Standard dose cisplatin with rhG-CSF allows sufficient harvesting of PBSC for autotransplantation in patients with ovarian cancer

We have investigated the feasibility of a program of autologous peripheral blood stem cell (PBSC) harvesting and transplantation in patients with ovarian cancer. From four patients, PBSC was collected during hematopoietic recovery following aplasia induced by standard dose cisplatin 70 mg m⁻² with etoposide 500 mg m⁻² or adriamycin 40 mg m⁻² and cyclophosphamide 500 mg m⁻² plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) at a dose of 75 µg day⁻¹ given intracutaneously. In apheresed patients, we harvested an average of 2.31 × 10⁵ kg⁻¹ colony-forming unit granulocyte/macrophage (range 0–5.22) per cycle. Low hematologic toxicity was observed during the hematopoietic reconstitution of the four patients subjected to PBSC support with G-CSF (5 µg kg⁻¹ day⁻¹ given by continuous infusion) after high-dose chemotherapy (carboplatin 900 mg m⁻² and etoposide 900 mg m⁻²). The patients were not evaluable for a response because we performed consolidated high-dose chemotherapy. However, no evidence of recurrence has been observed 11.8 months (range 2–19) after high-dose chemotherapy. We can conclude that standard dose cisplatin in combination with etoposide or adriamycin and cyclophosphamide plus rhG-CSF allows sufficient harvesting of PBSC for autotransplantation in patients with ovarian cancer.     

Advances in the management of advanced and recurrent uterine papillary serous carcinoma

Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer that accounts for 5–10% of all cases. Over 50% of the patients with UPSC present with advanced stage disease ⁽¹⁾ . Among patients with noninvasive uterine disease, 40% have advanced stage UPSC ⁽¹⁾ ; therefore, complete surgical staging is crucial to determine prognosis and treatment ⁽²⁾ . Optimal tumor debulking (<1cm) is associated with a better prognosis and improved overall survival ⁽³⁾ . After initial surgical staging, patients with high stage UPSC have an improved overall survival if treated with chemotherapy (platinum-based or paclitaxel-based therapy) ⁽¹⁾ . Even with chemotherapy, the disease free interval is approximately 1 year ^(4–6) . The role of radiation in these patients is unclear. Up to 30% of recurrences occur outside of the abdomen and pelvis (unpublished data). While the response rate to chemotherapy in the recurrent setting is up to 80%, the duration of response is approximately 7 months ^(4–6) . Because the disease free interval in the adjuvant setting and the duration of response in patients with recurrent disease is limited, better strategies are needed to treat patients with this disease. We have recently evaluated Her-2/neu overexpression and amplification in a series of patients with UPSC. Her-2/neu overexpression was independently associated with a poor prognosis, however the rate of specific gene amplification was only 3% ⁽⁷⁾ . We have found that imatinib-targeted kinases are overexpressed in UPSC ⁽⁸⁾ . We currently are evaluating imatinib (Gleevec, Novartis) and paclitaxel for the treatment of UPSC in patients with advanced or recurrent disease.     

Serum CA 125 as a tumor marker and the expression of c-erbB-2 oncogene in tubal malignancies

Serum CA 125 levels were evaluated in 26 patients with fallopian tube malignancies. CA 125 was elevated preoperatively in seven samples (median 178 U ml⁻¹ range 41–19021 U ml⁻¹), and postoperatively in eight of nine (89%) samples collected from patients with residual disease (median 109 U ml⁻¹ range 10–1883 U ml⁻¹) but only in one of seven (14%) samples from patients without residual disease (median 14, range 5–170 U ml⁻¹) ( P < 0.001). Changes in the serum CA 125 level during chemotherapy correlated with the clinical course of disease in 13 of 14 patients with a pre-chemotherapy serum CA 125 level> 35 U ml⁻¹. Nine patients with clinical remissions showed decreasing serum CA 125 levels, one with clinically stable disease showed decreasing levels and four with disease progression showed increasing levels. Serum CA 125 levels were measured in four patients before second-look laparotomy. Two of three with positive findings at laparotomy had elevated serum CA 125 levels whilst the third had a normal level. One patient with negative findings at second-look surgery had a normal CA 125 level. Disease relapse was associated with elevated serum CA 125 levels in nine of 10 patients (median 108 U ml⁻¹, range 27–38200 U ml⁻¹). Using immunohistochemical staining, none of the tumors showed positive cytoplasmic staining for c-erbB-2 (NEU) oncogene. This report shows that CA 125 is a reliable tumor marker for monitoring patients with cancer of the fallopian tube during active treatment and follow-up.     

