Gynecologic oncology--preparing for the third decade.
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Certification↗
Biomedical subjects
C J Cohen
Publications and source records attributed to C J Cohen.
Ca channels in adrenal glomerulosa cells: K+ and angiotensin II increase T-type Ca channel current.
Ca channel currents were studied in freshly dispersed bovine adrenal glomerulosa cells to better understand the control of aldosterone secretion by extracellular K concentration (Ko) and angiotensin II (AII). The whole-cell variation of the patch voltage clamp technique was used. Two types of Ca channels were found. One type is similar to the "T-type" Ca channels found in many excitable cells. These channels deactivate slowly (tau approximately equal to 7 ms at -75 mV) and inactivate rapidly during strong depolarizations. The second channel type activates and inactivates at more positive potentials than the T-type Ca channels and deactivates rapidly. These channels are similar to the "L-type" Ca channels found in muscle and nerve. Our studies provide three reasons for concluding that T-type Ca channels have an important role in mediating stimulus-secretion coupling in response to high K+ or AII: (i) aldosterone secretion and steady-state current through T-type Ca channels are biphasic functions of Ko and both increase in parallel for Ko = 2-10 mM; (ii) nitrendipine blocks the T-type Ca channels and the stimulation of aldosterone secretion by high K+ or AII with similar potency; (iii) AII increases Ca entry through the T-type Ca channels.
Adrenal Cortex↗
Extrauterine pelvic malignant mixed mesodermal tumors. A study of 10 cases with immunohistochemistry.
Ten cases of extrauterine malignant mixed mesodermal tumors (MMMTs), nine ovarian, and one pelvic, are presented. One patient had a purely epithelial primary ovarian tumor and MMMT in her recurrent tumors. All the other patients had MMMT in their primary and recurrent tumors. Eight patients had heterologous MMMT including cartilage, striated muscle, and adipose tissue in one case. Two patients had homologous MMMT. All cases presented with metastases involving abdominal organs that were either MMMT or epithelial neoplasms and MMMT. Five patients had recurrent tumors, one extensively involving the spleen. In all recurrent tumors, the mesenchymal components were considerably more abundant than in the primary tumors. Immunohistologic studies of intermediate filaments were performed in seven cases, revealing cytokeratin-positive epithelial structures, vimentin-positive mesenchymal (including cartilaginous) structures, as well as coexpression of cytokeratin and vimentin in anaplastic and giant tumor cells in some cases. Some anaplastic spindle cells, which on routine stains were suggestive of stromal cells, stained positive for cytokeratin, thus identifying their epithelial nature. Desmin staining performed in five cases showed positive staining of rhabdomyoblasts in only one case. Myoglobin staining performed in seven cases was positive in four. The histogenesis from primitive müllerian structures and the natural history of these uncommon neoplasms are discussed in light of the pathological and immunohistochemical data presented.
Aged↗
Clinical trial of etoposide and cisplatin as salvage therapy in advanced ovarian carcinoma.
The combination of etoposide and cis-platinum was evaluated in the treatment of advanced ovarian cancer. Of 13 treated patients, 4 demonstrated complete clinical responses and 3 demonstrated partial clinical responses. The mean progression free interval was 14 months+ for the complete responders and 8.3+ months for the partial responders. The 100 mg/m2 dose of etoposide appears to be critical in attaining response. This etoposide and cisplatinum combination appears to be effective as a salvage regimen in ovarian carcinoma.
Adult↗
Nimodipine block of calcium channels in rat anterior pituitary cells.
