High-dose cisplatin combination chemotherapy in the treatment of advanced epithelial ovarian carcinoma.

We treated 25 newly diagnosed patients with advanced epithelial ovarian cancer with an intensive induction chemotherapy regimen using high-dose cisplatin in combination with cyclophosphamide and doxorubicin. All patients had either stage IIIC or stage IV disease. Two intensive induction courses of chemotherapy were administered at 28-day intervals, which consisted of cisplatin 40 mg/m2 daily for 5 days, cyclophosphamide 500 mg/m2 day 1, and doxorubicin 40 mg/m2 day 1. Four courses of chemotherapy using cisplatin 60 mg/m2, doxorubicin 40 mg/m2, and cyclophosphamide 500 mg/m2 followed the high-dose induction therapy. Two of the first six patients died during high-dose induction therapy (one died of neutropenia and sepsis, one of intercurrent intracerebral hemorrhage). Doxorubicin was subsequently omitted from the induction therapy due to unacceptable myelosuppression; no deaths occurred in the remaining 19 patients, and myelosuppression was manageable. Peripheral neuropathy was the most severe side effect with this regimen. This complication was unpredictable, developed during the third or fourth month of treatment, and was disabling in five patients. Other toxicity included prolonged nausea and vomiting (eight patients), ototoxicity (five patients), and nephrotoxicity (two patients), but these did not compromise therapy. All 23 assessable patients had objective response to therapy. Four of 12 patients who underwent second-look laparotomy had pathologic complete response, while four additional patients had only microscopic residual disease. The median survival for the entire group was 25 months. Four patients remain continuously disease-free 23 to 48 months following completion of therapy. Although this regimen was tolerated by most patients, the unpredictable occurrence of disabling neuropathy may limit its usefulness.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional nature of glomerular injury in progressive diabetic glomerulopathy.

We describe in physiological terms the increasing glomerular capillary wall (GCW) dysfunction of 20 patients with diabetic glomerulopathy and heavy proteinuria. The clearances of uncharged polysaccharide markers of graded size were used to probe the glomerular filter on three occasions over a 24-mo period. The findings were analyzed with a theoretical model of solute transport that depicts most of the GCW as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway. Initially, the mean glomerular ultrafiltration coefficient Kf is computed to have been 3-5 times lower and mean pore radius of the major membrane component (r0) 2 A smaller than normal control values. In contrast, the model computes the fraction of filtrate volume permeating the nondiscriminatory shunt pathway (omega 2) to have been sixfold elevated above control values and to have correlated strongly in individual patients with the fractional clearances of albumin (r = .72) and of IgG (r = .73). Sequential studies after 12 and 24 mo revealed an invariable decline in glomerular filtration rate (GFR). Fractional clearances of albumin and IgG increased with time in most patients but declined in a few instances (20-25%). Change in omega 2 tended to occur in parallel with fractional protein clearance, regardless of its direction. We conclude that in progressive diabetic glomerulopathy GFR declines because of a loss by glomerular capillaries of ultrafiltration capacity, proteinuria is largely a consequence of increasingly impaired barrier-size selectivity, and the foregoing injuries reflect damage to different parts of the GCW and may become dissociated from one another with the passage of time.

Mechanisms of proteinuria in diabetic nephropathy. II. A study of the size-selective glomerular filtration barrier.

We evaluated the size-selective properties of the glomerular barrier in 30 patients in whom diabetic nephropathy was associated with urinary IgG losses. Neutral dextrans of graded size were used to characterize glomerular membrane-pore structure. A fractional IgG clearance (relative to freely permeable inulin) smaller or greater than 0.001 was used to distinguish patients with minor (group 1, N = 14) and major (group 2, N = 16) urinary IgG leakage, respectively. Fractional clearances of dextrans (theta D) of smaller size (radii 20-40 A) were similar, but those of larger dextrans (radii 42-60 A) were elevated in group 2 relative to group 1 patients. When plotted on log-normal probability coordinates, the correlation between theta D and radius in healthy subjects is linear, suggesting that glomerular pores form one population with a normal distribution. In diabetic nephropathy with urinary IgG leakage, however, theta D for large molecules was elevated and departed from linearity, suggesting a bimodal pore size distribution within the glomerular membrane. A pore model of solute transport revealed (1) the upper pore mode was highly permeable to large dextrans equivalent in size to IgG and (2) the fraction of glomerular filtrate permeating the large pores was greater in group 2 than in group 1 patients with diabetic nephropathy, 6% versus 3%, respectively. We conclude that urinary IgG leakage in diabetic nephropathy is determined by the development of a subpopulation of enlarged pores. The magnitude of urinary IgG losses appears to be a function of the membrane area-fraction occupied by the enlarged pores.