Circulating placental proteins (hCG, SP1 and PP5) in trophoblastic disease

Summary. Scrum human chorionic gonadotrophin (hCG), pregnancyspecific β₁-glycoprotein (SP₁) and placental protein 5 (PP5) levels have been measured by radioimmunoassay in 20 patients (116 samples) with hydatidiform mole, one patient (nine samples) with invasive mole and 10 patients (103 samples) with choriocarcinoma. Measurement of both serum SP₁ and hCG are useful in the monitoring of these diseases. The presence of PP5 in hydatidiform mole and its absence in choriocarcinoma support the hypothesis that PP5 is closely associated with the invasive activity of malignant trophoblast.     

Paclitaxel in combination with cisplatin is less effective for peripheral blood progenitor cell mobilization

Abstract. Kurata H, Takakuwa K, Tsuneki I, Aoki Y, Tanaka K. Paclitaxel in combination with cisplatin is less effective for peripheral blood progenitor cell mobilization.
The purpose of this study was to determine the efficacy of paclitaxel in combination with cisplatin and granulocyte-colony stimulating factor (G-CSF) for mobilization of peripheral blood progenitor cells (PBPC). Twenty-seven patients with gynecological cancer received paclitaxel and cisplatin (TP, n = 9) or other platinum-based chemotherapy ( n = 18) (etoposide and cisplatin [ n = 5]; cyclophosphamide, adriamycin, and cisplatin [ n = 8]; or pepleomycin, etoposide, and cysplatin [ n = 5]). Each combination was followed by G-CSF. The mean number of colony-forming unit granulocyte macrophage (CFU-GM)/kg and CD34⁺ cells/kg collected per cycle was 1.2 × 10⁵ and 0.8 × 10⁶ after the TP regimen, compared with 2.6 × 10⁵ ( P < 0.05) and 2.0 × 10⁶ for patients who received other platinum-based chemotherapy. The CFU-GM target yield (≥1.0 × 10⁵/kg) was achieved in 56% and 83% patients in the TP and comparison group, respectively. With the TP regimen, a younger age (≤50 years of age) and fewer prior chemotherapy cycles (≤2) were associated with the CFU-GM targeted yield (<0.05). In conclusion, TP mobilized PBPC less effectively than other platinum-based chemotherapy. Therefore, the TP regimen may need to be changed to another appropriate regimen when PBPC mobilization is planned for high-dose chemotherapy in gynecological cancer patients.     

Evaluation of serum CA 125 level as a tumor marker in borderline tumors of the ovary

Serum CA 125 was evaluated as a tumor marker in 85 patients with borderline ovarian tumors. Serum CA 125 levels were elevated preoperatively in 18 of 20 (90%) samples (median 66, range 5–272 U ml⁻¹). Preoperative serum CA 125 levels did not correlate to FIGO stage. Preoperative serum CA 125 levels were elevated in seven of nine (78%) with serous tumors (median 131, range 5–272 U ml⁻¹) and in all 11 with mucinous tumors (median 62, range 41–157 U ml⁻¹). There was no significant difference in the CA 125 levels between these two histologic types. Postoperative serum CA 125 levels, measured 3–6 weeks after primary laparotomy, were significantly lower than the preoperative ones ( P < 0.001). No difference in the postoperative CA 125 levels was found between those with and those without residual disease after surgery. Postoperative serum CA 125 levels were elevated in eight of 60 (13%) without residual tumor. None of these had relapsed at the time of analysis (26–87 months after surgery). Serum CA 125 levels tended to correlate with disease evolution during chemotherapy. Two with disease remissions had falling levels, one with stable disease had falling level and one with disease progression had rising level. Serum CA 125 samples were obtained before second-look laparotomy in seven patients. Two with negative findings at second-look had normal levels. Of five with positive findings at laparotomy only two had elevated serum CA 125 levels. Disease relapse was associated with elevated serum CA 125 levels in only one of six patients.     

Elevated intravesicular fluid luteinizing hormone concentration in hydatidiform mole

Summary. Concentrations of human chorionic gonadotrophin (β-hCG), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PRL) were measured by radioimmunoassay in the serous fluid of hydatid vesicles obtained from 27 patients with hydatidiform mole. High amounts of all four hormones were found in every case. The mean concentrations ± SEM were 710.8 ± 100.8 i.u./l×10⁻³ for β-hCG, 13.8 ± 0.3 i.u./l for FSH, 302.2 ± 34.5 i.u./l×10⁻³ for LH and 2610.8 ± 562.1 m-i.u./l for PRL. It is suggested that aberrations in the mechanisms controlling the synthesis and release of luteinizing hormone-releasing factor (LH-RF) could result in chronically elevated LH levels leading to changes characteristic of this disease.     

