Treatment with Ca2+ ionophore improves embryo development and outcome in cases with previous developmental problems: a prospective multicenter study.

STUDY QUESTION: Does calcium ionophore treatment (A23187, calcimycin) improve embryo development and outcome in patients with a history of developmental problems/arrest? SUMMARY ANSWER: Application of A23187 leads to increased rates of cleavage to 2-cell stage, blastocyst formation and clinical pregnancy/live birth. WHAT IS KNOWN ALREADY: Studies on lower animals indicate that changes in intracellular free calcium trigger and regulate the events of cell division. In humans, calcium fluctuations were detected with a peak shortly before cell division. Interestingly, these calcium oscillations disappeared in arrested embryos. Mitotic division blocked with a Ca(2+) chelator could be restored by means of ionophores in an animal model. STUDY DESIGN, SIZE, DURATION: This prospective, multicenter (five Austrian centers), uncontrolled intervention study (duration 1 year) includes 57 patients who provided informed consent. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were complete embryo developmental arrest in a previous cycle (no transfer), complete developmental delay (no morula/blastocyst on Day 5), or reduced blastocyst formation on Day 5 (≤15%). Severe male factor patients and patients with <30% fertilization rate after ICSI were excluded because these would be routine indications for ionophore usage. The total of the 57 immediately preceding cycles in the same patients constituted the control cycles/control group. In the treatment cycles, all metaphase II-oocytes were exposed to a commercially available ready-to-use ionophore for 15 min immediately after ICSI. After a three-step washing procedure, in vitro culture was performed as in the control cycles, up to blastocyst stage when achievable. MAIN RESULTS AND THE ROLE OF CHANCE: Fertilization rate did not differ (75.4 versus 73.2%); however, further cleavage to 2-cell stage was significantly higher (P < 0.001) in the ionophore group (98.5%) when compared with the control cycles (91.9%). In addition, significantly more (P < 0.05) blastocysts formed on Day 5 in the study compared with the control group (47.6 versus 5.5%, respectively) and this was associated with a significant increase (P < 0.01) in the rates of implantation (44.4 versus 12.5%), clinical pregnancy (45.1 versus 12.8%) and live birth (45.1 versus 12.8%). All babies born at the time of writing (22/28) were healthy. LIMITATIONS, REASONS FOR CAUTION: The frequency of patients showing embryo developmental problems was expected to be low; therefore, a multicenter approach was chosen in order to increase sample size. In one-third of the cycles, the clinician or patient requested a change of stimulation protocol; however, this did not influence the developmental rate of embryos. WIDER IMPLICATIONS OF THE FINDINGS: This is the first evidence that developmental incompetence of embryos is an additional indication for ionophore treatment. The present approach is exclusively for overcoming cleavage arrest. STUDY FUNDING/COMPETING INTERESTS: No funding received. T.E. reports fees from Gynemed, outside the submitted work. All co-authors have no interest to declare.

[Sociodemographic aspects are associated with breast cancer screening behaviour of female patients: results of a cross-sectional survey]. / Soziodemografische Aspekte stehen im Zusammenhang mit dem Brustkrebsscreeningverhalten von Patientinnen: Ergebnisse einer Querschnittsuntersuchung.

In Austria, opportunistic mammography screening for detection of early-stages breast cancer is offered for women older than 40 years. In spite of public discussions on the effectiveness of mammography screening, evidence-based educative information material for female patients available online and in print is lacking. The present study describes the influence of the 3 sociodemographic characteristics migration background, education, and age on the individual's breast cancer screening behaviour as well as on the usage of various information sources on breast cancer for patients. In total, 333 outpatients of the Department of Obstetrics and Gynaecology, General Hospital, Vienna, Austria, participated in a monocentric cross-sectional study. Regarding breast cancer screening, 93.4% (n=282) of the female patients had at least one previous mammogram. Furthermore, 86.3% of the participants regularly consulted their gynaecologist, while women with migration background reported less frequent (p=0.02), and well-educated as well as older patients reported more frequent (p<0.02) gynaecological consultations. Higher-educated women (p=0.04) and participants aged between 50 and 69 years (p<0.05) felt better informed on breast cancer-related topics, whereas a migration background was not associated with the perceived level of information. Medical doctors (67.9%) as well as pertinent folders (33%) were the most relevant information sources on breast cancer. Mass media (22.8%) were also a relevant information source on this issue, whereas the Internet (10.5%) was quite rarely referred to for this purpose. The results of the present study show that female patients perceived the medical doctor as the most important source of medical information on breast cancer. The public health-care system could facilitate positive health communication in the doctors/patient relationship by providing homogenous, quality assured educative information material.