In vitro inhibition of endometrial cancer growth by a neonatal rat testicular secretory product.

The ability of a neonatal testicular product to inhibit cancer cell line growth of Mullerian origin was tested in an "in vitro" system. Preliminary experiments indicated that increasing concentration of neonatal rat testicular homogenates showed increasing endometrial cancer (HEC-1) cell growth inhibition. Further investigation revealed that testes organ culture, similarly, inhibited HEC-1 cell growth. It is, therefore, concluded that neonatal rat testes elaborated a substance (or substances) which may be effective as an anti-tumor agent.

Evaluation of the clinical efficacy of embryo cryopreservation.

To fully evaluate the advantages of a cryopreservation program a method needs to be established to express the additional patients pregnant from cryopreservation. The patient specific method considers cryopreservation as augmentation only among patients without a pregnancy from the fresh transfer, or from previously transferred frozen material from the same harvest. In an analysis of the pregnancy rate at the Jones Institute between January 1996 and December 1998 we found a fresh pregnancy rate of 40.8% in the good responders and 28.8% in poor responders. The patient specific pregnancy rate in the same cycles was 53.4% in good responders and 32.3% in poor responders. Good responders less than 35 years of age with ten or more mature eggs at retrieval had a fresh pregnancy rate of 40.2% and a patient specific pregnancy rate of 57.9%. It is exceedingly important for the physician and patient to understand and comprehend the potential in cryopreserved material.

Alveolar soft part sarcoma of the uterus.

Two patients with alveolar soft part sarcoma of the uterus are described. One of the sarcomas was a submucosal nodule of the cervix, and the second was a minuscule, incidentally discovered lesion in the corpus. Both lesions contained periodic acid-Schiff-positive, diastase-resistant cytoplasmic granules, and characteristic membrane-bound crystalline inclusion bodies were demonstrated in the cervical lesion.

Surface morphology of the human endometrium. Basic and clinical aspects.

The human endometrium is an extremely sensitive target for steroid hormones. During the menstrual cycle, this tissue undergoes dynamic changes that are reflected on the surface morphology of the epithelium and that can be followed by scanning electron microscopy. The morphologic changes peak at the midsecretory phase, with the formation of the so-called pinopodes. Increasing evidence suggests that these pinopodes are accurate markers for endometrial receptivity, and their detection may be of high clinical utility in the preparation of endometrium before embryo transfer. This article recapitulates published figures of endometrial ultrastructure and presents some unpublished data from ongoing studies.

Endometrial receptivities after leuprolide suppression and gonadotropin stimulation: histology, steroid receptor concentrations, and implantation rates.

The effect of markedly supraphysiologic levels of E2 and P4 on the endometrium was assessed by examining endometrial histology, E2 and P4 receptor concentrations, and embryo implantation rates in IVF cycles with and without leuprolide use. Results suggest that 1) the high ovarian response common in leuprolide pretreated cycles can advance endometrial histology, but only up to a certain limit, 2) P4 greater than 25ng/ml or E2 greater than 200pg/ml on the day of transfer was associated with non-lagging endometria, 3) implantation rate in high response cycles is not impaired and may be increased, 4) earlier P4 supplementation in low response cycles may be beneficial, 5) extraordinarily high response (E2 greater than 5000pg/ml) may be detrimental to implantation, and 6) the optimal histology for implantation appears to be at least day 16.

Management of stage II endometrial adenocarcinoma.

