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PubMed2004

Measurement of spinal cord atrophy in multiple sclerosis.

In multiple sclerosis (MS), the spinal cord is a common area of involvement, and its dysfunction is likely to be responsible for much of motor disability. It has been reported that atrophy in the cervical spinal cord occurs early and is detectable in patients presenting with a clinically isolated syndrome. This finding has important implications for the early treatment of patients with MS because atrophy is thought to reflect destructive, irreversible pathology and subclinical impairment. Recent clinical trials of disease-modifying agents have included spinal cord imaging and, in particular, the measurement of atrophy as a secondary or exploratory measure of treatment efficacy. This review summarizes the underlying pathology responsible for spinal cord atrophy and the methods available to measure it. The relationships between spinal cord atrophy, other magnetic resonance imaging parameters, and clinical disability are also discussed.

Atrophy↗

PubMed2004

Chemoradiation with raltitrexed (Tomudex) in preoperative treatment of stage II-III resectable rectal cancer: a phase II study.

PURPOSE: To evaluate the impact of preoperative chemoradiation with raltitrexed (Tomudex(1)) on tumor response, sphincter preservation, and toxicity in patients with locally advanced rectal cancer. METHODS AND MATERIALS: Between 1998 and 2002, 54 consecutive patients with Stage T3 or T2N+ resectable rectal carcinoma were treated with preoperative chemoradiation, i.v. bolus of raltitrexed on Days 1, 19, and 38 and concurrent 50 Gy external beam radiotherapy. Surgery was performed 6-8 weeks after the end of chemoradiation. RESULTS: No patients had Grade 4 acute toxicity. Grade 3 acute toxicity occurred in 16.6% of cases and was hematologic in 6 patients and GI in 2. The overall clinical response rate was 88.8%, with a complete response in 5.5%, partial response in 83.3%, and no change in 9.2%. No patient showed disease progression. All patients underwent surgery. Sphincter saving was obtained in 83.3% of patients. No perioperative mortality occurred, and the perioperative morbidity rate was 5.5%. Of 20 resected patients (37%) who were candidates for abdominoperineal resection at diagnosis (anorectal ring distance < or =30 mm), 13 (65%) underwent a sphincter-saving procedure. At pathologic examination, 13 (24%) of 54 patients had a complete pathologic response (pT0) and 10 (18.5%) had rare isolated residual cancer cells (pT, microscopic foci). Overall, 42.5% had major downstaging. The tumor regression grade (TRG), using Mandard's score system, was also applied and was TRG1 in 13 patients, TRG2 in 11, TRG3 in 20, and TRG4 in 10 patients; no patient had TRG5. CONCLUSION: The use of raltitrexed in a neoadjuvant chemoradiation schedule promoted high pathologic tumor downstaging and use of a sphincter-saving procedure. The low toxicity profile supports the rationale to explore raltitrexed combined with other drugs with different biologic targets.

Aged↗

PubMed2000

Immunological cytokine correlates of protective immunity and pathogenesis in leprosy.

The in vitro production of interferon (IFN)-gamma, interleukin (IL)-5, tumour necrosis factor (TNF)-alpha and IL-10 by blood mononuclear cells in response to whole Mycobacterium leprae and polyclonal stimulii of 23 individuals, representing a variety of conditions in relation to exposure/susceptibility to M. leprae, was assayed. In most cases, healthy household contacts of newly diagnosed multibacillary leprosy patients, designated exposed household contacts (EC), showed low-to-undetectable in vitro IFN-gamma production in addition to substantial TNF-alpha production in response to M. leprae. In contrast, peripheral blood mononuclear cells from previously exposed contacts (R) regarded as resistant-to-leprosy released low-to-moderate levels of IFN-gamma together with a mixed cytokine profile resembling a T helper (Th)0-type response. TNF-alpha/IL-10 ratios in response to M. leprae and Concanavalin A were significantly higher in EC than in R contacts suggesting a role for the TNF-alpha/IL-10 ratio in restraining mycobacteria proliferation and spreading early in infection. The cytokine profiles of leprosy patients were taken as reference points. Post-treatment lepromatous leprosy patients secreted relatively high levels of IL-10 in response to M. leprae, whereas one self-cured tuberculoid leprosy patient produced simultaneously high levels of IFN-gamma and TNF-alpha. In addition, the quantitative changes in the cytokines released by peripheral blood mononuclear cells in EC contacts after Bacille Calmette-Guérin (BCG) vaccination were investigated. Vaccination induced amplification of IFN-gamma production with a concomitant decrease in TNF-alpha/IL-10 ratios that resembled the cytokine pattern observed in R contacts. IFN-gamma production was observed in response to both a cross-reactive antigen (Ag 85) and a M. leprae-specific protein (MMP-I), which attests to a BCG nonspecific stimulation of the immune system, thereby casting these antigens as likely candidates for inclusion in a subunit vaccine against leprosy. Finally, a model for protective x pathologic response to mycobacteria is presented.

