in 2.3 percent of patients. During a median follow-up of 48 months, distant metastasis occurred in 14.7 percent of patients and local recurrence occurred in 6.2 percent of patients. The four-year, disease-free and overall survival rates were 67.6 and 80.1 percent, respectively. CONCLUSIONS: Preoperative tegafur suppositories are associated with low toxicity and may lead to anal sphincter-sparing surgery with acceptable postoperative complications and favorable local and distal control.

Adult↗

PubMed1990

Tumor reduction surgery and long-term survival in advanced ovarian cancer: a DACOVA study.

Three hundred sixty-one patients with FIGO stage III and IV ovarian cancer were treated with cis-platinum combination chemotherapy in a Danish multicenter trial. Primary surgery was performed at 58 different departments; 32% of the patients were operated at a department associated with an oncologic center, 50% at a general gynecologic department, and 18% at a general surgical department. Complete pathologic response and long-term survival were similar for patients operated on in the different departments. Patients who underwent radical surgery or optimal debulking had a 10% risk of progression during chemotherapy and a 5-year survival of 46%. Patients who underwent suboptimal debulking and exploratory laparotomy had a 40% risk of progression during chemotherapy and a 5-year survival of 14%. Complete pathologic response showed an insignificant difference between radical surgery and optimally tumor reduction (57% versus 41%) and a significant difference between suboptimal tumor reduction and exploratory laparotomy (19% versus 6%). Patients secondarily tumor reduced had a survival rate superior to that of patients not secondarily tumor reduced (25% versus 4% at 4 years).

Adenocarcinoma↗

PubMed2003

p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy.

PURPOSE: Adjuvant therapy, either preoperatively or postoperatively, and modifications of surgery have been used to try to improve outcome of surgery for rectal cancer in regard to both local recurrence and survival. Assessment of prognosis in patients after resection is currently primarily based on clinicopathologic factors. These predict the subsequent behavior of the tumor only imperfectly. The aim of this study was to evaluate three potential molecular genetic markers of prognosis (p53, deleted in colorectal cancer gene, and thymidylate synthase) in Dukes Stage B and C low rectal tumors treated with adjuvant therapy and to determine whether they correlate with survival, local recurrence, or the pathologic response to adjuvant therapy (assessed by extent of tumor regression and tumor down-staging). METHODS: Sixty locally advanced low rectal tumors resected after preoperative chemoradiotherapy or radiotherapy alone were studied by immunohistochemical staining for p53, deleted in colorectal cancer gene, and thymidylate synthase. In addition, p53 gene mutations were sought by polymerase chain reaction-single-strand conformation polymorphism analysis. These results were correlated with survival, local recurrence, and pathologic response to adjuvant therapy. RESULTS: Lack of thymidylate synthase staining by immunohistochemistry was associated with tumor down-staging after preoperative chemoradiotherapy but not after radiotherapy or for these two combined groups. There was no correlation between p53, deleted in colorectal cancer gene, or thymidylate synthase immunohistochemical staining or between p53 polymerase chain reaction-single-strand conformation polymorphism and local recurrence or survival in locally advanced low rectal cancers treated with preoperative adjuvant therapies. CONCLUSION: Prediction of prognosis in patients with locally advanced low rectal cancers treated with preoperative adjuvant therapies continues to be problematic. Thymidylate synthase immunohistochemistry appears to be the most promising factor of those assessed in predicting tumor down-staging after preoperative chemoradiotherapy for locally advanced low rectal cancers.

Adenocarcinoma↗

PubMed2006

A phase II trial of neoadjuvant cisplatin-fluorouracil followed by postoperative intraperitoneal floxuridine-leucovorin in patients with locally advanced gastric cancer.