Charts of 36 patients with clinical stage II endometrial adenocarcinoma over ten years were reviewed. All were staged before any treatment, in accordance with International Federation of Gynecology and Obstetrics (FIGO) guidelines. Although details of treatment varied, two main protocols were used. Fourteen patients were treated with the "standard" protocol involving external whole-pelvis radiation, followed by intracavitary cesium and then hysterectomy. In 1981, a "modified" protocol was introduced, which called for a hysterectomy immediately following intrauterine and vaginal cesium. External radiation therapy was given only to those patients found to have deep myometrial invasion or cervical involvement. Of 14 patients treated by this protocol, seven had no surgical indication for postoperative external radiation. There was no increase in recurrence in these patients, and the five-year survival rate was 76% for patients treated with the modified protocol compared with 65% for those who had standard therapy. Morbidity related to external radiation therapy occurred in two patients with the standard protocol and one patient who received pelvic radiation on the modified protocol.

The split thickness graft technic for vaginal agenesis.

A heterogenous group of patients with agenesis of the vagina treated at The Johns Hopkins Hospital between 1956 and 1975 is reported. The split thickness autogenous skin graft technic of McIndoe was used in 44 patients with Rokitansky-Kuster-Hauser syndrome, 9 male hermaphrodites, 7 patients with the testicular feminization syndrome, and in 4 male transsexual patients. Urinary tract abnormalities were found in 49% of patients with the Rokitansky syndrome. The functional results were quite satisfactory. The graft was satisfactory in all but 3 patients who required a partial second skin graft. Rectovaginal fistula with spontaneous closure occurred in 1 patient, and a transsexual patient developed a urethrovaginal fistula which was repaired surgically. Better results with the take of the skin graft have been obtained since a foam rubber vaginal form has been used and routine prophylactic antibiotics administered. Severe condylomata acuminata of the neovagina developed in 3 patients.

Pregnancy rates after reconstructive surgery on the fallopian tubes.

PIP: Current practices at Johns Hopkins Hospital with regard to surgery for tubal disease are presented. Statistical support for a particular point could not always be provided, but overall end results are given. Between 1965 and 1972, 66 patients at the Johns Hopkins Hospital had tuboplasties: 24 salpingolyses, 18 fimbrioplasties, 6 anastomoses, 8 cornual implantations, and 10 multiple procedures. The average patient age was 29.3. The duration of infertility was between 8 months and 10 years, with an average of 53.2 months. 41 of the patients had primary and 25 had secondary infertility. The operations of lysis of adhesions were done for patients whose hysterosalpingograms or dye studies at endoscopy showed patent tubes where peritubal adhesions were visualized. Fimbrioplasty has proved to be the most frustrating operation. Resection and anastomosis was almost exclusively done for repair of the tubes after surgical ligation. A high percent of good results are expected after cornual implantation. The pregnancy rates after correction of obstruction at various sites were 58% for salpingolysis, 22% for fimbrioplasty, 50% for midtubal obstructure, 38% for cornual implantation, and 20% for multiple procedures. The overall pregnancy rate was 39.4%. These rates depended on the length of the followup: the shorter the duration of followup, the lower the pregnancy rate. In order to circumvent this problem, expectancies of pregnancy, when followed up for an indefinite time, were calculated by computer. By this algorithm, it was found that 50% of patients could expect pregnancy following tuboplasties of all kinds: 66% after tubolysis, 40% after fimbrioplasty, 50% after anastomosis, 38% after cornual implantation, and 21% after multiple procedures.^ieng

Male hermaphroditism with bilateral testes, well-formed Müllerian structures, and 45,X chromosome complement.

A patient is presented who was short in stature and had an enlarged phallus, normal vagina, uterus, fallopian tubes, and bilateral testes but with a 45,X karyotype from peripheral leukocytes. This is believed to be the first such patient ever reported. Such patients and other previously described male hermaphrodites with a 45,X karyotype indicate that, contrary to the general rule that patients with 45,X karyotype do not require a laparotomy, patients with such a karyotype should be explored if their genitalia are ambiguous.

The fallability of X-chromatin as a screening test for anomalies of the X chromosome.

