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PubMed2005

Cauda equina syndrome secondary to constipation: an uncommon occurrence.

Suspected spinal cord or cauda equina pathology is an emergency that must be dealt with swiftly, with appropriate referral and investigations. Constipation is a clinical diagnosis of exclusion, but should not be forgotten as a cause of major morbidity when severe in nature. It can mimic an acute abdomen, sepsis and even spinal cord pathology. We describe a case of cauda equina syndrome in a young man. The pathology responsible was found to be constipation with faecal impaction, once nerve and bony pathology were excluded. When treated, there was almost immediate resolution of the neurologic signs and urinary retention.

Child↗

PubMed1997

Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience.

PURPOSE: To determine whether breast conservation and prolonged neoadjuvant chemotherapy have efficacy in locally advanced breast cancer (LABC), as measured by survival and rate of breast conservation. MATERIALS AND METHODS: Eighty-nine patients with stage III disease were enrolled at the University of Michigan (UM) onto a prospective nonrandomized trial. Patients received nine 21-day cycles of neoadjuvant chemohormonal therapy that consisted of doxorubicin 30 mg/m2 and cyclophosphamide 750 mg/m2 intravenously on day 1, conjugated estrogens 0.625 mg orally twice daily on days 6 to 8, methotrexate 40 mg/m2 and fluorouracil 500 mg/m2 intravenously on day 8, and tamoxifen 10 mg orally twice daily on days 9 to 14. Patients with a negative biopsy received radiation only, while those with residual disease underwent mastectomy and postoperative radiotherapy. Eight more cycles of chemohormonal therapy were administered after local-regional therapy. RESULTS: The clinical response rate to neoadjuvant therapy was 97%, 28% of patients had a complete pathologic response evaluated at biopsy. Five-year overall and disease-free survival probabilities were 54% and 44%, respectively. The median disease-free survival time was 2.4 years. The 5-year actuarial rates of local-regional control with local failure as only first failure were 82% and 78% following radiotherapy, and mastectomy and radiotherapy, respectively (P = .99). CONCLUSION: Prolonged neoadjuvant chemohormonal therapy and biopsy-driven local therapy have efficacy in LABC, with 28% of patients being candidates for breast conservation and a 5-year overall survival rate of 54%.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

[Update on docetaxel and breast cancer].

Docetaxel (Taxotère) has been developed in breast cancer during the last decade. First its activity in monotherapy was proven in metastatic setting after failure of anthracycline therapy. Then the association with anthracycline demonstrated substantial activity leading to its development in early stages of breast cancer and its incorporation in adjuvant and neoadjuvant settings. Recently the first adjuvant trial comparing the association TAC versus FAC was presented. In the TAC arm, the disease free survival was better comparing with FAC (p = 0.0011) and survival was better in the subgroup with less than four positive lymph nodes. In the neoadjuvant setting, the incorporation of docetaxel after an anthracycline-based regimen (protocols Aberdeen and NSABP-B27) led to better clinical response, subsequently to better breast conservation and more important the increase of the pathological response rate. Improvement of survival has been reported in the Aderbeen study but a longer follow-up of the NSABP B27 study is required to confirm the impact of Taxotère in the outcome of breast cancer. The next step will be the development of the combination of the most active chemotherapeutic regimen with targeted therapies according to molecular characteristics of the tumor. The integration of trastuzumab with taxane-based chemotherapy has already demonstrated high activity in metastatic breast cancer with overexpression of HER2 and adjuvant trials are ongoing.

Antibodies, Monoclonal↗

PubMed1981

[Structure of anorexia nervosa].

The author presents her findings in social, psychodynamic and biological fields of 35 patients suffering from anorexia nervosa and 30 patients suffering from post pill amenorrhoea. Both groups show a decreased response to LH-releasing hormones, a prolonged time of acrale reheating and pathological responses to the administration of insulin and adrenalin. The disturbances are more severe in the group of anorectic patients and are discussed as signs of a dysfunction of the cerebro-hypothalamic-pituitory axis. The psychodynamics of the patients and the educational style of the parents (EBF 70, Böttcher) show similarities between both groups.

Adolescent↗

PubMed1976

Fetal heart rate response to amniocentesis in cases of decreased fetal movements.

Eleven women with fetal distress as manifested by a decrease of fetal movements up to cessation underwent amniocentesis for amniotic fluid evaluation under continuous FHR monitoring. All the fetuses showed abnormal heart rate response, manifested by absence of FHR acceleration or early or late deceleration. The pathologic response, or lack of response of fetal heart rate during amniocentesis is suggested as an additional test to evaluate the severity of fetal distress.

