Antibody-based profiling of the phosphoinositide 3-kinase pathway in clinical prostate cancer.

PURPOSE: As kinase inhibitors transition from the laboratory to patients, it is imperative to develop biomarkers that can be used in the clinic. The primary objectives are to identify patients most likely to benefit from molecularly targeted therapies and to document modulation of the drug target. Constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway and its downstream effectors, as a result of PTEN loss or by other mechanisms, occurs in a high proportion of prostate cancers, making it an ideal template for the design of clinical trials involving PI3K pathway inhibitors. Prostate cancers also present unique organ-specific challenges, in that tumors are heterogeneous and diagnostic tissue is extremely limited. EXPERIMENTAL DESIGN: Working within these limitations, we have developed a set of immunohistochemical assays that define activation of the PI3K pathway in clinical samples. Results and CONCLUSIONS: Using both univariate and multivariate analyses, we show that loss of PTEN is highly correlated with the activation of AKT, and this, in turn, is associated with the phosphorylation of S6, one of its main effectors. These three antibodies are potentially able to define a molecular signature of PTEN loss and/or AKT pathway activation in prostate cancer.     

Phase II study of 1alpha-hydroxyvitamin D(2) in the treatment of advanced androgen-independent prostate cancer.

PURPOSE: In this single institution Phase II trial, we evaluated the efficacy of the vitamin D analogue, 1alpha-OH-D(2), in patients with advanced hormone-refractory prostate cancer. Experimental Design: The patients initially received 1alpha-OH-D(2) at 12.5 micro g p.o. every day, which was dose adjusted for hypercalcemia. Given the cytostatic nature of the drug, the primary study end point was progression-free survival for a minimum of 6 months. The secondary end point was further characterization of drug toxicity. RESULTS: A total of 26 patients was enrolled. Using the intent-to-treat population, stable disease was seen for an average of 19.2 weeks (median 12 weeks, range 3-108 weeks). Twenty patients were evaluable for response. The one patient that achieved disease stabilization for >2 years elected to come off-study because of patient preference. His last disease evaluation showed no evidence of progression. No objective responses were seen. Previous and ongoing clinical observations strongly imply that PSA could be a misleading surrogate marker for clinical effect with this type of drug. Therefore, prostate-specific antigen was not used as a marker for disease response. Toxicity was as expected with mild hypercalcemia and associated symptoms like constipation and prerenal azotemia seen in some patients. Six (30%) evaluable patients experienced stable disease for >6 months, suggesting possible cytostatic activity. CONCLUSION: The results of this and other trials suggest further clinical investigation in this disease with vitamin D analogues alone or in combination with other agents, such as chemotherapy, should be pursued.     

Underestimation of breast cancer with II-gauge vacuum suction biopsy

OBJECTIVE. The purpose of this study was to determine the mammographic and histologic features of cancerous lesions underestimated using 11-gauge vacuum suction biopsy. MATERIALS AND METHODS. Retrospective review of 11-gauge vacuum suction biopsy was performed to identify lesions diagnosed as atypical ductal hyperplasia or carcinoma. The histology of the core and surgical specimens was compared. Of 158 cases of cancer, underestimation occurred in 15 (9.5%). The mammographic and histologic features were assessed. RESULTS. Of 15 underestimated cases, six were atypical ductal hyperplasia that proved to be cancer (5 ductal carcinoma in situ and 1 invasive) and nine were ductal carcinoma in situ that proved to have invasion. The underestimation rate for calcifications was 16.3% (14/86) and for masses was 1.6% (1/64) (p = 0.007). Most (5/6) underestimated atypical ductal hyperplasia cases were reported as "markedly atypical," and four of nine underestimated ductal carcinoma in situ cases were reported as "possible invasion." No significant difference was seen in the number of core specimens obtained or the sizes of the lesions for underestimated cases versus accurately diagnosed cases. The percentage of calcifications retrieved was significantly different (p = 0.017). No underestimations were found among cases in which the entire mammographic lesion was removed at vacuum suction biopsy. CONCLUSION. The cancer underestimation rate with vacuum suction biopsy was 9.5%. The underestimation rate for calcifications (16.3%) was significantly higher than that for masses (1.6%) (p = 0.007). The percentage of the lesion removed was an important factor in reducing underestimation, as reflected by the percentage of calcifications retrieved and the instances of complete resolution of the lesion seen on mammography.     

Estrogen effects on tyrosine hydroxylase-immunoreactive cells in the ventral mesencephalon of the female rat: further evidence for the two cell hypothesis of dopamine function

The present study was undertaken to examine the differential effect of estrogen (E) on the expression of tyrosine hydroxylase (TH) in the substantia nigra compacta (SNc) and in two subdivisions of the ventral tegmental area in ovariectomized (ovx) and ovx plus estradiol benzoate (ovx+E)-treated female rats. Cell counting of TH-immunoreactive perikarya of the SNc, paranigral (PN) and interfascicular (IF) nucleus was performed and compared. Our findings demonstrate that E eliminated TH immunoreactivity from a number of midbrain neurons, while it seemingly did not affect it in others. This signifies a differential effect of E on ventral mesencephalic dopaminergic neurons.     