Cisplatin, carboplatin, and cyclophosphamide combination chemotherapy in advanced-stage ovarian carcinoma: an Eastern Cooperative Oncology Group pilot study.

Cyclophosphamide (CTX) 600 mg/m2, carboplatin 280 mg/m2, and cisplatin 50 mg/m2 were administered on day 1 every 4 weeks to 41 previously untreated ovarian cancer patients with residual disease greater than 2.0 cm after primary laparotomy. Of 22 patients with measurable disease treated with up to eight cycles of therapy, the overall clinical response rate was 73% (exact 95% confidence interval [CI], 50% to 89%), with 50% complete response (CR). Six of 11 clinical CR (cCR) patients underwent surgical restaging; three pathologic CRs (pCRs) and three pathologic partial responses (pPRs) with residual disease less than 2.0 cm were documented. Fourteen patients had nonmeasurable but assessable disease; the clinical response rate was 57% (Cl, 29% to 82%) with two (14%) CRs. Second-look surgery was performed in one of the two cCR patients; a pPR was documented. Five patients with nonassessable disease were stable during chemotherapy; two underwent surgery and had pCRs. The median time to treatment failure (TTF) was 14.8 months, and median survival for the 41 patients is 26.7 months. Overall, 37% of the patients had progression-free intervals of at least 2 years, and 27% have survival times in excess of 3 years. Hematologic toxicity was substantial but manageable, with 58% and 66% experiencing a granulocyte nadir less than 500/microL and a platelet nadir less than 50,000/microL, respectively. One treatment-associated fatality occurred as a result of leukopenic sepsis and renal failure in the setting of progressive disease and ureteral obstruction. Mild to moderate nausea and vomiting occurred in most patients, but none experienced severe ototoxicity or peripheral neuropathy. Over all courses, 73% of the projected dose intensity of CTX and carboplatin and 86% of cisplatin were delivered. Since granulocytopenia and thrombocytopenia were dose-limiting, the addition of colony-stimulating factors that support both myeloid and megakaryocyte precursors may permit further dose intensification.

A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer.

Between October 1981 and June 1983, the Eastern Cooperative Oncology Group (ECOG) conducted a prospectively randomized trial (EST 1581) of the four most active chemotherapy regimens for metastatic non-small-cell lung cancer (NSCLC). Four hundred eighty-six good performance status patients (PS 0 or 1; 81%) were randomized to receive cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); mitomycin, vinblastine, and cisplatin (MVP); etoposide and cisplatin (VP-P); or vindesine and cisplatin (VDA-P). All regimens were administered in the doses and schedules originally reported. Complete response (CR) plus partial response (PR) rates for the four regimens were CAMP, 17%; MVP, 31%; VP-P, 20%; and VDA-P, 25%. The response rate for MVP was significantly higher in patients with squamous and adenocarcinoma histologies, but there was no impact on median survival (overall, 24.5 weeks). The duration of response did not differ by treatment as previously suggested for VDA-P. There were 15 CRs (CAMP, one; MVP, six; VP-P, two; VDA-P, six), and 12 patients have survived more than 2 years. Toxicity was significant with 20 treatment-related deaths. CAMP was significantly less toxic than the other regimens (P less than .001). VDA-P demonstrated significantly more life-threatening (seven) and lethal (three) episodes of nephrotoxicity (P less than .001) despite an aggressive hydration program that in itself caused significant morbidity. Analysis of the toxicity data showed, however, that most of the severe toxicity occurred in the 19% of patients who were initially PS 2, suggesting that they are not appropriate candidates for trials of new agents or combinations. None of these regimens can be recommended as a standard therapy for metastatic NSCLC.