Liver function following pregnancy complicated by the HELLP syndrome

Serum levels of aminotransferases, lactate dehydrogenase, gammaglutamyl transferase, alkaline phosphatase, albumin and conjugated bilirubin, measured in 54 women at a median of 31 months (range 3–101) after pregnancies complicated by the HELLP syndrome, were not elevated. Total bilirubin levels, however, were elevated in 20'1/0 of these women; this represents a significant difference from the prevalence in 151 women with a previous normal pregnancy (  χ²= 12.23  ,   P < 0.001  ), or in the normal female population (  χ²= 22.34  ,   P < 0.00001  ). This raises the possibility that a dysfunction of the bilirubin-conjugating mechanism represents a risk factor for the development of the HELLP syndrome.     

Comparison of pregnancy-specific β1-glycoprotein (SP1) and ultrasound in predicting the date of delivery

Summary. The accuracy of ultrasound measurements (crown-rump length and gestational sac diameter) and the serum concentration of pregnancy-specific β₁-glycoprotein (SP₁) in the prediction of the date of birth was analysed in a study population of 94 patients. When measured before 8 weeks after the last menstrual period (LMP) the serum concentration of SP₁, was found to be a good predictor of the expected date of delivery and a good alternative to ultrasound, but it was of limited use when determined at a later gestation.     

Serum markers for Down's syndrome in women who have had in vitro fertilisation: implications for antenatal screening

To examine the Down's syndrome screening positive rate among in vitro fertilisation (IVF) pregnancies, we measured second trimester serum marker levels in singleton IVF pregnancies (cases) and in five non–IVF pregnancies (controls) matched to each case for gestational age, age of mother, and duration of storage of the serum sample. There were 151 IVF pregnancies in which alpha fetoprotein, unconjugated oestriol (uE₃), free β–human chorionic gonadotrophin (hCG) and total hCG were measured, 104 IVF pregnancies in which free α-hCG was measured, and 39 IVF pregnancies in which inhibin A was measured. Median uE₃ levels were 6% lower (   P = 0.003  ), median free β–hCG 9% higher (   P = 0.024  ), and median total hCG 14% higher (   P = 0.026  ) in IVF pregnancies compared with controls. The screen positive rate in the IVF pregnancies (28%) was about twice as high as that in controls (17%). High hCG levels may be explained by progesterone remaining high in IVF pregnancies. The low uE₃ levels remain unexplained. In Down's syndrome screening in IVF pregnancies hCG and uE₃ values should be adjusted to avoid the high screen positive rate.     

Thromboxane A2 and prostacyclin levels in molar pregnancy

Summary. Plasma levels of thromboxane (TX) A₂ and prostacyclin (PGI₂), as measured by radioimmunoassay of their respective stable metabolites TXB₂ and 6–keto PGF_1α, were studied in six molar pregnancies immediately before, immediately following and 24 h after evacuation of the uterus. The mean (SD) levels for TXB₂ were 150 (41), 137 (32) and 125 (25) pg/ml respectively, and for 6–keto PGF_1α the respective values were 225 (52), 226 (127) and 213 (49) pg/ml. There was no significant difference in the levels of prostanoids between the samples taken at the various time intervals. The concentration of these prostanoids in molar intravesicular fluid was also determined. Their respective mean (SD) pg/ml values were 3682 (760) for TXB₂ and 2969 (744) for 6–keto PGF_1α. In 15 normal pregnancies of equivalent gestation, the mean amniotic fluid levels of TXB₂ and 6–keto PGF_lα were 34 (17) and 146 (86) pg/ml respectively. The ability of molar trophoblast to generate the prostanoids from [¹⁴C]arachidonic acid in vitro was also demonstrated. Mean (SD) values for TXB₂ and 6-keto PGF_1α were 12.2 (2.6) and 13.2 (1.8) pg/mg protein/min, respectively. It is likely that the high concentrations of prostanoids in vesicular fluid reflect the synthesizing ability of the villus vesicles. The mole contributes little to the circulatory prostanoids possibly because its villi are deficient in blood circulation.     

Reduced in-vitro fertilization of human oocytes from patients with raised basal luteinizing hormone levels during the follicular phase

Summary. A series of 62 women were managed in the University of Western Australia/PIVET Laboratory in-vitro fertilization programme. In 60 of them follicle growth was stimulated with clomiphene citrate' with or without additional human menopausal gonadotrophin (hMG) and in two with hMG alone. Follicles were aspirated at laparoscopy following an hCG trigger injection and occasionally following a spontaneous luteinizing hormone (LH) surge. Oocytes were inseminated with 0·5×10⁵−10⁵ sperm/ml 3–6 h later. A significant reduction ( P <0·001) in the fertilization rate of mature oocytes was observed in those patients whose basal serum LH values were >1 SD above the mean. Fifty-nine women subsequently had embryo transfer and of 10 clinical pregnancies, none occurred in those with elevated LH values. Reduced fertilization may be a reflection of premature oocyte maturation or ageing. This may have clinical implications in the management of some patients with unexplained infertility.     