In 13 of 148 patients suspected of anomalies of the X chromosome, the X-chromatin test was misleading. Therefore, if an anomaly is suspected, a karyotype as well as an X-chromatin study is indicated.

Squamous carcinoma of the cervix complicating pregnancy: recurrence in episiotomy after vaginal delivery.

A patient developed recurrence of squamous carcinoma of the cervix in the episiotomy scar after vaginal delivery through the involved cervix. At the time of her radical hysterectomy, all margins and nodes were free of tumor, suggesting implantation at delivery as the etiology of the recurrence. Review of the literature revealed three other cases of episiotomy recurrence. All cases were either clinically unsuspected or had negative Papanicolaou tests during pregnancy. Careful surveillance and early therapy appear to give a more favorable prognosis for this unusual type of recurrence.

Radical surgery for the treatment of early invasive cervical carcinoma (stage IB): review of 15 years' experience.

From 1963 through 1977, 108 patients with stage IB cervical carcinoma were treated with radical hysterectomy and pelvic lymphadenectomy at the University of California, San Francisco. Forty-four of 48 patients followed for 5 or more years after surgery are known to be alive (5-year survival rate, 91.7%). The 5-year survival rate of all 108 patients using the life-table method is 93.4%. Complications in this series were few; only 1 patient developed a ureterovaginal fistula.

Secondary surgical treatment of the masculinized external genitalia of patients with virilizing adrenal hyperplasia.

Among 84 patients with virilizing adrenal hyperplasia operated on for deformed genitalia and followed for 7 to 22 years (mean 12 9/12 yr), 25 (30%) required secondary operations. For the most part, the secondary procedures were to provide a vaginal orifice adequate for coitus. The difficulties were due either to failure to adequately exteriorize the orifice at the first operation or to contraction of the outlet due to scar formation. Simple operative procedures to correct these difficulties are described.

Pregnancy related to infertility diagnosis, number of attempts, and age in a program of in vitro fertilization.

Three hundred nineteen infertility patients who did not become pregnant with standard therapies presented to Norfolk for in vitro fertilization between January 1981 and December 1983. There were 560 laparoscopic cycles with 105 pregnancies. The pregnancy rate was 18.8% by cycle, 24.5% by transfer, and 33% by patient. The overall pregnancy rate was found to be independent of infertility diagnosis, age, and number of attempts.

Pregnancy success following surgical correction of imperforate hymen and complete transverse vaginal septum.

Pregnancy success was evaluated in 48 women following surgical correction of a vaginal obstruction due to imperforate hymen (N = 22) or to a complete transverse vaginal septum (N = 26). Pregnancy success was more likely to occur following surgical correction of imperforate hymen (P less than .05). Patients with a complete transverse septum in the middle or upper vagina were less likely to conceive than were patients with a septum in the lower vagina. Prompt diagnosis and surgical correction to drain accumulated blood may preserve preserve fertility possibly through the prevention of endometriosis.

Spontaneous abortion after midtrimester amniocentesis.

Of 371 consecutive patients who underwent midtrimester diagnostic amniocentesis, 8 subsequently aborted spontaneously (2.2%), and 1 had a stillbirth at 24 weeks of gestation (0.17%). In 3 of the 9 patients who suffered fetal loss, infection appears to have played a significant role. Whereas midtrimester diagnostic amniocentesis is widely considered to be a safe and accurate procedure, the possibility of hazard to the patient and her fetus remains and should be considered during the preliminary counseling session.

A genetic male patient with 17 alpha-hydroxylase deficiency.

A patient with 46,XY karyotype and 17 alpha-hydroxylase deficiency is reported who illustrates marked virilization of the external genitalia. Marked phallic development and almost complete labioscrotal fusion with no development of a utriculovaginal pouch were noted. Because the perineum was essentially similar to that seen in male-to-female transsexuals, vaginal construction required the McIndoe procedure. Hence, although some patients with 17 alpha-hydroxylase deficiency have minimal virilization of the external genitalia, this patient's history indicates the operative management necessary in the opposite extreme, when patients show complete masculinization. Hormonal evaluation after gonadectomy revealed the enzyme deficiency based on abnormalities of steroid secretion by the adrenal cortex.