Significant correlations between atmospheric spectra according to Baumer and the in vitro incorporation of [3H]thymidine into the nuclear DNA of C6-glioma cells.

Significant correlations between certain spectra of atmospherics (spherics) according to Baumer (a.t.B), i.e. naturally occurring electro-magnetic impulses in the range of 4-50 kHz, and several diseases or biological parameters have been published earlier. Now we show that there exists a highly significant negative correlation (r = -0.61, P greater than 0.004) between the occurrence of 28 kHz impulses (a.t.B.) and the in vitro incorporation of thymidine into the nuclear DNA of C6-glioma cells. The positive correlation with the 10 kHz impulses (a.t.B) (r = 0.39), however, is statistically not significant (P greater than 0.055).

Phase II trial of misonidazole (MISO) and cyclophosphamide (CYC) in metastatic renal cell carcinoma.

In animal models pre-treatment with misonidazole, a hypoxic cell radiosensitizer, enhances the antineoplastic effects of alkylating agent chemotherapy. Laboratory data suggest that hypoxic tumor cells may be more resistant to chemotherapy because of suboptimal drug delivery, reduced rates of cell division, or because hypoxia confers relative drug resistance. The therapeutic potential depends on the tumor type, doses of radiosensitizer and alkylating agent, the time interval between drug administration, and the ratio of sensitization of normal and malignant tissues. A Phase II trial of misonidazole and cyclophosphamide was initiated by the Eastern Cooperative Oncology Group to determine the response rate and toxicity in patients with metastatic renal cell cancer. Patients received 5 gm/m2 of misonidazole intravenously two hr before 1200 mg/m2 of cyclophosphamide every 3 wk. Patients with prior chemotherapy or radiotherapy received 1000 mg/m2 of cyclophosphamide. Misonidazole was discontinued after a total dose of 15 gm/m2. The median total misonidazole dose was 23.5 gm (range 4.5-34.5 gm). The median number of cyclophosphamide cycles was 2 (range 1-12). Of the 30 patients evaluable for response, only one patient had an objective partial response. Twenty-nine patients had stable or progressive disease. One patient remains on cyclophosphamide after 9 mo. Estimated median survival is 4.8 mo. There have been no lethal toxicities; however, 9 patients (25%) experienced life-threatening leukopenia and an additional 42% experienced severe hematologic toxicity. Eight patients had WBC less than 1000 on days 7-14 of cycle 1. Thrombocytopenia and grade 3 anemia occurred in 1 and 2 patients, respectively. Moderate or severe nausea and vomiting occurred in 47% and 19% of patients, respectively. Only 3 patients experienced severe neurotoxicity. Four additional patients had moderate neurotoxicity. In summary, misonidazole in this dosing schedule does not enhance the antitumor activity of cyclophosphamide in renal cell carcinoma.

The transfer of interleukin-8 across the human placenta perfused in vitro.

OBJECTIVE: To assess the placental transfer of interleukin (IL)-8 in vitro. METHODS: Eighteen placentas obtained immediately after delivery were perfused with a mixture of 125I-labeled IL-8 (IL-8*) and unlabeled IL-8 in two different concentrations. Antipyrine was coinfused in all experiments as a reference compound. Fetal-to-maternal and maternal-to-fetal perfusions were performed. Radioactivity was measured in a gamma counter at the end of each perfusion experiment. In four experiments, unlabeled IL-8 was analyzed in addition to labeled IL-8 to exclude a change in the IL-8/IL-8* ratio resulting from membrane transfer. RESULTS: Two of the 18 experiments had to be discarded because of poor transfer of antipyrine. There was only faint accumulation of radioactivity in the transplacental compartment, regardless of whether the test substance was added maternally or fetally. Because measurement of unlabeled IL-8 yielded negative results, the radioactivity is clearly attributable to free iodine 125, which is generated during IL radiolabeling or which disassociates from IL-8 in small amounts after radiolabeling. CONCLUSION: Interleukin-8 does not appear to cross the placenta by simple diffusion, regardless of the concentration or the perfusion rate. The impermeability of the placenta to the diffusion of IL-8 might explain why there is insufficient correlation between serum and amniotic fluid cytokine concentrations of pregnant women and the presence of the amnion infection syndrome.

