An optimal three-stage design for phase II clinical trials

A phase II clinical trial in cancer therapeutics is usually a single-arm study to determine whether an experimental treatment (E) holds sufficient promise to warrant further testing. When the criterion of treatment efficacy is a binary endpoint (response/no response) with probability of response p, we propose a three-stage optimal design for testing H₀: p ≤ p₀ versus H₁: p ≥ p₁, where p₁ and p₀ are response rates such that E does or does not merit further testing at given levels of statistical significance (α) and power (1 ? β). The proposed design is essentially a combination of earlier proposals by Gehan and Simon. The design stops with rejection of H₁ at stage 1 when there is an initial moderately long run of consecutive treatment failures; otherwise there is continuation to stage 2 and (possibly) stage 3 which have decision rules analogous to those in stages 1 and 2 of Simon's design. Thus, rejection of H₁ is possible at any stage, but acceptance only at the final stage. The design is optimal in the sense that expected sample size is minimized when p = p₀, subject to the practical constraint that the minimum stage 1 sample size is at least 5. The proposed design has greatest utility when the true response rate of E is small, it is desirable to stop early if there is a moderately long run of early treatment failures, and it is practical to implement a three-stage design. Compared to Simon's optimal two-stage design, the optimal three-stage design has the following features: stage 1 is the same size or smaller and has the possibility of stopping earlier when 0 successes are observed; the expected sample size under the null hypothesis is smaller; stages 1 and 2 generally have more patients than stage 1 of the two-stage design, but a higher probability of early termination under H₀; and the total sample size and criteria for rejection of H₁ at stage 3 are similar to the corresponding values at the end of stage 2 in the two-stage optimal design.     

Chromosomal aberrations and micronucleus frequency in nurses occupationally exposed to cytotoxic drugs

In this study, we evaluated the effect of low level occupationalexposure of nurses in a medical oncology unit in Cairo, Egypt,to anticancer drugs. Twenty nurses who constantly handled thesedrugs and 20 controls, matched according to age and sex, wereexamined. Metaphase chromosomes were studied. Percentages ofmetaphases with chromosomal aberrations were significantly higher(P < 0.001) in the exposed group (6.1 ± 2.7) versusthe controls (2.6 ± 1.6). The detected chromosomal aberrationswere in the form of chromatid gaps, chromatid breaks and acentricfragments. Micronucleated peripheral blood lymphocytes werealso analyzed in cytochalasin B treated binucleated lymphocytes.There was significant increase in cells with micronuclei (P< 0.001) in nurses (10.05 ± 4.71) in comparison tothe matched control (5.42 ± 2.22) (P < 0.001). Nursesexposed to the cytotoxic drugs for     

Evaluation of {beta}-endorphin and interleukin-6 in seminal plasma of patients with certain andrological diseases

Human semen contains large amounts of opioid peptides and cytokines.We have measured the concentrations of interleukin (IL)-6 in140 semen samples and of -endorphinin 77 semen samples. Themedian concentration of endorphinin seminal plasma from normozoospermicmen(n = 23) was 154.7 pg/ml (10th—90th percentiles, 42.0—774.6),and there was no significant difference in the -endorphin concentrationamong normozoospermic, oligozoospermic (n= 28), asthenozoospermic(n= 15), azoospermic(n= 4) and post-vasectomy (n= 7) samples.There was no correlation between -endorphin concentration andsperm characteristics, nor with blood hormones. Endorphinconcentration was lower in cases with immunelogical infertility,as revealed by a positive direct mixedantiglobulin reactiontest (n = 12) ( > 0.01), than inmatched controls. The medianconcentration of IL-6 insamples with normal sperm concentration,motility andmorphology with or without white blood cells (n=39) was 26.1 pg/ml (10th–90th percentiles, 7.3–172.3),and there was no significant difference in the IL-6 concentrationamong normozoospermic, oligozoospermic (n= 46),asthenozoospermic(n= 32), azoospermic (n= 13) and post-vasectomy (n= 10) samples.The IL-6 concentration was significantly higher in cases ofvaricocele (n= 22)without white blood cells in semen (P <0.001) than in matched controls without varicocele (n= 23).In addition, the IL-6 concentration was elevated (P < 0.0001)in cases with accessory sex gland inflammation (n= 40). IL-6concentration was positively correlated with white blood cellsin semen (n= 60, r = 0.59, P < 0.0001), but there was nocorrelation with -endorphin concentration. The IL-6 concentrationchosen to differentiate between cases with and without accessorygland inflammation was 45.3 pg/ml, with a specificity of 80.6%and a sensitivity of 92.5%. It is concluded that -endorphinin seminal plasma playsan immune suppressive role, and thatincreased IL-6 concentration may be related to testicular dysfunctionincases with varicocele. Furthermore, IL-6 is an accurate markerof accessory sex gland inflammation.     

