Editor's Choice - The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events.

OBJECTIVE/BACKGROUND: The objective was to observe for 1 year all patients in Norway operated on for symptomatic carotid stenosis with respect to (i) the time from the index event to surgery and neurological events during this time; (ii) the level in the healthcare system causing delay of surgical treatment; and (iii) the possible relationship between peri-operative use of platelet inhibitors and neurological events while awaiting surgery. METHODS: This was a prospective national multicentre study of a consecutive series of symptomatic patients. Patients were eligible for inclusion when referred for surgery. An index event was defined as the neurological event prompting contact with the healthcare system. All 15 departments in Norway performing carotid endarterectomy (CEA) participated. RESULTS: Three hundred and seventy one patients were eligible for inclusion between 1 April 2014 and 31 March 2015, and 368 patients (99.2%) were included. Fifty-four percent of the patients contacted their general practitioner on the day of the index event. Primary healthcare referred 84.2% of the patients to hospital on the same day as examined. In hospital median time from admission to referral for vascular surgery was 3 days. Median time between referral to the operating unit and actual CEA was 5 days. Overall, 61.7% of the patients were operated on within 2 weeks of the index event. Twelve patients (3.3%) suffered a new neurological event while awaiting surgery. The percentage of patients on dual antiplatelet therapy was lower (25.0%) in this group than among the other patients (62.6%) (p = .008). The combined 30 day mortality and stroke rate was 3.8%. CONCLUSION: This national study with almost complete inclusion and follow-up shows that the delays occur mainly at patient level and in hospital. The delay is associated with new neurological events. Dual antiplatelet therapy is associated with reduced risk of having a new neurological event before surgery.

Evaluation of left ventricular function in coronary bypass surgery.

OBJECTIVES: To evaluate non-invasive indexes measuring systolic and diastolic ventricular function. Eleven coronary artery bypass grafting (CABG) patients were investigated in order to assess the ability of preoperative ejection fraction (EF) and end diastolic pressure (EDP) to predict left ventricular function determined non-invasively at surgery. DESIGN: End-systolic elastance (Ees) was assessed perioperatively using transoesophageal echocardiographic area estimation and arterial pressure monitoring during preload variations (caval balloon). Diastolic function was evaluated using three different echo/Doppler indexes. RESULTS: EF correlated positively to Ees (r = 0.69, p = 0.03). No correlations were found between EDP and the perioperative diastolic indexes. Ees fell from pre-bypass to post-bypass (from 9.0 +/- 2.7 to 4.7 +/- 1.7 mmHg/cm2, mean +/- SD, p < 0.001), but no alterations in diastolic parameters occurred. CONCLUSIONS: A positive correlation was found between preoperative EF and Ees at surgery. The semi-invasive Ees detected a systolic "stunning" after cardiopulmonary bypass and is promising as a surveillance tool for left ventricular perioperative function and treatment. No correlations between preoperative EDP and non-invasive diastolic indexes were found, and assessment of perioperative diastolic function needs further refinement.

Clear cell carcinoma of the endometrium. Prognosis and metastatic pattern.

BACKGROUND: To establish the prognosis, metastatic pattern, sites of treatment failure, and effect of various treatment modalities, a large series of patients with endometrial clear cell carcinomas (ECCC) was analyzed. METHODS: Between 1970 and 1992, 181 patients with ECCC were treated. All pathologic slides and medical journals were reviewed. Clinical and histopathologic characteristics and type of treatment were analyzed with the univariate log rank test and multivariate Cox analysis. RESULTS: The 5- and 10-year actuarial disease free survival rates were 43% and 39%, respectively. Pathologic stage, clinical stage, age, and myometrial invasion were the only significant prognostic variables in the univariate analysis. In the multivariate analysis, pathologic stage and age were the sole independent prognostic factors. Two-thirds of the patients with relapse relapsed outside the pelvis. The most frequent extrapelvic sites of relapse were the upper abdomen, lungs, and liver. Four of six patients treated with platinum-containing combination chemotherapy showed response, whereas none of the patients treated with single agent alkylating chemotherapy or progestagens responded. CONCLUSIONS: Pathologic stage and age were the two most important prognostic factors in clear cell carcinoma of the endometrium. In Stage I disease, depth of myometrial invasion, age, and subtype of clear cell carcinoma were the sole independent prognostic factors. Two-thirds of the patients relapsed outside the pelvis.