1. Ca channels were studied in the GH4C1 clonal cell line derived from rat anterior pituitary cells. The whole-cell variation of the patch-electrode voltage-clamp technique was used. 2. Two types of Ca channels were found. One type ('slowly inactivating' channels) is insensitive to changes in holding potential, does not inactivate during test pulses lasting several seconds, and deactivates very quickly upon repolarization. For holding potentials less than -40 mV, a second type of Ca channel is available for opening. This population ('transient' channels) differs from the first type in that it activates at more negative potentials, inactivates rapidly with either Ca or Ba as the charge carrier, deactivates about 10 times more slowly upon repolarization, and is less selective for Ba over Cs. 3. Nimodipine preferentially blocks the slowly inactivating channels. Block of these channels is time- and voltage-dependent, such that block is maximized by long depolarizations. 4. A comparison of the voltage dependence of steady-state nimodipine block with the voltage dependence of channel activation indicates that channel block is directly proportional to the number of open channels. The results are accounted for by a model that postulates 1:1 high-affinity drug binding to open Ca channels. The apparent dissociation constant for binding to open channels is 517 pM. Similar binding constants were previously reported for the inhibition of high-K-induced hormone secretion and high-affinity ligand binding of [3H]nimodipine to isolated plasma membranes. 5. The rate of onset of nimodipine block increases with the test potential, in quantitative agreement with the model of open-channel block. The apparent association rate is about 9.6 X 10(7) M-1 s-1; the dissociation rate is about 0.050 s-1. At therapeutic concentrations (less than 10 nM) nimodipine block takes many seconds to reach equilibrium. 6. Nimodipine should have little effect on stimulus-secretion coupling in healthy pituitary cells in vivo because: (a) the drug binds very weakly to the transient channels that are open at normal resting potentials, and (b) negligible high-affinity binding occurs during spontaneous activity because the onset of block is very slow.
Action Potentials↗
Prognostic factors: cisplatin regimens for patients with ovarian cancer after failure of chemotherapy.
For 129 ovarian cancer patients failing prior chemotherapy, overall clinical response rates were: 21% with cisplatin, 36% with cisplatin plus doxorubicin, 52% with cyclophosphamide added to the two drugs, and 44% with hexamethylmelamine added to the three drugs. Median survival was six or seven months in each trial. Twenty-five percent of the patients survived nine months with cisplatin and 14 to 16 months with each of the three combinations. Characteristics associated with best rate of response included: performance status 1 (completely ambulatory), age greater than or equal to 50, residual tumor less than or equal to 5 cm, and two or less prior cytotoxic drugs. In multivariate analyses, performance status dominated, although age and possibly treatment (cisplatin versus others) were significant. With performance status removed from the model, all of the remaining factors became significant. Factors associated with best survival included: performance status 1, tumor size less than or equal to 5 cm, and complete or partial response. In a multivariate analysis for survival, performance status entered the model. In a series of analyses with performance status removed, tumor size or response entered the model. These findings provide reasons to study both treatment with cisplatin before disease progression reduces the number of favorable characteristics and systematic second attempts at debulking surgery.
Adult↗
Catheter complications associated with intraperitoneal chemotherapy.
Intraperitoneal administration of chemotherapy in ovarian carcinoma is currently under investigation. Numerous recent publications have described clinical studies employing a variety of chemotherapeutic drugs. Little information exists regarding the delivery systems employed or the complications encountered. This study reviews our experience with "single-use" and "long-term" catheters. Thirty-three catheters were placed in 28 patients. Of these catheters, 12 were long-term Tenckhoff catheters and 21 were temporary single-use catheters. Both types of catheters had complications associated with their usage. However, there was a dramatic difference in the number and severity of complications when the two groups were compared. Sixty-seven percent of the Tenckhoff catheters were associated with complications. Nineteen percent of the patients with single-use catheters experienced complications. This 19%, however, represented only 3.8% of the total number of single-use catheter insertions. In our hands, the temporary percutaneous approach has been a safe one, which is technically easy to perform with minimal complications.
Catheterization↗
Cytotoxic chemotherapy for patients with endometrial carcinoma.