Amniocentesis↗

PubMed2003

Comparison of intrathecal chemotherapy for leptomeningeal carcinomatosis of a solid tumor: methotrexate alone versus methotrexate in combination with cytosine arabinoside and hydrocortisone.

OBJECTIVE: To compare the efficacy of intrathecal methotrexate single therapy with three-drug combination therapy in patients with leptomeningeal carcinomatosis. METHODS: Fifty-five patients who had pathologically proven leptomeningeal carcinomatosis of a solid tumor were evaluated in terms of pathological response. Group M (n = 29) received methotrexate 15 mg and group MHA (n = 26) received methotrexate 15 mg, hydrocortisone 15 mg/m(2) and ara-C 30 mg/m(2) twice a week intrathecally until a cytological response was obtained. RESULTS: Primary sites of the tumor were the lung (n = 33), breast (n = 13) and stomach (n = 5). The pathology of 45 patients was adenocarcinoma. The cytological response rate to intrathecal chemotherapy was significantly higher in the MHA group than in the M group (38.5 vs 13.8%, P = 0.036). The median survival was 18.6 weeks in the MHA arm and 10.4 weeks in the M arm (P = 0.029). CONCLUSION: Combination intrathecal chemotherapy with methotrexate, cytosine arabinoside and hydrocortisone showed more favorable effects than methotrexate single therapy for leptomeningeal carcinomatosis in solid tumors.

Adenocarcinoma↗

PubMed1978

Toxic responses in gerbils treated topically with aflatoxin B1 and dimethylformamide.

Male and female Mongolian gerbils failed to show observable pathological responses in the liver to topically applied AFB1 and DMF indicating that percutaneous absorption of AFB1 is absent in this species. In males, some responses in weight changes were attributed, proportionally, to increased doses of DMF. Unexplained and currently under investigation is the possibility that AFB1 may have reduced the response of some animals to DMF. This response may relate in some way to the modification of absorption of DMF in the gerbil since AFB1 is known to have an influence on cell membranes.

Administration, Topical↗

PubMed2004

The responses of a tropical breed of domestic rabbit, Oryctolagus cuniculus, to experimental infection with Trichostrongylus colubriformis.

Clinical, parasitological and pathological responses of a tropical out-bred domestic rabbit to experimental Trichostrongylus colubriformis infection were used to evaluate its suitability as a laboratory host and model for studying the host-parasite relationships of T. colubriformis. In the first experiment, three groups each of 16, predominantly juvenile male, 8- to 10-week-old rabbits were given a single pulse infection with 500, 5000 or 25000 infective larvae (L3) of T. colubriformis, to represent low, medium and high levels of infection, respectively. A fourth group of 16 rabbits of similar age formed the uninfected controls. In the second experiment, two groups of 10 juvenile (8- to 10-week-old) and 10 adult (8- to 10-month-old) rabbits were similarly infected with 20000 L3, with appropriate naive controls. Prepatency was 14 and 16 days and peak faecal egg counts occurred on days 24 and 20 after infection in young and adult rabbits respectively. Peak worm counts occurred on day 14 in both age groups and at all levels of infection. Subsequently, parasite burdens declined in a highly significantly dose- and age-dependent manner. At low and moderate levels of infection, approximately 83-98% of worms were recovered from the first 60 cm of the small intestine. Worm fecundity was also significantly influenced by host age and larval dose. Host age also had a significant effect on worm length. Infections with T. colubriformis were associated with a highly significant loss of body weight, accompanied by anorexia, diarrhoea and 25% mortality at high dose levels during the patent period of infection. There were no significant changes in packed cell volume and eosinophil counts at all ages and levels of infection but significant lymphocytosis occurred at the high dose level between days 7 and 21. Parasite-specific serum IgG responses were not related to worm burden. Overall, data showed that this miniature, docile and relatively inexpensive breed of rabbit is a potentially valuable laboratory host for studying T. colubriformis infections. The larval dose, duration of infection and host age were major determinants of host responsiveness to primary infections in this rabbit genotype.

Animals↗

PubMed2004

Evidence-based use of neoadjuvant taxane in operable and inoperable breast cancer.