Schwangerschaftsprotein 1 (SP1) in serum and cerebrospinal fluid of patients with gestational trophoblastic disease

Summary. The β subunit of human chorionic gonadotrophin (β-hCG) and Schwangerschaftsprotein 1 (SP1) were measured by radioimmunoassay in the serum and cerebrospinal fluid (CSF) of 46 postmolar and postpartum patients who developed gestational trophoblastic disease. There was a significant correlation between β-hCG and SP1 serum levels. The mean serum SP1 level in high-risk patients was significantly higher than that in low-risk patients. There was a significant correlation between serum and CSF β-hCG levels. The ratio of serum to CSF β-hCG levels was low in the three patients with clinical evidence of intracranial metastasis. SP1 was present in the CSF of only one of these three patients, but it could be detected in the CSF of another four patients without clinical evidence of metastases in the central nervous system. The two low-risk patients with SP1 present in the CSF showed poor response to intramuscular methotrexate.     

Serum CA125 assay at the time of relapse has no prognostic relevance in patients undergoing chemotherapy for recurrent ovarian cancer: a multicenter Italian study

The present retrospective study assessed the prognostic value of serum CA125 assay at relapse in 73 patients with recurrent epithelial ovarian cancer. At the time of relapse, serum CA125 levels ranged from 7 to 7000 U ml⁻¹. The 25%, 50% and 75% quantiles of CA125 levels were 76, 178 and 339 U ml⁻¹, respectively. Antigen values were >35 U ml⁻¹ in 67 (91.8%) of the 73 patients. Median time to recurrence was 16 months (range, 4–62 months). Serum CA125 levels at relapse were not related to site of recurrence, time to recurrence, FIGO stage, histologic type, tumor grade and residual disease after initial surgery. Sixty patients received salvage chemotherapy at relapse. In these patients survival after recurrence was significantly related to time to recurrence ( 6 months vs < 6 months, P  = 0.0371; 12 months vs >12 months, P  = 0.0014; 16 months vs >16 months, P = 0.0001), but not to CA125 level at relapse (at any cut-off value for the antigen: 35, 76, 178 and 339 U ml⁻¹ ), site of recurrence, FIGO stage, histologic type, tumor grade and residual disease after initial surgery. In conclusion, time to recurrence was the only variable predictive of further survival in patients undergoing salvage chemotherapy for recurrent ovarian cancer, whereas serum CA125 level at relapse had no prognostic relevance.     

Colposcopic differential diagnosis of dysplasia, carcinoma in situ and microinvasive carcinoma of the cervix

Summary: Two hundred and twenty-eight patients with cervical neoplasia, detected in routine uterine cancer screening at the Center for Adult Diseases, Osaka, from 1973 through 1977 were selected. The histological diagnosis was as follows: dysplasia, 69; carcinoma in situ, 102; and microinvasive carcinoma, 57. A retrospective study of this material was made with the aid of adequate colposcopic colour photographs, and features likely to be useful in differential diagnosis were determined.
Atypical vessels were seen in 24 of 36 patients (67%) with Stage la¹ lesions, but only in a few of those with Stage 0² lesions. Punctation, mosaic and white epithelium were less evident in stage la² than in Stage 0¹ and Stage 0². Punctation, mosaic and white epithelium in patients with dysplasia were less formed, and their borders were less distinct than in patients with Stage 0 lesions. These characteristic changes are of value in accurate colposcopic diagnosis.     