Endometrial carcinoma is now the most common gynecologic cancer in the United States and its incidence is increasing. Many investigators attribute this to exogenous factors over which little control has been exerted in the western world. Obesity, dietary fat content, and changing patterns of parity and lifestyle seem significant. Moreover, there appears to be an emerging virulence noted, particularly in some centers. Improved surgical staging and a better understanding of virulence factors will increase the number of patients requiring treatment to fields larger than heretofore recognized. We can expect that one third of the patients with endometrial cancer will require treatment for widespread disease or recurrent disease. Progestational treatment is useful in approximately one-third of all patients with recurrent disease. Thus, systemic nonhormonal chemotherapy must be developed if cure rates in this disease are to improve appreciably. In 1974, only 126 patients had been reported to have been treated with cytotoxic chemotherapy for endometrial cancer. Since that time, experience has demonstrated that the most active single agents are adriamycin, cisplatin, and hexamethylmelamine. These drugs produce a 30-40% response rate when used individually. Multidrug regimens employing various combinations have achieved responses of 15-85% with and without the inclusion of a progestational agent. The median duration of response has been increased but cures are still relatively few. Adverse effects are tolerable and age is not a contraindication to the administration of cytotoxic chemotherapy. Adjuvant treatment is being tested and optimism for future success is justified.
Antineoplastic Agents↗
Histologic correlates and virulence implications of endometrial carcinoma associated with adenomatous hyperplasia.
The association of endometrial carcinoma (EC) with endocrinopathies manifested by obesity, nulliparity, and/or increased estrogen levels of exogenous or endogenous estrogens is now well-known. EC is also seen in patients without these findings. Are these different cancers? Seventy-four cases of EC were reviewed and classified into two groups: group I, with associated adenomatous hyperplasia (AH), 31 cases; and group II, without associated AH, 43 cases. Group I included more well-differentiated and less invasive carcinomas; histologically, the pattern was glandular in all cases. In Group II, the EC were less well-differentiated, more invasive, and included, besides adenocarcinomas, clear-cell, papillary, and anaplastic carcinomas with giant tumor cells. Squamoid features were found in both groups. The possible existence of two types of EC, a hormonal-dependent EC associated with AH (which is believed to result from hyperestrogenism, and to have a better clinical prognosis), and an "independent" EC, not associated with AH, is discussed.
Adult↗
Elevation of serum CA 125 prior to diagnosis of an epithelial ovarian carcinoma.
In a single fortuitous case it has been possible to measure serum levels of CA 125 during 3 years preceding the diagnosis of an epithelial ovarian carcinoma. CA 125 levels were elevated 10-12 months prior to clinical detection of the malignancy. CA 125 deserves further evaluation as a marker for early detection of ovarian cancer.
Agammaglobulinemia↗
A dihydropyridine (Bay k 8644) that enhances calcium currents in guinea pig and calf myocardial cells. A new type of positive inotropic agent.
Bay k 8644 is a structural analog of nifedipine with positive inotropic activity. The mechanism of drug action was evaluated by measuring the effects of Bay k 8644 on twitch tension, action potential configuration, and calcium channel currents in myocardial cells. Bay k 8644 increases twitch tension in guinea pig atria without changing the time course of tension development. The drug does not occlude the effect of isoproterenol on twitch tension. The effects of Bay k 8644 on atrial twitch tension are highly dependent on the frequency of stimulation. Maximal inotropic effects are observed at approximately 0.5 Hz, but no inotropic effect occurs at 0.003 Hz (a rested-state contraction). Since positive inotropic effects only occur with frequent electrical stimulation, they are not due to an intracellular action or to mechanisms that elevate cell calcium in quiescent muscle, such as inhibition of the Na,K-ATPase. Bay k 8644 increases the action potential duration of calf ventricular muscle and Purkinje fibers. Effects on action potential duration are occluded by 1 microM nisoldipine, which specifically blocks calcium channels. The interaction of Bay k 8644 with calcium channels in calf Purkinje fibers was studied using the two-microelectrode voltage clamp technique. Strontium was used as a charge carrier to minimize current through calcium-activated channels and to avoid changes in calcium conductance due to changes in intracellular calcium. Bay k 8644 increases strontium currents and alters the time- and voltage-dependence of channel opening. The greatest percent increase in strontium current occurs for weak depolarizations. For strong depolarizations, strontium current is increased most at the beginning of a test pulse. The drug-induced changes in calcium channel gating are inconsistent with a calcium- or cyclic adenosine monophosphate-mediated effect, and indicate a novel mechanism of action on calcium channels. Thus, Bay k 8644 is the first positive inotropic agent shown to act specifically and directly on calcium channels.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Surgical considerations in ovarian cancer.