Adolescent↗

PubMed2005

Bax, a predictive marker for therapeutic response to preoperative chemoradiotherapy in patients with rectal carcinoma.

In an attempt to improve local control and survival in patients with advanced rectal carcinoma, neoadjuvant chemoradiation therapy (CRT) has been increasingly used in patient management. However, a significant proportion of patients shows poor response to adjuvant CRT. Thus, the ability to predict CRT responsiveness in patients with rectal cancer would benefit effective management. Several molecular markers related to regulation of cell cycle, apoptosis, or DNA repair have been proposed as candidate predictors of therapeutic response to CRT, but, to date, none has been definitively proven to be predictive of CRT response. To evaluate the use of various molecular markers as predictors of the response to CRT in rectal carcinoma, we investigated immunohistochemical expressions of p53, p21 WAF1/CIP1 , Bcl-2, Bax, Ki-67, Ku-70, and 2 new candidate markers (histone deacetylase 1 and metabotropic glutamate receptor 4) in pretreatment biopsy samples of 130 rectal carcinomas. We further compared the expressions of these molecular markers with the pathological responses of the tumors after therapy. We found that Bax expression, among the markers studied, was exclusively related to tumor regression. Its expression was significantly higher in the complete response group as compared with the partial response group (54% versus 29%, P = .017). This result confirms that apoptosis plays an important role in tumor response to CRT and provides evidence that Bax may serve as a predictable molecular marker for chemoradiosensitivity in rectal carcinoma.

Adult↗

PubMed1982

Ultrastructure of the pulmonary alveolar septa after hemodynamic edema.

Increased numbers of micropinocytotic vesicles were observed in cells of the air-blood barrier of isolated dog lungs after increased filtration from the microcirculation had created septal edema and alveolar flooding. In studies of dog lungs in vivo, increased rates of filtration from the microcirculation were not associated with increased numbers of cellular vesicles. Since extravascular fluid accumulation in these studies was restricted to the extraalveolar connective tissue spaces, alveolar septal edema and potentially associated increases in alveolar interstitial tissue pressures also failed to occur. Even though the specific sites of increased filtration from the pulmonary microcirculation were not determined, these results are consistent with the interpretation that fluid accumulation in the alveolar septa does not occur until pulmonary lymphatic capacity is overcome. Furthermore, increased cellular vesiculation, which was observed in the isolated lung studies only after septal edema had developed, was not associated with increased filtration but was more likely a response to distension of the septal interstitium. Accordingly, the increased number of vesicles could represent a cellular defense mechanism against excessive interstitial fluid accumulation by providing a pathway for the return of excess filtrate to the blood and alveolar surfaces. The expanded vesicular population, on the other hand, could signify an initial cellular pathologic response, with subsequent coalescence of the more closely packed vesicles eventually leading to the formation of cytoplasmic vacuoles and ultimately to disruption of the lining cell layers.

Animals↗

PubMed2000

p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma.