Combination chemotherapy of advanced ovarian cancer with hexamethylmelamine, cis-Platinum, and doxorubicin after failure of prior therapy.

Forty-nine women received a combination of cis-platinum and hexamethylmelamine (36 also received doxorubicin) for advanced ovarian cancer progressing after therapy that included an alkylating agent or extended field radiation. Twenty-six (53%) had an objective remission that lasted a median of 6 months from start of treatment. Response rate was independent of age, extent of prior therapy, and performance status. A long interval from initial diagnosis to entry, response to therapy, and ambulatory performance predicted improved survival from entry. No patient is surviving free of disease. Myelosuppression and vomiting were moderately severe but tolerable. Azotemia and peripheral neuropathy were infrequent and milk. These drugs have major activity in this poor-risk group and should be studied as part of initial therapy when enhanced efficacy and reduced toxicity are to be expected.

Vascular reconstruction for limb salvage in sarcoma of the lower extremity.

OBJECTIVES: To examine the patency and limb-salvage characteristics of vascular reconstruction in patients with sarcomas of the lower extremity who had been treated with limb-preserving resection and to examine patient survival during a long follow-up period. DESIGN: Retrospective cohort study. SETTING: University hospital, tertiary referral center. PATIENTS: From 1984 to 1992, 14 patients underwent limb-preserving resection of sarcomas in the proximal lower extremity, with 20 vascular reconstructions performed. OUTCOME MEASURES: Color Doppler scans documented patency of the vascular reconstructions. Clinical evaluation included functional results in terms of limb movement and quality of life. Local tumor control and systemic recurrence were examined by repeated radiologic examination. Overall survival as well as time and cause of death were assessed. RESULTS: A total of 13 patients had patent vascular grafts, while the venous graft became occluded in 1 patient. Limb function was rated as excellent or good in 9 patients, as fair in 3, as poor in 1, and could not be clinically estimated in 1. Postoperative thrombosis of the venous graft was detected in 3 patients and was effectively managed by thrombectomy in 2. Three patients underwent reoperation because of hematoma or complications caused by local infection. The tumor endoprosthesis had to be replaced in 3 patients. During follow-up periods that ranged from 15 to 132 months (mean, 55 months), 4 patients died. In all of these patients the cause of death was systemic recurrence in the lung. Two additional patients developed pulmonary metastases, but at the time of this report, they were still alive as long as 132 months after operative resection or chemotherapy. No local recurrence was found. CONCLUSION: Limb-preserving resection of sarcoma of the lower extremity can be performed with satisfactory function of the limb maintained, even if it becomes necessary to resect the femoral vessels. Autologous venous graft for vascular reconstruction is the treatment of choice. In spite of the high incidence of metastases, considerable long-term survival is possible.

Phase II study of mitoguazone, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with diffuse histologic subtypes of non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Study (PE481).

Mitoguazone, an investigational agent with significant activity in advanced lymphoma, was added to a modified CHOP regimen (COPA) in an effort to improve the activity of standard therapy in 66 previously untreated patients with stages II-IV lymphoma and diffuse histology of intermediate or high grade other than lymphoblastic in this phase II pilot study. The regimen was well tolerated and the complete response rate in diffuse large cell lymphoma was 55%. Sixty-five percent of all complete responders were in complete response for at least one year. Despite these excellent results. it is unlikely that the addition of mitoguazone improved results compared with those obtained with standard therapy alone, since similar results have been frequently reported with the latter.

Early detection of preeclampsia by determination of platelet aggregability.