Neoadjuvant chemotherapy (NC) is standard therapy for patients with locally advanced breast cancer and is increasingly used for early-stage operable disease. The aim of NC is a pathological complete response (pCR) in the breast and axillary lymph nodes, which is the best predictor of improved outcome and prolonged survival. The taxanes docetaxel and paclitaxel are potent agents in breast cancer management, with promising single-agent activity and acceptable tolerability in the neoadjuvant setting. In this review of the taxanes as NC for operable and inoperable breast cancer, we include all fully published Phase II-III studies enrolling > or =30 patients. Current evidence suggests that the sequential administration of taxane- and anthracycline-based therapy may be superior to concomitant administration. Indeed, until the recent Phase III Aberdeen study (n = 162), it was uncertain whether NC could prolong survival. In this study, sequential docetaxel after anthracycline-based NC significantly enhanced the clinical response rate and pathological complete response, and yielded a significant 3-year survival advantage, versus anthracycline-based NC alone. Recently, the Phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B27 trial (n = 2411) showed that sequential docetaxel after doxorubicin-cyclophosphamide significantly increased both clinical and pathological response rates for operable breast cancer, with the benefit evident in both estrogen receptor-positive and estrogen receptor-negative patients. This apparent superiority of a sequential anthracycline-taxane regimen is limited to docetaxel, with no similar Phase III trials of paclitaxel versus a non-taxane-based comparator having been conducted to date. In conclusion, current evidence supports the inclusion of a taxane in NC schedules for patients with large and locally advanced breast cancer.

Anthracyclines↗

PubMed2006

Pathologic, radiologic and PET scan response of gastrointestinal stromal tumors after neoadjuvant treatment with imatinib mesylate.

AIM: The aim of this study is to review the radiologic, PET scan and pathologic response and the outcome of patients with advanced GIST treated with neoadjuvant IM followed by surgical resection. MATERIALS AND METHODS: We report a case and review 36 patients reported in MEDLINE with advanced GIST treated with neoadjuvant IM followed by surgical resection. RESULTS: Thirty-seven patients with a median age of 56 years (range, 32-76 years) at presentation were treated with neoadjuvant IM. Radiologic response accurately predicted pathological response in 31/36 patients, whereas PET scan was accurate in predicting treatment response in only 6/23 patients. CONCLUSION: This study demonstrates that the pathologic response of GIST to IM is usually incomplete and does not correlate with the complete response seen on PET scan. This finding suggests that surgical resection will continue to play a vital role in the treatment of patients with advanced disease responding to IM treatment.

Adult↗

PubMed2006

Allergic fungal sinusitis.

Many common chronic inflammatory rhinosinusitis conditions (hypertrophic sinus disease [HSD]) have the histopathological profile of allergic or asthmatic inflammation. Allergic fungal sinusitis (AFS) is both a type of noninvasive fungal rhinosinusitis and a type of HSD. AFS has clinicopathological features that make it similar, but not identical, to allergic bronchopulmonary aspergillosis (ABPA). Allergic mucin is a defined pathological entity occurring in ABPA, AFS, and in the HSD "eosinophilic mucin rhinosinusitis (EMRS)." Diagnosis of AFS requires a careful review of surgical reports, histopathology, and culture results. Treatment includes surgery and aggressive postoperative medical management of allergic inflammatory disease. Prognosis is good with integrated medical-surgical follow-up, but recurrence remains problematic. The association of ABPA, AFS, and HSD with class II genes of the major histocompatibility complex places the initiation of these inflammatory diseases within the context of antigen presentation and the acquired immune response. Pathological immunomanipulation of this response by local microbial superantigens may be a common mechanism for disease pathogenesis. Future research into the molecular biology of these related conditions may offer insight into the pathogenesis of other chronic inflammatory diseases.

Chronic Disease↗

PubMed1999

The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation.

T cells constantly sample their environment using receptors (TCR) that possess both a germline-encoded low affinity for major histocompatibility complex (MHC) molecules and a highly diverse set of CDR3 regions contributing to a range of affinities for specific peptides bound to these MHC molecules. The decision of a T cell "to sense and to respond" with proliferation and effector activity rather than "to sense, live on, but not respond" is dependent on TCR interaction with a low number of specific foreign peptide:MHC molecule complexes recognized simultaneously with abundant self peptide-containing complexes. Interaction with self-complexes alone, on the other hand, generates a signal for survival without a full activation response. Current models for how this distinction is achieved are largely based on translating differences in receptor affinity for foreign versus self ligands into intracellular signals that differ in quality, intensity, and/or duration. A variety of rate-dependent mechanisms involving assembly of molecular oligomers and enzymatic modification of proteins underlie this differential signaling. Recent advances have been made in measuring TCR:ligand interactions, in understanding the biochemical origin of distinct proximal and distal signaling events resulting from TCR binding to various ligands, and in appreciating the role of feedback pathways. This new information can be synthesized into a model of how self and foreign ligand recognition each evoke the proper responses from T cells, how these two classes of signaling events interact, and how pathologic responses may arise as a result of the underlying properties of the system. The principles of signal spreading and stochastic resonance incorporated into this model reveal a striking similarity in mechanisms of decision-making among T cells, neurons, and bacteria.