PURPOSE: The p53 gene plays a critical role in cellular response to DNA damage and has been implicated in the response to platinum compounds in ovarian carcinoma patients. Because taxanes could induce p53-independent apoptosis, we assessed the relevance of p53 gene status to response in ovarian carcinoma patients receiving paclitaxel and platinum-containing chemotherapy. PATIENTS AND METHODS: Forty-eight previously untreated patients with advanced disease received standard paclitaxel/platinum-based chemotherapy. In tumor specimens collected at the time of initial surgery, before therapy, p53 gene status and expression were examined by single-strand conformation polymorphism, sequence analysis, and immunohistochemical analysis. Microsatellite instability analysis was performed on available samples from 30 patients. RESULTS: Thirty-four (71%) of the 48 patients had a clinical response. Pathologic complete remission was documented in 13 (27%) of 48 patients. p53 mutations were detected in 29 (60%) of 48 tumors. Among the patients with mutant p53 tumors, 25 patients (86%) responded to chemotherapy. Only nine (47%) of 19 patients with wild-type p53 tumors responded to the same treatment. The overall response rate and the complete remission rate were significantly higher among patients with mutant p53 tumors than among patients with wild-type p53 tumors (P: =.008). Most of the tested tumors not associated with complete remission (10 of 12 tumors) were also characterized by microsatellite instability. The complete remission rate was higher among patients with tumors without microsatellite instability (five of seven patients). CONCLUSION: In contrast to the limited efficacy of treatment with paclitaxel in combination with standard platinum doses against wild-type p53 ovarian tumors, patients with mutant p53 ovarian tumors were more responsive to paclitaxel-based chemotherapy. The pattern of response to chemotherapy containing paclitaxel is different from that associated with high-dose cisplatin therapy. Determining p53 mutational status can be useful in predicting therapeutic response to drugs effective in ovarian carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

An otherwise typical case of non-Japanese hairy cell leukemia with CD10 and CDw75 expression: response to cladaribine phosphate therapy.

Hairy cell leukemia (HCL) in Western patients typically expresses CD19, CD20, CD11c, CD25, HLA-DR, and IgG/lambda and lacks expression of CD5 and CD10. The immunophenotype is in contrast to Japanese HCL which typically expresses CD5 and CD10. Western and Japanese HCL also differ in their clinical presentation and response to treatment with alpha-interferon. We report a case of non-Japanese HCL which presented typically with pancytopenia; however, the immunophenotype was atypical with expression of CD10 and CDw75. CDw75 expression has not previously been described in either Japanese or non-Japanese HCL. The patient achieved a marked partial pathologic response and complete clinical response to treatment with cladaribine phosphate.

Antigens, CD↗

PubMed1997

The role of chemotherapy in the management of non-metastatic operable extremity osteosarcoma.

Original articles published between 1991-1996 were selected according to specified criteria, and reviewed to provide answers to nine important questions about the role of chemotherapy in the management of non-metastatic extremity osteosarcoma: (1) Does adjuvant chemotherapy improve survival? (2) Are the results of the Rosen T10 protocol reproducible in different settings? (3) Is chemotherapy with two of the most active drugs (DOX/DDP) an effective adjuvant treatment, and comparable to other multiagent regimens? (4) Does histological response to neoadjuvant chemotherapy correlate with reduced local recurrence and/or improved survival? (5) Does a change of chemotherapy for patients whose tumors show a poor histological response to chemotherapy improve survival? (6) Does chemotherapy given before surgery (neoadjuvant) improve survival? (7) Are certain drugs, or their method of administration (route, duration, total dose, dose intensity, pharmacokinetics) important in determining outcomes? (8) Can new agents such as Ifosfamide be incorporated into intensive multi-agent chemotherapy, and does this improve pathological response and/or survival? (9) Can dose intensity of treatment be increased with G-CSF? The brief answers to questions 1-3 and 7-9 are "Yes"; question 4 "Yes, but may be changing"; and questions 5, 6 "Not proven," and these are expanded in the text. Future directions for treatment of osteosarcoma are covered under the headings identification of new agents, dose intensification, circumvention of drug resistance, immunotherapy, and insulin-like growth factor.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Tissue responses to degenerative changes in the temporomandibular joint: a review.