A primary consideration for effective management of ovarian cancer is distinguishing patients with advanced bulky disease from those with other stages of disease. It is important to determine whether a tumor is confined to one ovary or is more wide-spread. Surgical management includes removal of both ovaries and tubes, the uterus, omentum, and bulk of the disease. The degree of bulk reduction achieved significantly impacts on survival. Conservation is justified in some cases. Intraperitoneal treatment with platinum-based chemotherapy postsurgery appears to substantially benefit patients with minimal residual disease. In a study comparing two catheter methods, fewer complications were noted with the disposable single-use catheter than with the implanted catheter. Surgical endstaging can definitively identify cured patients. However, it is a difficult procedure and is contraindicated in patients with severe intercurrent illness, previous extensive radiotherapy, and an obliterated peritoneal cavity.
Catheterization↗
Endocervical carcinoma: a study of 23 patients with clinical-pathological correlation.
Twenty-three patients with endocervical carcinomas diagnosed at the Mount Sinai Medical Center during the last 5 years were reviewed (clinical history and histologic material). The tumors were endocervical-type adenocarcinomas, adenosquamous carcinoma, mucinous (colloid), papillary, and clear cell carcinomas. Eight associated carcinomas in situ were found. Younger patients tended to have more adenosquamous carcinomas, perhaps related to the frequency of squamous metaplasia in sexually active women. Twenty-two out of twenty-three patients were multiparous, many of them grand multiparas. In two patients the tumor followed parturition, and in two patients it was found in the cervical stump. No association with oral contraceptives was found. Multiparous women seem to be at increased risk for this malignancy. The early detection of endocervical carcinoma is based on the recognition of dysplasia and adenocarcinoma in situ in the biopsy material. This is of particular significance in the endocervical cancer because its location often prevents early detection.
Adenocarcinoma↗
Use of indwelling right atrial catheter in gynecological oncology: a preliminary report.
Experience with the utilization of an indwelling right atrial catheter in patients with gynecological cancer is reviewed. The technique of placement is described and the complications in 21 patients are presented. Fever was the major complication in 5 out of 21 patients of whom 2 had positive blood cultures. The catheter had to be removed in 3 patients. The median duration of catheter placement was 45 days, the shortest being 8 hr and the longest being 1 year. Most of the patients were myelosuppressed or had no other venous sites accessible. A safe regimen for management of the catheter and indication for its removal are presented.
Catheters, Indwelling↗
Maximal upstroke velocity as an index of available sodium conductance. Comparison of maximal upstroke velocity and voltage clamp measurements of sodium current in rabbit Purkinje fibers.
We compared the maximal upstroke velocity of action potentials in short rabbit Purkinje fibers with sodium currents measured with a two-microelectrode voltage clamp. The number of sodium channels available to open during a sudden depolarization was varied either by blockade with tetrodotoxin or by inactivation with steady depolarizations. In both cases, the maximal upstroke velocity was found to be a very nonlinear measure of the number of available sodium channels. For example, 3 microM tetrodotoxin blocks 85% of the sodium channels, but reduces the maximal upstroke velocity by only 33%. Voltage clamp and upstroke velocity experiments were reconstructed with a computer model of the rabbit Purkinje fiber preparation that was closely based on experimental measurements of passive cable properties and sodium channel characteristics. The simulations indicate that our voltage clamp measurements of sodium current accurately report changes in channel availability, but they also show that the maximal upstroke velocity is a strongly nonlinear index of available sodium conductance. Most of the nonlinearity arises from the activation kinetics of the sodium channels: as the pool of available channels decreases, a greater percentage of those channels activate and contribute inward current at the time of the maximal upstroke velocity. Simulations predict that the maximal upstroke velocity-available sodium conductance relationship would still remain nonlinear at 37 degrees C or under different stimulus conditions that give uniform or continuously propagated action potentials. The nonlinearity may invalidate inferences based on earlier maximal upstroke velocity experiments: the existence of two types of sodium channels with different tetrodotoxin sensitivity, steady state voltage dependence of tetrodotoxin block, voltage range over which sodium channels inactivate, and rapid, then slow recovery of sodium channel availability following a sudden repolarization. All of these conclusions need to be reevaluated.