The effects of ketamine and its enantiomers on the morphine- or dexmedetomidine-induced antinociception after intrathecal administration in rats

BACKGROUND: The spinal administration of some N-methyl-d-aspartate receptor antagonists results in antinociception and potentiates the effects of opioids and alpha2-adrenoceptor agonists, but ketamine and its enantiomers have not been examined. The present study investigated the interactions of racemic ketamine, R(-)-ketamine and S(+)-ketamine with morphine and with dexmedetomidine. METHODS: Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-flick test. Analgesic latencies were converted to the percentage maximum possible effect. The dose that yielded 50% of the maximum possible effect (ED50) and dose-response and time-course curves were determined for the ketamines (30-300 microg), morphine (0.1-3.0 microg), dexmedetomidine (0.3-10.0 microg), and mixtures of two doses of ketamines (30 or 100 microg) with different doses of morphine or dexmedetomidine for fixed-dose analysis. RESULTS: Neither racemic ketamine nor its enantiomers alone had a significant effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomidine each produced dose-dependent antinociception, with ED50 of 1.7 microg (95% confidence interval: 1.04-2.32) and 4. 85 microg (3.96-5.79), respectively. A low dose (30 microg) of racemic ketamine or its enantiomers did not influence the ED50 of morphine significantly. Coadministration of 100 microg racemic ketamine or S(+)-ketamine, but not R(-)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ketamine or its isomers significantly decreased the ED50 value for dexmedetomidine, although the higher dose of racemic or S(+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S(+)-ketamine also prolonged the effects of dexmedetomidine. CONCLUSIONS: These data indicate that racemic ketamine and S(+)-ketamine, but not R(-)-ketamine, exhibit similar effectiveness in potentiating the antinociceptive effects of both morphine and dexmedetomidine.     

Secondary biogenic amine deficiencies: genetic etiology,therapeutic interventions,and clinical effects

neurogenetics - Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that...     

Topical treatments of laparoscopic port sites can decrease the incidence of incision metastasis

BACKGROUND: Anecdotal reports of port site tumor recurrence have dampened the enthusiasm for laparoscopic colectomy for cancer. We developed a rat model that creates a high incidence of port site metastasis following laparoscopic intervention. Our goal was to assess the feasibility of minimizing implantations using port site irrigation prior to wound closure. METHODS: Colon cancer carcinomatosis was established in 46 female BD9 rats using intraperitoneal injections of 10(6) DHD-K12-TRb rat colon cancer cells. This preparation yielded an 81% incidence of port site metastasis in a control group. Laparoscopic sham surgery was performed using four ports and a CO(2) pneumoperitoneum. Four treatment groups were studied by irrigating each port site as follows: Group I, sterile water; group II, normal saline; group III, heparin; group IV, 5-fluorouracil (5-FU). The animals were killed at 4 weeks, and the port sites were examined for tumors. RESULTS: There were no differences in port site metastasis between controls and groups I, II, and III. The 5-FU group showed a significant decrease (30% vs 81%) in metastasis. CONCLUSIONS: Port site irrigation with 5-FU at the time of laparoscopy reduces the incidence of port site tumor implantation in a rat colon cancer model. This finding may have utility in patients at high risk of such metastasis who undergo laparoscopy for colon cancer.     

Gonadotropic pituitary carcinoma: HER-2/neu expression and gene amplification. Report of two cases

The authors report on two gonadotropic carcinomas of the adenohypophysis that occurred in a55-year-old man (Case 1) and a 53-year-old woman (Case 2), with signs of mass effect and amenorrhea, respectively. Both lesions were macroadenomas. The tumor in Case 1 metastasized to dura mater, skull, nasal sinus, and larynx 2 years after patient presentation, whereas that in Case 2 spread to vertebral bodies and ribs after a 19-year latency. Histologically, the primary, recurrent, and metastatic lesions in Case 1 featured brisk mitotic activity and high MIB-1 levels as well as p53 labeling indices. Immunoreactivity for HER-2/neu was assessable only in rare neoplastic cells of the second recurrence and in 80% of cells of the dural metastasis. Low-level HER-2/neu gene amplification was evident in the recurrent tumors and metastasis. The sellar and metastatic tumors in Case 2 resembled benign gonadotropic adenoma with oncocytic change; p53 accumulation, HER-2/neu overexpression, and HER-2/neu gene amplification were not present. The results indicate that low-level amplification of the HER-2/neu gene might be associated with pituitary carcinomas in which more aggressive behavior is seen. Further studies are needed to determine whether HER-2/neu plays a role in the pathogenesis of pituitary carcinoma.