Primary orbital Ewing sarcoma in a middle-aged woman

A 43-year-old woman had unilateral exophthalmos caused by primary orbital Ewing sarcoma. Specialized immunohistochemical stains, primarily MIC-2 (CD99), aided in the diagnosis of Ewing sarcoma. Twenty-two months after radiotherapy and multiagent chemotherapy, the patient remained tumor free. To our knowledge, this is the first reported case of orbital Ewing sarcoma to present in an adult beyond the fourth decade of life.     

Endotoxemia during supraceliac aortic crossclamping is associated with suppression of the monocyte CD14 mechanism: possible role of transforming growth factor-beta1

PURPOSE: Monocyte CD14 and its soluble form (sCD14) mediate the proinflammatory response to endotoxemia. The aim of this study was to measure the changes to these factors after major aortic surgery and the possible inhibitory role of transforming growth factor-beta(1) (TGF-beta(1)) during these procedures. METHODS: Twenty-four patients with supraceliac aortic crossclamping during thoracoabdominal aortic aneurysm (TAAA) repair and 12 patients with infrarenal aortic crossclamping as part of infrarenal aneurysm repair (AAA) were studied. Blood was collected at incision, aortic clamping, and reperfusion and at 1, 8, and 24 hours after reperfusion. Samples were assayed for endotoxin, peripheral blood monocyte CD14 expression, sCD14, tumor necrosis factor-alpha, and TGF-beta(1). RESULTS: Although there was significant endotoxemia on reperfusion in both groups of patients, peak plasma endotoxin levels were significantly higher in patients with TAAA (P =.001). Monocyte CD14 and plasma sCD14 were significantly decreased in patients with TAAA at reperfusion and 1 hour after reperfusion (P <.01, both points). In patients with AAA, a significant upregulation of CD14 was observed at 24 hours after reperfusion (P <.01), but no significant changes in sCD14 were observed. TNF-alpha showed no significant changes during the study period in both groups. In patients with TAAA, TGF-beta(1) showed significant elevation at all time points (P <.01); whereas in patients with AAA, TGF-beta(1) showed no significant changes. CONCLUSION: Splanchnic ischemia reperfusion in patients who undergo supraceliac aortic clamping is associated with peripheral blood monocyte CD14 suppression and significant elevation of TGF-beta(1). TGF-beta(1) may play an important role in modulating the immune response to endotoxemia during major aortic aneurysm surgery.     

Magnetic resonance imaging and hysteroscopy to diagnose colo-uterine fistula: a rare complication of diverticulitis

Colo-uterine fistula of diverticular origin is an extremely rare disease due to the resistance of uterine tissue. Methods for diagnosis remain to be established. Non-invasive imaging like magnetic resonance imaging (MRI) may help to establish a proper diagnosis, but confirmation may be reached by diagnostic hysteroscopy or even surgical exploration. We report a 78-year-old female who presented with continuous dull aching pain associated with increasing constipation. MRI suspected a fistula between the posterior aspect of the uterine body and the sigmoid colon which contained extensive diverticulosis. Hysteroscopy confirmed the fistulous opening, but colonoscopy confirmed diverticular disease with no evidence of malignancy. The patient had en block surgical treatment of the uterus and the adjacent colon, followed by an uneventful recovery. The sensitivity and specificity of non-invasive imaging procedures to diagnose such cases remain to be established. As imaging procedures cannot rule out neoplasia, endoscopic procedures need to be added.     

Magnetic resonance imagining (MRI) and serial β-human chorionic gonadotrophin (β-hCG) follow up for placenta percreta

Background Placenta percreta is a rare obstetric condition associated with life-threatening hemorrhage. MR imaging has a role in prenatal diagnosis of these cases. However, its role in the postnatal diagnosis and in the follow up yet to be established. Case A 33-year-old patient has adherent placenta following spontaneous delivery at 37 weeks gestation. MR imaging diagnosed placenta percreta. Intramuscular methotrexate treatment was initiated with follow up with serial β-human chorionic gonadotrophin (β-hCG). In spite of dropping of the level of β-hCG, the trophoblastic tissue was still present 6 weeks postnatally where the patient complained of vaginal bleeding where she opted to abdominal hysterectomy. Conclusion Patients who are suitable for non-surgical therapy, T2-weighted MR imaging may, in conjunction with serial β-hCG assays, provide an alternative treatment modality for cases of placenta percreta.