Action Potentials↗
Multidrug treatment of advanced and recurrent endometrial carcinoma: a Gynecologic Oncology Group study.
Patients (358) with advanced (FIGO stages III and IV) or recurrent endometrial cancer were treated with one of two regimens: 1) melphalan and 5-fluorouracil daily for four days, repeated every four weeks with megace daily for eight weeks and 2) adriamycin, 5-fluorouracil, and cyclophosphamide, intravenous bolus every 21 days with megace daily for eight weeks. All patients were randomized except for 63 with known cardiac disease who were assigned to regimen 1 (to avoid adriamycin) and studied separately. Stratification was effected for performance status, history of previous progestational therapy, presence or absence of measurable disease, and stage of disease. The objective response rate in those with measurable disease was 36.8% in both groups; 36.8% of each group had stable disease, and only 26.4% progressed on treatment. Response was unaffected by site of recurrence, time to first recurrence, presence or absence of previous treatment by progestational or radiation therapy, or age. Grade of tumor and performance status did affect response, although 44 of 57 objective responders had undifferentiated tumors. The two combinations achieved response rapidly, required careful supervision, and were especially useful in treating patients with usually poor prognostic features.
Adenocarcinoma↗
Improved therapy with cisplatin regimens for patients with ovarian carcinoma (FIGO Stages III and IV) as measured by surgical end-staging (second-look operation).
Between 1974 and 1982, 273 patients with epithelial cancer of the ovary (International Federation of Gynaecology and Obstetrics Stages III and IV) were randomized in four therapeutic trials. In Trial I Adriamycin plus cisplatin versus cisplatin alone versus thiotepa plus methotrexate was tested. The superiority of Adriamycin plus cisplatin in producing the best response rate led to its use as the reference arm in subsequent trials. All investigational arms included cisplatin plus other drugs (cyclophosphamide, Adriamycin, hexamethylmelamine, and thiotepa) in various combinations. Eligibility for second look required complete clinical remission and completion of at least 10 cycles of chemotherapy. To date, 73 second-look operations have been performed on randomized patients. An additional 43 nonrandomized patients underwent second-look procedures and are analyzed separately. Between 40% and 46% of patients treated with cisplatin regimens had no disease at second look. Cell differentiation and volume of postoperative disease did not influence response.
Aged↗
Cisplatin regimens and improved prognosis of patients with poorly differentiated ovarian cancer.
Patients with advanced ovarian carcinoma, Stage III or IV (International Federation of Gynaecology and Obstetrics), were randomized to primary chemotherapy with doxorubicin (Adriamycin) and cisplatin plus or minus hexamethylmelamine, and cyclophosphamide (CHAP). The four-drug CHAP regimen produced a 57% complete clinical response rate and a 26% partial response rate for clinically evaluable patients. The median survival of CHAP patients is 25 months. The two-drug Adriamycin-cisplatin (AP) regimen produced a 43% complete response rate and a 35% partial response rate. The median survival is 18 months. The four-drug regimen produced a significantly longer median survival (28 versus 18 months) for patients with poorly differentiated tumors than for patients with well-differentiated tumors on either treatment. Examination of treatment failure or death by treatment, histology, and size of largest residual tumor and comparison to similar patients treated with AP in this and two preceding controlled trials also suggest that CHAP is superior to AP for patients with poorly differentiated tumors.
Altretamine↗