BACKGROUND: The aim of the study was to evaluate the efficacy and toxicity of neoadjuvant chemotherapy with intravenous (i.v.) cisplatin and fluorouracil (5-FU), surgery and postoperative intraperitoneal (i.p.) floxuridine (FUdR) and leucovorin (LV) in patients with locally advanced gastric cancer. PATIENTS AND METHODS: Preoperative staging was confirmed by laparoscopy (LAP). Two cycles of i.v. cisplatin (20 mg/m(2)/day, rapid infusion) and 5-FU (1000 mg/m(2), continuous 24-h infusion), given on days 1-5 and 29-34, were followed by a radical gastrectomy and a D2 lymphadenectomy. Patients having R0 resections were to receive three cycles of i.p. FUdR (1000 mg/m(2)) and LV (240 mg/m(2)), given on days 1-3, 15-17 and 29-31. Intraperitoneal chemotherapy was begun 5-10 days from surgery. RESULTS: Thirty-eight patients were treated. Both preoperative and postoperative chemotherapy were well tolerated. T stage downstaging (pretreatment LAP versus surgical pathological stage) was seen in 23% of patients. The R0 resection rate was 84%. Neither an increase in postoperative morbidity nor operative mortality was noted. With a median follow-up of 43.0 months, 15 patients (39.5%) are still alive (median survival 30.3 months). Good pathologic response, seen in five patients (15%), was associated with better survival (P = 0.053). Peritoneal and hepatic failures were found in 22% and 9% of patients, respectively. Quality of life seemed to be preserved. CONCLUSIONS: Neoadjuvant cisplatin/5-FU followed by postoperative i.p. FUdR/LV can be safely delivered to patients undergoing radical gastrectomy and D2 lymphadenectomy. The R0 resection and the survival rates are encouraging. An association between pathologic response and patient outcome was suggested.

Adenocarcinoma↗

PubMed2005

Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study.

PURPOSE: Neoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival. PATIENTS AND METHODS: Patients (n = 219) were randomly assigned to ifosfamide 5 g/m(2) during 24 hours plus cisplatin 75 mg/m(2), or paclitaxel 175 mg/m(2) plus ifosfamide 5 g/m(2) during 24 hours and cisplatin 75 mg/m(2) every 3 weeks for three courses. RESULTS: Grades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%; odds ratio, 3.22; 95% CI, 1.69 to 5.88; P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75; 95% CI, 0.48 to 1.17; P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66; 95% CI, 0.39 to 1.10; P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88; 95% CI, 2.50 to 13.84; P < .0001). CONCLUSION: The TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival.

Adult↗

PubMed2006

Prognostic value of tumour regression grading and depth of neoplastic infiltration within the perirectal fat after combined neoadjuvant chemo-radiotherapy and surgery for rectal cancer.

OBJECTIVE: To evaluate histological variables correlated with pathological response to chemo-radiotherapy protocols for rectal cancer and with local recurrence and survival. METHODS: From 1994 to 2003, 58 patients with rectal cancer were enrolled in a non-randomised study based on standardised treatment with radiotherapy, 5-fluorouracil, and surgical resection, followed by histological examination, including tumour regression grading and depth of neoplastic infiltration within the perirectal fat. All patients were followed up. Mean (SD) length of follow up was 55.3 (28.1) months, range 5 to 108. RESULTS: No case was found with no regression (grade 0). Tumour regression was defined as grade 1 in 24.5% of cases, grade 2 in 58.5%, grade 3 in 7.5%, and grade 4 (complete regression) in 9.5%. Neoplastic infiltration of >4 mm within the perirectal fat was found in 25.6% of cases in grade 1, 55.8% in grade, 2.7% in grade 3, and 11.6% in grade 4. In 80% cases of pT4 depth of neoplastic infiltration within the perirectal fat was >4 mm (100% were pN+), and the same spread was also found in 53.4% of pT2 and 86.2% of pT3. Pathological response was associated with regression grade (p = 0.006) and depth of neoplastic infiltration within the perirectal fat (p = 0.04). Tumour regression grading was an independent variable for pT (p = 0.0002), pN status (p = 0.00004), pathological staging (p = 0.000001), and local recurrence (p = 0.003). CONCLUSIONS: Involvement of the lateral resection margins correlates with a poor prognosis and indicates the likelihood of local recurrence of rectal cancer. Tumour regression grading and the depth of neoplastic infiltration within the perirectal fat are important prognostic factors that need to be evaluated routinely.