The articular cartilage covering of the mandibular condyle and the articular eminence, as well as the tissue of the articular disc, may be affected by degenerative changes associated with osteoarthrosis. Degenerative changes of cartilage alter its physical properties and, as a result, affect its ability to withstand compressive and shearing stresses. Increased friction between the articular surfaces may impair joint movement and may elicit compensatory or pathologic responses of the cartilage and the adjacent tissues, such as capsule and ligaments, synovial membrane, subchondral bone, and associated musculature. In this review, these structural changes are described and related to common signs and symptoms of craniomandibular dysfunction, such as clicking, locking and instability, pain and tenderness, restricted ranges of mandibular motion, crepitation, deformity, muscle wasting, and changes of occlusion.

Adaptation, Biological↗

PubMed2004

Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration.

Tumor-necrosis factor (TNF), a pleiotropic cytokine, triggers physiological and pathological responses in several organs. Here we show that deletion of the mouse gene Timp3 resulted in an increase in TNF-alpha converting enzyme activity, constitutive release of TNF and activation of TNF signaling in the liver. The increase in TNF in Timp3(-/-) mice culminated in hepatic lymphocyte infiltration and necrosis, features that are also seen in chronic active hepatitis in humans. This pathology was prevented when deletion of Timp3 was combined with Tnfrsf1a deficiency. In a liver regeneration model that requires TNF signaling, Timp3(-/-) mice succumbed to liver failure. Hepatocytes from Timp3(-/-) mice completed the cell cycle but then underwent cell death owing to sustained activation of TNF. This hepatocyte cell death was completely rescued by a neutralizing antibody to TNF. Dysregulation of TNF occurred specifically in Timp3(-/-), and not Timp1(-/-) mice. These data indicate that TIMP3 is a crucial innate negative regulator of TNF in both tissue homeostasis and tissue response to injury.

ADAM Proteins↗

PubMed2004

Neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: experience at a single institution.

HYPOTHESIS: Patients receiving neoadjuvant chemoradiotherapy followed by surgery (CRS) undergo downstaging of their tumor and have improved survival when compared with patients undergoing surgery followed by adjuvant chemoradiotherapy (SCR). DESIGN: Retrospective study. SETTING: Tertiary-care university medical center. PATIENTS: One hundred twenty-three patients with squamous cell carcinoma and adenocarcinoma of the esophagus underwent Ivor-Lewis esophagectomy from January 1, 1990, through December 31, 2001. Of these, 31 received CRS; 27, SCR; and 65, surgery alone. INTERVENTIONS: Patients were candidates for neoadjuvant or adjuvant therapy if they had locally advanced disease (T3/T4 N0 or any T stage with N1). Neoadjuvant and adjuvant therapies were nonrandomized and based on the preference of the treating oncologist and surgeon. MAIN OUTCOME MEASUREMENTS: Pathological downstaging was analyzed in the patients receiving CRS. Operative mortality, postoperative morbidity, median survival, and overall survival were compared between the CRS and SCR groups. RESULTS: Pathological downstaging (as characterized by TNM staging) was observed in 20 (64%) of the patients receiving CRS. Complete pathological responses occurred in 5 (16%) of the patients undergoing CRS. No 30-day mortality was observed in either treatment group. No statistical difference in survival was observed between groups, although a trend suggested improved survival with neoadjuvant therapy (3-year survival in CRS and SCR groups was 45% and 22%, respectively; P =.15). Complete pathological responders in the CRS group had a 1-year survival of 80% compared with 29% in nonresponders (P =.25). No statistical differences were observed between groups in relation to blood loss, length of hospital stay, mortality, or morbidity. CONCLUSIONS: Neoadjuvant chemoradiotherapy effectively downstages cancer in patients with locally advanced esophageal disease. Morbidity and operative mortality were not significantly different between patients receiving neoadjuvant and adjuvant therapy. The difference in overall survival between the 2 groups did not reach statistical significance, although a trend at 3 years was observed.

Adenocarcinoma↗

PubMed2004

The sensitive giant: the role of titin-based stretch sensing complexes in the heart.

Every heart beat is not equal. As physiological demands of the cardiovascular system change, cardiac myocytes modulate contractile parameters including the rate and force of contraction. Adaptive responses require the sensing of biomechanical signals involving the interface between the contractile cytoskeleton (myofibrils) and the sarcolemma at specialized cell-cell junctions (intercalated discs) and cell-substrate adhesion complexes (costameres). Recent studies have shed insight into how protein complexes within cardiac myocytes sense biomechanical signals, processes required for normal adaptive or pathological responses. This new evidence suggests that complexes associated with the giant, myofibrillar protein titin sense myocyte stretch. Here, we discuss evidence supporting titin being an ideal biomechanical sensor.