Animals↗

PubMed2002

Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes.

Molecular processes regulating the gain of NMDA receptors modulate diverse physiological and pathological responses in the CNS. Group I metabotropic glutamate receptors (mGluRs), which neighbor NMDA receptors and which can be coactivated by synaptically released glutamate, couple to several different second messenger pathways, each of which could target NMDA receptors. In CA3 pyramidal cells we show that the activation of mGluR1 potentiates NMDA current via a G-protein-independent mechanism involving Src kinase activation. In contrast, mGluR5-mediated enhancement of NMDA current requires G-protein activation, triggering a signaling cascade including protein kinase C and Src. These results indicate that one neurotransmitter, glutamate, can activate two distinct and independent signaling systems to target the same effector. These two pathways are likely to contribute significantly to the highly differentiated control of NMDA receptor function.

Animals↗

PubMed1993

Immunoprophylaxis and immunotherapy of respiratory syncytial virus-infected mice with respiratory syncytial virus-specific immune serum.

The effects of passive respiratory syncytial virus (RSV) immune serum given as preinoculation prophylaxis, postinoculation prophylaxis, and as therapy on d 5 after inoculation were evaluated in an illness model of RSV infection in BALB/c mice. Pre- and postinoculation prophylaxis reduced RSV replication in lung after primary RSV infection and prevented illness. Day 5 treatment did not affect peak titer of RSV in lung but resulted in more rapid recovery from illness than seen in untreated mice. Prophylaxis prevented antibody responses and lymphocytic infiltrates in lung after primary RSV infection. Treatment caused diminished antibody and pathologic responses. Prophylaxis increased susceptibility to reinfection, although illness after rechallenge was mild. Mice treated therapeutically were less susceptible to reinfection than mice treated prophylactically, but they also experienced mild illness after rechallenge. Passive antibody prophylaxis and treatment of RSV infection are promising approaches to attenuating lower respiratory tract illness from primary RSV infection. The ability to measure illness endpoints and pathology make the BALB/c mouse model of RSV infection a useful system for the preclinical evaluation of immunoprophylactic and immunotherapeutic modalities.

Animals↗

PubMed2002

Anti-tumor effects of letrozole.

The use of drugs, which inhibit estrogen biosynthesis, is an attractive treatment for postmenopausal women with hormone-dependent breast cancer. Estrogen deprivation is most specifically achieved using inhibitors which block the last stage in the biosynthetic sequence, i.e., the conversion of androgens to estrogens by the aromatase enzyme. Recently, a new generation of aromatase inhibitors has been developed. Among these, letrozole (Femara) appears to be the most potent. When given orally in milligram amounts per day to postmenopausal women, the drug almost totally inhibits peripheral aromatase and causes a marked reduction in circulating estrogens to levels that are often undetectable in conventional assays. Similarly, neoadjuvant studies demonstrate that letrozole substantially inhibits aromatase activity in both malignant and nonmalignant breast tissues, and markedly suppresses endogenous estrogens within the breast cancers. These studies also illustrate anti-estrogenic and anti-proliferative effects of letrozole in estrogen receptor (ER)-rich tumors. Thus, tumor expression of progesterone receptors and the cell-cycle marker Ki67 is significantly and consistently reduced with treatment. Additionally, clear pathological responses as evidenced by decreased cellularity and increased fibrosis are seen in the majority of cases. These results translated into clinical benefit in a series of 24 breast cancers treated neoadjuvantly with letrozole (either 2.5 or 10 mg): tumor volume reductions > 25% were observed in 23 women, and > 50% reductions in 18 patients. Pathological and clinical effects are seen much more consistently than with tamoxifen. Thus, in a multicenter randomized trial of letrozole vs. tamoxifen (PE 024), clinical study outcomes were superior for letrozole in comparison with tamoxifen with regard to overall tumor response and an increase in the proportion of patients treated by breast conserving surgery. Letrozole has also been used in advanced breast cancer, both as second-line hormone treatment following tamoxifen failure, and more recently as first-line therapy. Trials of second-line treatment in which letrozole has been compared with either older aromatase inhibitors or progestins have shown equivalent or superior clinical activity and improved tolerability favoring letrozole. In first-line comparison with tamoxifen in metastatic disease, a phase III trial of over 900 postmenopausal women showed letrozole to be significantly better than tamoxifen in terms of overall tumor response rates, clinical benefit, and time to treatment failure. In summary, letrozole is an exceptionally potent and specific endocrine agent. In patients with ER-rich tumors, high rates of pathological and clinical response have been documented, and large phase III trials against established treatments such as tamoxifen and progestin suggest superior (or at least equivalent) clinical efficacy. Letrozole is a drug of immense potential and in the future is likely to occupy a central role in the management of postmenopausal women with hormone-dependent breast cancer.

