Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.

PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.     

A ureterocutaneous fistula forty years after nephrectomy

The case of a woman presenting with a ureterocutaneous fistula 40 years after nephrectomy is described. Because of advanced respiratory disease and absence of infective activity, a conservative line of treatment with saline rinse was given. At 3 months follow-up the fistula had become chronic, with a small opening without signs of infection and ultrasound revealed no abscess.     

Bicarbonate versus citrate in oral rehydration therapy in infants with watery diarrhea: a controlled clinical trial

In a double-blind, randomized trial, we compared the efficacy of bicarbonate-containing oral rehydration solution vs citrate-containing solution in the treatment of infantile diarrheal dehydration and acidosis. Ninety-seven infants 3 to 24 months of age were entered in the study; 49 received bicarbonate-containing solution and 48 citrate-containing solution. The two groups were similar in all respects at the beginning of the study. Oral rehydration was successful (i.e., no intravenously administered fluids were required) in 85% of study patients; the success rate was similar in both treatment groups. Serum total CO2 concentration increased in a similar fashion in both groups, reaching near normal values at 48 hours after admission. We conclude that sodium citrate can be substituted for sodium bicarbonate in the formulation of the orally administered rehydration solution recommended by the World Health Organization for treatment of diarrheal dehydration in infants.     

Surgical and pathologic outcomes of fertility-sparing radical abdominal trachelectomy for FIGO stage IB1 cervical cancer

ObjectivesTo describe the surgical and pathologic findings of fertility-sparing radical abdominal trachelectomy using a standardized surgical technique, and report the rate of post-trachelectomy adjuvant therapy that results in permanent sterility.MethodsA prospectively maintained database of all patients with FIGO stage IB1 cervical cancer admitted to the operating room for planned fertility-sparing radical abdominal trachelectomy was analyzed. Sentinel node mapping was performed via cervical injection of Technetium and blue dye.ResultsBetween 6/2005 and 5/2008, 22 consecutive patients with FIGO stage IB1 cervical cancer underwent laparotomy for planned fertility-sparing radical abdominal trachelectomy. Median age was 33 years (range, 23–43). Histology included 13 (59%) with adenocarcinoma and 9 (41%) with squamous carcinoma. Lymph-vascular invasion was seen in 9 (41%) cases. Only 3 (14%) needed immediate completion radical hysterectomy due to intraoperative findings (2 for positive nodes, 1 for positive endocervical margin). Median number of nodes evaluated was 23 (range, 11–44); and 6 (27%) patients had positive pelvic nodes on final pathology — all received postoperative chemoradiation. Sixteen (73%) patients agreed to participate in sentinel node mapping which yielded a detection rate of 100%, sensitivity of 83%, specificity of 100% and false-negative rate of 17%. Eighteen of 19 (95%) patients who completed trachelectomy had a cerclage placed, and 9/22 (41%) patients had no residual cervical carcinoma on final pathology. Median time in the operating room was 298 min (range, 180–425). Median estimated blood loss was 250 ml (range, 50–700), and median hospital stay was 4 days (range, 3–6). No recurrences were noted at the time of this report.ConclusionsCervical adenocarcinoma and lymph-vascular invasion are common features of patients selected for radical abdominal trachelectomy. The majority of patients can undergo the operation successfully; however, nearly 32% of all selected cases will require hysterectomy or postoperative chemoradiation for oncologic reasons. Sentinel node mapping is useful but until lower false-negative rates are achieved total lymphadenectomy remains the gold standard. Investigating alternative fertility-sparing adjuvant therapy in node positive patients is needed.     

Spheciosterol sulfates, PKCzeta inhibitors from a philippine sponge Spheciospongia sp

Three new sterol sulfates, spheciosterol sulfates A-C (1-3), and the known sterol sulfate topsentiasterol sulfate E (4) have been isolated from the sponge Spheciospongia sp., collected in the Philippines. Structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1-4 inhibited PKCzeta with IC50 values of 1.59, 0.53, 0.11, and 1.21 microM, respectively. In a cell-based assay, 1-4 also inhibited NF-kappaB activation with EC50 values of 12-64 microM.     

Clinical validation of routine antenatal anti-D prophylaxis questions the modelling predictions adopted by NICE for Rhesus D sensitisation rates: results of a longitudinal study

OBJECTIVE: To compare the rates of Rh(D) sensitisations with a policy of restricted routine antenatal anti-D prophylaxis (first pregnancy only) with the rates predicted with universal routine antenatal anti-D prophylaxis (all pregnancies). STUDY DESIGN: A retrospective longitudinal observational study involving 15,500 confinements in Rhesus D negative (Rh(D)-ve) women between 1990 and 2003 in a single health district was conducted. All Rh(D) sensitised pregnancies were identified and evidence for routine antenatal anti-D prophylaxis administration during the first pregnancy was investigated. The rate of Rh(D) sensitisations following a policy of restricted prophylaxis was compared with that predicted with mathematical modelling following universal prophylaxis. RESULTS: There were 50 newly sensitised and 37 previously sensitised pregnancies among 15,596 Rh(D)-ve women. For the calculated 13,575 Rh(D)-ve women whose first confinement was in Oxford and who were eligible for restricted prophylaxis, there were 30 new and 26 previously sensitised pregnancies. Of these 30 new sensitisations, 10 were nulliparae, 12 parity 1, and eight parity 2 or greater (third or later continuing pregnancy); only one of these latter eight women had received routine prophylaxis, four had delivered their first baby before the programme was introduced, and in three documentary evidence could not be confirmed that prophylaxis had been given. There was no difference between a policy of restricted and universal routine antenatal anti-D prophylaxis in the sensitisation rates for women during their third or subsequent pregnancy. CONCLUSIONS: This study has shown that restricted routine antenatal prophylaxis provides continuing protection for subsequent pregnancies although the mechanism for this is unclear. These results challenge the wisdom and expense of a policy of universal prophylaxis and prompt a need for further similar analyses to test the appropriateness of the NICE guideline.     

A further case with a small supernumerary marker chromosome (sSMC) derived from chromosome 1--evidence for high variability in mosaicism in different tissues of sSMC carriers

A prenatally ascertained case with a de novo small supernumerary marker chromosome (sSMC) derived from chromosome 1 is reported. Due to a fetal heart defect the parents decided in favour of an induced abortion. Postmortem, a molecular cytogenetic study on eleven formalin fixed, paraffin-embedded tissues of the fetus was performed, to further characterize the levels of mosaicism of the sSMC(1). sSMC presence varied between 13 and 62% within different tissues of sSMC carriers. This finding is something common in sSMC carriers and could explain why up to the present no clinical correlations for sSMC mosaicism and clinical outcome in the corresponding carriers could be established.