Animals↗

PubMed2003

Preoperative chemoradiotherapy in cancer of the thoracic esophagus.

Surgery with or without adjuvant radiotherapy (RT) is the standard treatment of esophageal cancer. Preoperative radio- and chemotherapy (CT) have been introduced to improve prognosis. We report a phase II prospective non-randomized trial of preoperative RT (42 Gy/25) plus CT (cisplatin 20 mg/mq/day plus 5-fluorouracil 600 mg/mq/day, 1-5 weeks) for the treatment of thoracic esophageal cancer. From 1993, 50 patients were enrolled (40 men and 10 women, mean age 57 years, range 30-75 years). Squamous cell carcinoma accounted for 90% of cases; 10% were adenocarcinoma. Downstaging of the disease was obtained in 77.3% of cases; there were 13 (29.5%) complete responses (CR) and 21 (47.7%) partial responses (PR). Median survival was 28 and 25 months, respectively, for CR and partial response (PR) plus stable disease (SD) and progressive disease (PD) (P = 0.05). Progressive-free median survival was 22 and 17 months, respectively, for CR and PR + SD + PD (P = 0.08). Multimodal treatment of esophageal cancer showed promising results, although not significant, in terms of survival and disease progression for patients achieving a complete pathologic response.

Adenocarcinoma↗

PubMed1989

Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections.

Neuropeptides such as substance P are implicated in inflammation mediated by sensory nerves (neurogenic inflammation), but the roles in disease of these peptides and the peptidases that degrade them are not understood. It is well established that inflammation is a prominent feature of several airway diseases, including viral infections, asthma, bronchitis, and cystic fibrosis. These diseases are characterized by cough, airway edema, and abnormal secretory and bronchoconstrictor responses, all of which can be elicited by substance P. The effects of substance P and other peptides that may be involved in inflammation are decreased by endogenous neutral endopeptidase (NEP; also called enkephalinase, EC 3.4.24.11), which is a peptidase that degrades substance P and other peptides. In the present study, we report that rats with histories of infections caused by common respiratory tract pathogens (parainfluenza virus type 1, rat corona-virus, and Mycoplasma pulmonis) not only have greater susceptibility to neurogenic inflammatory responses than do pathogen-free rats but also have a lower activity of NEP in the trachea. This reduction in NEP activity may cause the increased susceptibility to neurogenic inflammation by allowing higher concentrations of substance P to reach tachykinin receptors in the trachea. Thus decreased NEP activity may exacerbate some of the pathological responses in animals with respiratory tract infections.

Animals↗

PubMedDate not supplied

Cytological and cytoarchitectural changes in the feline cerebral cortex during experimental infantile hydrocephalus.

While many reports have documented the effects of hydrocephalus on the ependyma and periventricular white matter, primarily in adult animal models, little is known about alterations specific to neurons. The present study has evaluated qualitatively the effects of hydrocephalus on the neurons and vasculature of the cerebral cortex in a neonatal animal model. The cisterna magna of 4 to 11-day-old kittens was injected with a solution of 25% kaolin to induce hydrocephalus. Ultrasonographic evidence of hydrocephalus was noted within 3-5 days of injection. Hydrocephalus progressed until day 18-25 postinjection when the animals were sacrificed. The cytologic and cytoarchitectural changes within the cortical mantle of affected animals were compared with control age-matched counterparts who had undergone intracisternal saline injections. Areas 4 (primary motor), 22 (association) and 17 (primary visual sensory) were examined light microscopically. Neurons from hydrocephalic brains exhibited 3 types of pathological response. Pyknotic somata were shrunken, disoriented and so hyperchromatic that neither nuclei or nucleoli could be delineated. Reactive somata were also shrunken and hyperchromatic, but nuclei and nucleoli could still be observed. Many neurons contained an abundance of vacuoles, giving their somata a flocculent appearance; these cells were termed 'spongy' neurons. Both normal and pathological neurons were smaller and disoriented, with a considerable decrease in neurons noted in areas 22 and 17 from severely hydrocephalic animals. The deeper cortical layers were more affected than the more superficial laminae in that more reactive and pyknotic neurons were present in layers V and VI. As the ventriculomegaly became more severe, changes could be observed in neurons within layers II and III. Furthermore, the cerebral vasculature exhibited a decrease in the number of vessels and a preponderance of profiles oriented parallel to the meningeal surface. The severity of these effects followed a rostral to caudal gradient, such that the occipital cortex demonstrated the most damage. These results suggest that both the motor deficits and the subtle cognitive deficiencies seen with hydrocephalus may be attributed to perturbation of neuronal and vascular elements in the cerebral cortex.