Adenocarcinoma↗

PubMed2005

Neoadjuvant chemoradiotherapy for esophageal carcinoma.

SUMMARY. Neoadjuvant chemoradiotherapy is often administered to patients with esophageal carcinoma in the belief that this will improve survival. However, its role in the management of esophageal carcinoma remains controversial. In this study we evaluated our experience with neoadjuvant chemoradiotherapy for the treatment of esophageal carcinoma. The study group was 115 patients who underwent esophagectomies between January 1999 and January 2004. Eighty-nine patients had adenocarcinoma and 26 had squamous cell carcinoma. Fifty-six patients underwent neoadjuvant chemoradiotherapy (two cycles of cisplatin and 5-fluorouracil with 45 Gy radiation) followed by esophagectomy. The other 59 patients proceeded directly to esophagectomy. Outcomes were determined prospectively, and follow-up was available for all patients. Neoadjuvant chemoradiotherapy achieved down-staging of the esophageal cancer in 43%, 43% and 46% of patients, according to T, N and TNM classifications, respectively. Neoadjuvant chemoradiotherapy resulted in a complete pathological response in seven (13%) patients. The surgical morbidity rate was 37% (42/115), and in-hospital mortality was 5% (6/115). There were no differences between patients who did and did not undergo neoadjuvant chemoradiotherapy in regard to completeness of resection, perioperative mortality and postoperative morbidity. Four-year survival was 33% following neoadjuvant chemoradiotherapy, compared with 19% for patients undergoing surgery alone. The administration of neoadjuvant chemoradiotherapy in patients with esophageal carcinoma down-staged nearly 50% of tumors, and a complete pathological response occurred in some of these patients. It was not associated with any increase in postoperative morbidity or perioperative mortality. In this non-randomized study, it was also associated with a trend towards a better survival outcome.

Adenocarcinoma↗

PubMed2005

Prognostic indicators in locally advanced gastric cancer (LAGC) treated with preoperative chemotherapy and D2-gastrectomy.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy is increasingly considered an effective treatment option for patients with gastric carcinoma. Aim of the study is to evaluate the prognostic significance of the pathological response and of known prognostic factors in a group of accurately staged locally advanced gastric cancer (LAGC) patients. METHODS: Thirty-three patients with LAGC, staged by laparoscopy, underwent D2-gastrectomy after preoperative chemotherapy. Survival was calculated by Kaplan-Meier method and differences were assessed by the Log-rank and Breslow test. Multivariate analysis was performed using the Cox proportional hazard model in backward stepwise regression. RESULTS: Curative resection (R0) was achieved in 81.8% of patients. A complete or subtotal pathological response was documented in 3 and 6%, respectively. Nineteen out of thirty-three (57.6%) patients were alive and 16 of them were free of relapse at last follow-up. Survival rates were 81, 67, and 59% at 12, 24, and 36 months, respectively. At univariate and multivariate analysis, only R0 resection was found to be an independent prognostic factor. CONCLUSIONS: In the current study, R0 resection is the most important prognostic factor for resectable LAGC; according to our results we feel encouraged to consider neoadjuvant chemotherapy a promising modality for increasing the R0-percentage of gastric carcinoma patients who could benefit from a curative surgery.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress.

Signaling by the calcium-dependent phosphatase calcineurin profoundly influences the growth and gene expression of cardiac and skeletal muscle. Calcineurin binds to calsarcins, a family of muscle-specific proteins of the sarcomeric Z-disc, a focal point in the pathogenesis of human cardiomyopathies. We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1. As a consequence of inappropriate calcineurin activation, mice with a null mutation in calsarcin-1 showed an excess of slow skeletal muscle fibers. The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload. In contrast, cardiac adaptation to other hypertrophic stimuli, such as chronic catecholamine stimulation or exercise, was not affected. These findings show important roles for calsarcins as modulators of calcineurin signaling and the transmission of a specific subset of stress signals leading to cardiac remodeling in vivo.

Adrenergic beta-Agonists↗