Preeclampsia is still a leading cause of maternal and fetal morbidity and mortality. There is evidence for the involvement of platelets. Therefore, we investigated the suitability of corrected whole blood impedance aggregometry as an early predictor of preeclampsia in 71 consecutive, high-risk pregnancies. According to the occurrence of preeclampsia, defined postpartum by an independent investigator, and the stage of pregnancy (early and late, cutoff: 25 weeks of gestation), four study groups were defined. Platelet aggregation data were corrected for the influence of hematocrit and platelet count by a special purpose software package. Women developing preeclampsia showed significantly higher platelet aggregation response compared to controls in early and late pregnancy. In early pregnancy, all women developing preeclampsia had aggregation responses to collagen higher than the highest responses among the controls. Hence, this test had a 100% positive predictive value of subsequent preeclampsia. Despite being significantly increased, platelet aggregability was of minor predictive value in late pregnancy. We conclude that preeclampsia is accompanied by exaggerated platelet aggregability, particularly perceptible early in the course of pregnancy. We propose collagen-induced whole blood platelet aggregation with correction for the influence of hematocrit and platelet count for early detection of preeclampsia.

Increased proliferative activity in selenium-deficient mouse liver.

Male albino NMRI mice were fed a selenium-deficient (Se-), torula yeast-based diet containing less than 10 ppb Se for at least 2 months (Se-) while a control group received the same diet supplemented (Se+) with 330 ppb Se as Na2SeO3. The Se-(-)animals showed multiple enzyme modulations of liver enzyme activities indicating that they were in a severely Se- state. No significant difference in the basic DNA synthesis rate of Se-(-)animals compared to Se+ controls was measured. However, when liver cell proliferation was induced by either hepatopoietin pretreatment or by partial hepatectomy, an about 3-fold increase in DNA replication rates was found in Se- compared to controls. We conclude that the enhanced proliferative activity in Se- mouse liver is expressed in an emergency situation.

Tumor mapping: new rationales, adjusted techniques, expanded applications.

Eleven consecutive patients with cancers of the oropharynx (4), hypopharynx (4), and oral cavity (3) were endoscoped and "tumor mapped" with a modified tattoo solution before beginning non-surgical antineoplastic therapy. The tattooed outlines were clearly visible at 7 weeks (5 patients after induction chemotherapy); at 14 weeks (2 patients after induction chemotherapy and radiotherapy); and between 12 and 16 weeks (4 patients after radiotherapy). The "tumor mapping" aided both the establishment of appropriate resection margins in cancers that had diminished in response to non-surgical therapy and the recognition of a tumor's lack of response to nonsurgical antineoplastic treatment.

Cervical cysts: cancer until proven otherwise?

A cystic neck mass can be either malignant or benign; 22% of patients (4/18) admitted with the tentative diagnosis of branchial cyst in a recent 2-year period (1977-1979) had metastatic carcinoma: epidermoid, thyroid or salivary gland. Preoperative fine needle aspiration was diagnostic in 1 instance and unhelpful in 2. Frozen section analysis of the gross specimen invariably provided the correct diagnosis. All patients with malignancies had subclinical primary disease and in 1 instance random biopsies identified its origin. The prudent surgeon will avoid untoward results if he approaches a neck cyst in an adult as if it were malignant. Guidelines he can follow to prevent the inadvertent removal of a metastasis under the misapprehension that it is a benign neck cyst include: 1. Prior to operation, perform a thorough head and neck examination to identify a primary carcinoma; 2. Do a fine needle aspiration of the mass for cytology. A negative report must be considered inconclusive; 3. Make a gross examination in the operating room of the opened cyst and frozen section processing of suspicious areas; 4. Follow with a panendoscopy and random biopsies of appropriate areas and complete the neck dissection on the involved side, after a metastatic deposit has been recognized. The preoperative procurement of contingency consent for these procedures is understood.

Phase II study of methyl-glyoxal bis-guanylhydrazone (NSC 3296) in advanced ovarian cancer.