Animals↗

PubMed2004

Prognostic value of P53, MDM-2, and MUC-1 for patients with inflammatory breast carcinoma.

BACKGROUND: Inflammatory breast carcinoma (IBC) is a rare and aggressive malignancy. Therapy for patients with IBC is multidisciplinary, and response to preoperative chemotherapy is considered an important predictor of outcome. Although only a limited number of molecular markers have been investigated in this setting, none has exhibited prognostic value for patients with IBC. METHODS: Immunohistochemical assays for P53, MDM-2, and MUC-1 were performed retrospectively to evaluate potential correlations between these markers and pathologic response, time to progression (TTP), and overall survival (OS) in 19 patients with IBC. RESULTS: After a median follow-up period of 46 months, patients with tumors that overexpressed P53 and did not express MUC-1 had a significantly shorter median TTP and median OS compared with other patients. CONCLUSIONS: Expression of P53 and MUC-1 may be predictive of treatment efficacy and outcome for patients with IBC. Furthermore, these two markers may represent novel therapeutic targets in such patients.

Adult↗

PubMed1990

LH and FSH secretion and responses to GnRH and TRH in patients with clinically functionless pituitary adenomas.

Serum concentrations of LH and FSH and their response to the separate administration of GnRH (100 micrograms i.v.) and TRH (200 micrograms i.v.) have been studied preoperatively in 12 patients with a clinically functionless pituitary adenoma, of whom nine (3F: 6M) were found to secrete gonadotrophins in vitro. In three patients with a gonadotrophin-secreting adenoma (GSA) the pulsatile release of LH and FSH was also assessed preoperatively. An elevated serum FSH was recorded in six of nine patients with a GSA, and was subnormal in one, whilst an elevated LH was recorded in only two and was subnormal in six. A doubling of LH occurred in only four of the nine patients after GnRH and in three of six after TRH. None of the three patients with a non-GSA was shown to have an aberrant response to GnRH or TRH. In patients with a GSA, pulsatile release of LH and FSH was usually asynchronous and neither hormone demonstrated any regular harmonic pattern. These data show that in patients with a GSA the serum FSH level is usually elevated but this is not invariable, and the LH may well be low. Pathological responses of LH are frequently found following the administration of either GnRH or TRH and these stimulation tests should be performed separately in patients presenting with a clinically 'non-functioning' pituitary tumour to assist in the preoperative diagnosis. The absence of normal LH and FSH pulsing also appears to be a feature of GS adenomas, and suggests that tumorous gonadotrophin secretion is not under physiological control by hypothalamic GnRH.

Adenoma↗

PubMed1979

Deficits in the visual evoked potentials of cats as a result of visual deprivation.

Visual evoked potentials in response to contrast reversal of grating patterns were used as a measure of visual function in normal and visually deprived cats. In cats which had been dark reared from birth (BD cats) there was a characteristic change in VEP waveform from normal, for both eyes and for all spatial frequencies of testing stimulus. In cats which had one eye sutured from the age of one week (MD cats), the VEP from the deprived eye was smaller for contrast reversal of coarse patterns. Kittens given only restricted periods of monocular exposure gave VEPs which resembled the pathological responses of the BD cats. However, the amplitudes of response were larger for the more experienced eye at higher spatial frequency. This work reinforces the idea that two factors govern cortical development: competition and experience. Lack of sufficient visual experience leads to severe intracortical pathology.

Aging↗