First trimester urinary placental growth factor and development of pre-eclampsia

Objective  To compare urinary placental growth factor (PlGF) concentration at 11⁺⁰ to 13⁺⁶ weeks of gestation in women who subsequently develop pre-eclampsia with normotensive controls.
Design  Nested case–control study within a prospective study for first trimester prediction of pre-eclampsia.
Setting  Routine antenatal visit in a teaching hospital.
Population  Fifty-two women who developed pre-eclampsia and 52 controls matched for gestational age and sample storage time.
Methods  Urinary PlGF concentration and PlGF to creatinine ratio were measured in women who developed pre-eclampsia and their matched controls. Comparisons between groups were performed using Student's t test.
Main outcome measures  Development of pre-eclampsia.
Results  In the pre-eclampsia group, the median urinary PlGF concentration (20.6 pg/ml, interquartile range [IQR] 9.1–32.0 pg/ml) and median urinary PlGF to creatinine ratio (1.6 pg/mg, IQR 1.2–2.5 pg/mg) were not significantly different from the control group (11.8 pg/ml, IQR 5.5–29.8 pg/ml, P = 0.1 and 1.7 pg/mg, IQR 1.2–2.3 pg/mg, P = 0.3, respectively). There were no significant differences between women with early-onset pre-eclampsia requiring delivery before 34 weeks ( n = 13) and those with late-onset pre-eclampsia ( n = 39) and between women with pre-eclampsia and fetal growth restriction (FGR) ( n = 25) and those with pre-eclampsia and no FGR ( n = 27) in either median PlGF concentration or median urinary PlGF to creatinine ratio.
Conclusions  The development of pre-eclampsia is not preceded by altered urinary PlGF concentration in the first trimester of pregnancy.     

Integrin expression in cervical carcinoma

Heatley MK, Corke K. Integrin expression in cervical carcinoma. Int J Gynecol Cancer 1998; 8: 203–206.
Integrin expression was studied in a series of 36 cervical carcinomas using antibodies to integrins αvβ₅, α₃, β₁ and β₄. Integrins αvβ₅, α₃ and β₁ were localized to the cell membrane in well differentiated (0/13, 2/4 and 4/14 cases) and moderately differentiated adenocarcinomas (0/6, 1/5 and 1/6 cases, respectively) and in adenosquamous (2/6, 2/5 and 3/6) well differentiated (1/4, 0/3, and 3/5) and moderately differentiated (1/2, 1/3 and 1/3) squamous cell carcinomas. Two antibodies (AA3 and 439-B) located integrin β₄ to the cell membranes and cytoplasm of well (13/13 and 10/12 cases) and moderately differentiated (6/7 and 5/6 cases) adenocarcinomas, cases of adenosquamous carcinoma (6/6 and 5/6 cases), and well (4/4 and 3/4 cases) and moderately (3/3 and 3/4 cases) differentiated squamous cell carcinomas. In conclusion, integrin expression was identified most frequently with the antibodies to β₄ which was localized to cervical carcinomas of varying grades and histological types. Immuno-staining was identified less frequently with the antibodies to αvβ₅, α₃ and β₁.     

Thrombocythaemia and recurrent miscarriage

The incidence of thrombocythaemia (a platelet count >600×l0⁹/l) in a 10-year survey was 7 per 10⁶ population per year (R. M. Pettit, personal communication). It is generally a disease of late middle age, but a second population of young and mainly female patients has been described (Hoagland & Silverstein 1978). An increased platelet count can be secondary (after splenec-tomy, associated with inflammation, malignancy or iron deficiency) or due to a primary myeloproliferative disorder. We describe four patients in whom a series of miscarriages before 20 weeks gestation appears associated with thrombocythaemia and estimate the prevalence of this association in patients with unexplained repeated miscarriage.     

Incidence of urinary incontinence and constipation during pregnancy and postpartum: survey of current findings at the Rotunda Lying-in Hospital

Objective To assess the impact of pregnancy upon continence and constipation.
Design A questionnaire survey.
Setting Maternity wards in the Rotunda Lying In Hospital, Dublin, Republic of Ireland.
Population 7771 women who were delivered of liveborn infants.
Methods Questionnaires were delivered and collected by physiotherapy staff as part of routine postnatal care.
Results Analysis of data using χ² tests showed significant differences between three parity groups [primigravidae, multigravidae (2–4) and multigravidae (5+)] for symptoms of both urinary incontinence (  χ²= 119.54  , df = 2, P = 0.000) and constipation (  χ²= 12.53  , df = 3, P = 0.002); the incidence of both constipation and urinary incontinence increased with parity.
Conclusion The results of this survey have emphasised the relation between parity and postpartum incontinence which stresses the importance of early diagnosis and intervention.     

Dexamethasone-induced leucocytosis in pregnancy

The effect of intramuscular dexamethasone administration in late pregnancy on the maternal peripheral white cell count was examined in 20 women. The mean total white cell count increased from a baseline of 11–3 × 10⁹/L (SD 2–3) to 16–2 × 10⁹/L (SD 4–6) on day 1, normalising thereafter. This 43% increase represented composite changes in the neutrophil and lymphocyte counts which, on average, increased by 62% and decreased by 22%, respectively. It is concluded that prenatal dexamethasone induces a significant neutrophilia on the first day following administration. This information may be helpful when monitoring for infection.