Thirty-nine patients received 600 mg/m2 OF MGBG intravenously every week for the treatment of advanced refractory ovarian cancer. Twenty-seven of these received adequate trials, and only two had partial remissions lasting 3 1/2 and 4 months each. Toxicity was substantial, with severe hematologic toxicity in 26%, diarrhea in 22% (severe in 7%), skin rash in 26% (severe in 7%), and vomiting in 70% (severe in 11%). Fatigue, facial paresthesias, and flushing during drug administration were frequent. It appears that MGBG in this dose and schedule has little activity against advanced ovarian cancer.

High-dose megestrol acetate in the treatment of patients with ovarian cancer who have undergone previous treatment: Eastern Cooperative Oncology Group Study PD884.

High-dose megestrol acetate has been reported to be effective salvage therapy for women with ovarian carcinoma. The Eastern Cooperative Oncology Group performed this phase II study of oral megestrol acetate, 200 mg four times daily until disease progression, in 33 patients either with stage III or IV histologically confirmed ovarian carcinoma or with unresectable tumor in the pelvis with measurable or evaluable disease who progressed after treatment with one prior chemotherapy regimen. Thirty and 31 patients were evaluable for response and toxicity, respectively. No patient had an objective response and none had subjective improvement after a median treatment period of 1.4 months. Nausea or vomiting occurred in most patients, usually grade 1-2. Megestrol acetate is ineffective salvage therapy for patients with inoperable, previously treated ovarian carcinoma.

A randomized phase II study of m-AMSA (NSC 249992) and neocarzinostatin (NSC 157365) in non-small cell bronchogenic carcinoma. An Eastern Cooperative Group Study.

Eighty-nine patients with advanced non-small cell bronchogenic carcinoma were treated with either m-AMSA 120 mg/m2 intravenously every 3 weeks or neocarzinostatin 2.0 mg/m2 intravenously daily X 5 every 4 weeks. There were no responses in 40 evaluable patients who received m-AMSA and three partial responses (7.5%) in 40 patients who received neocarzinostatin. Two patients receiving m-AMSA had drug-related deaths. For m-AMSA the major toxicities were hematologic, while for neocarzinostatin the major toxicities were hematologic, gastrointestinal, and fever. We conclude that m-AMSA is inactive while neocarzinostatin has minimal activity in non-small cell bronchogenic carcinoma.

Pilot study of adriamycin and amsacrine (m-AMSA) in patients with advanced breast cancer.

Twelve patients with recurrent and metastatic breast cancer were treated with a combination of adriamycin and amsacrine (m-AMSA) to evaluate its efficacy and toxicity. Adriamycin was given at 40 mg/m2 i.v. and m-AMSA at 50 mg/m2 i.v. every 3 weeks. No response was observed. One patient received an escalated m-AMSA dose at 70 mg/m2 and the same dose of adriamycin. She died of treatment-related leukopenia and infection. We conclude that the combination of adriamycin and amsacrine at the dose and schedule used in our trial has little antitumor effect in the treatment of advanced breast cancer.

Fatal cryptosporidiosis complicating Kaposi's sarcoma in an immunocompromised man.

Fatal cryptosporidiosis in a bisexual immunosuppressed man with disseminated Kaposi's sarcoma and intractable diarrhea is described. Cryptosporidium sp. was isolated from the stool antemortem by Sheather's floation technique. This parasite should be considered in immunosuppressed hosts with chronic diarrhea when routine methods fail to demonstrate etiologic agent. Since this organism is already infectious when passed, stool precautions should be maintained.

Natural atmospherics and occurrence of seizures in six adolescents with epilepsy: a cross correlation study.

As already seen in a former study of 315 epileptic seizures in adults, subsequent investigation of 3333 epileptic seizures in six adolescents revealed a significant increase of the seizure frequency during days with a higher mean frequency of 28 kHz atmospherics, and a decrease during days with a (Baumer apparatus) distinctly higher amount of 10 kHz when compared with the daily mean frequency within the whole period. However, one patient showed an opposite behaviour regarding the correlations of 28 and 10 kHz atmospherics and the mean numbers of seizures.