Antineoplastic Agents↗

PubMed1997

Correlation of ischemia/reperfusion or partial outlet obstruction-induced spectrin proteolysis by calpain with contractile dysfunction in rabbit bladder.

OBJECTIVES: In the rabbit, both experimental ischemia and partial outlet obstruction of the urinary bladder induce similar dysfunctions with regard to the contractile responses to both field (neuronal) stimulation and postsynaptic receptor stimulation. Circumstantial evidence indicates that the pathologic response to both conditions is related to two connected processes-tissue ischemia and reperfusion injury-that result in a marked increase in intracellular calcium ([Ca2+]i), followed by the activation of the Ca(2+)-dependent neutral protease calpain. Calpain activation results in the proteolysis of specific membrane proteins, including those of neuronal membranes (resulting in progressive denervation of the detrusor) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), resulting in the previously reported decrease in SERCA. The current study is designed to generate direct support for the theory that both ischemia and partial outlet obstruction result in the activation of calpain. METHODS: Separate sets of rabbits were subjected to 1 or 2 hours of ischemia, followed by reperfusion for different lengths of time, or partial outlet obstruction for different lengths of time. We determined the state of calpain activation by quantitating tissue proteolysis of alpha-spectrin by Western blot analysis. Correlative organ bath studies were conducted to observe the contractile responses of bladder strips to field stimulation and bethanechol administration. RESULTS: (1) Sixty minutes of ischemia followed by 30 minutes of reperfusion resulted in (a) a reduction in the contractile responses to field stimulation and bethanechol (89% and 57%, respectively), and (b) a 72% decrease in native alpha-spectrin, with a concomitant 300% increase in its breakdown products (BDPs). Neither alpha-spectrin nor its BDPs had returned to control levels after 72 hours of reperfusion. (2) Twenty-four hours after the creation of a partial obstruction, alpha-spectrin BDP levels were increased 330%, then gradually fell to 130% of control levels by 14 days after obstruction. Concomitantly, the native alpha-spectrin level was decreased 74% 24 hours after obstruction and remained low through 7 days after obstruction. At 14 days after obstruction, the alpha-spectrin levels had recovered to 75% of control levels. CONCLUSIONS: These findings suggest that Ca(2+)-dependent proteolysis of the preferred calpain substrate alpha-spectrin in urinary bladder tissues is increased significantly by both ischemia/reperfusion and partial outlet obstruction. Temporally, proteolysis precedes the reduced muscle function resulting from these pathologic conditions.

Animals↗

PubMed2001

ACE inhibition in aortic stenosis: dangerous medicine or golden opportunity?

Conventionally angiotensin-converting enzyme (ACE) inhibitors are contraindicated in patients with aortic stenosis. Abundant evidence is now available showing that angiotensin II has a central role in the development of left ventricular hypertrophy (LVH), myocardial contractile failure and diastolic dysfunction in response to pressure overload. In animal models, ACE inhibitors have been shown to attenuate these pathological responses. In humans there is no such evidence available, however uncontrolled studies have shown that these agents are not only tolerated but are associated with acute improvements in haemodynamics and diastolic function. Further studies are merited to assess the possible role of ACE inhibitors in aortic stenosis both before and after valve replacement. Potential benefits may include prevention of LVH, improved diastolic function, reduction of arrhythmias and preservation of left ventricular function.

Adult↗

PubMed2005

Treatment effects in pediatric soft tissue and bone tumors: practical considerations for the pathologist.

Dramatic improvements in survival for children with cancer have led to increased numbers of posttreatment pathologic specimens, particularly in bone and soft tissue sarcomas. Current therapeutic protocols in North America require specific pathologic classification and stratify patients based on clinical, biologic, and pathologic features. For osteosarcoma, the pathologic response to therapy predicts prognosis and modifies the treatment regimen. Ongoing studies aim to assess the response to therapy and outcome in other types of soft tissue and bone tumors. The pathologic evaluation of pretreatment and posttreatment specimens is critical for therapeutic decisions and prognostic assessment. A standardized approach to posttherapy pathologic specimens, with attention to appropriate use of ancillary tests, and assessment of clinical and biologic significance of therapy-induced pathologic changes has significance for patient management and treatment protocols.

Bone Neoplasms↗