Export of guanosine 3',5'-cyclic monophosphate (cGMP) from human erythrocytes characterized by inside-out membrane vesicles.

The present study was undertaken to characterize the export of cGMP from human erythrocytes at 37 degrees C. Inside-out membrane vesicles were exposed to cGMP and [3H]-cGMP in the presence and absence of 2 mmol l-1 ATP. In the absence of ATP, an equilibrium was reached within 15 min for the lowest tested concentration (0.65 mumol l-1), and the amount of cGMP in the vesicles was linearly correlated to the cGMP concentrations in the incubate. These observations suggest that the ATP-independent process represents passive diffusion or non-saturated binding to membrane components. In the presence of ATP, cGMP accumulated linearly during the test period (up to 120 min) and the transport into the inside-out vesicles was dependent on both low- and high-Km transport. The kinetic parameters for the low-Km process were determined after 5 and 120 min, the Km values being 4.6 (SD 1.9) and 4.7 (SD 1.1) mumol l-1 (n = 3), respectively. The corresponding Vmax values were 400 (SD 50) and 440 (SD 70) fmol mg-1 min-1. The high-Km process was characterized by Km = 170 (SD 50) mumol-1 and Vmax = 1610 (SD 280) fmol mg-1 min-1 (n = 5). The present data demonstrate an ATP-requiring saturable transport system for cGMP in human erythrocytes.

Radical radiotherapy versus brachytherapy plus surgery in carcinoma of the cervix 2A and 2B--long-term results from a randomized study 1968-1980.

To investigate whether surgery or radiotherapy should be preferred in the early stages of carcinoma of the cervix a randomized study was performed in which operable patients with small FIGO stage 2 squamous cell carcinoma were included. Of these patients, 122 were in stage 2A and 20 in stage 2B. The patients were treated with intracavitary radium, followed by either radical surgery with pelvic lymphadenectomy (Group A, 72 patients) or high-voltage external irradiation 40 Gy to a pelvic field (Group B, 70 patients). Postoperative irradiation 40 to 50 Gy was given in Group A if lymph node metastases were found at operation. Fourteen patients in Group A and 23 in Group B died of recurrent disease. The 5-, 10-, and 20-year survival in Group A was 87, 84 and 81% respectively compared with 72, 69, and 68% in Group B, p < 0.05. Twenty-three (34%) of 67 radically operated patients had metastases to pelvic lymph nodes. A high rate of pelvic and para-aortic recurrences accounts for the difference between Groups A and B. Young patients (<40 years) with large tumours had a high risk of recurrent disease. Severe urinary and gastrointestinal complications were more common in Group A, especially among patients given postoperative radiotherapy. Lymphoedema was seen almost exclusively in Group A. Two patients in Group A and one in Group B died of complications to treatment. The corrected 10-year survival of 69.5% as achieved in the radiotherapy arm of this series is comparable to other reported studies. The high survival rate in the operated group, despite a very high metastases rate, suggests that surgery is applicable also in stage 2 patients.

Effect of probenecid, verapamil and progesterone on the concentration-dependent and temperature-sensitive human erythrocyte uptake and export of guanosine 3',5' cyclic monophosphate (cGMP).

Elevated extracellular cGMP levels have been observed in various clinical conditions, and the analyte has been proposed as a diagnostic marker of cardiovascular as well as malignant diseases. However, the use of extracellular cGMP as a pathophysiological marker requires detailed knowledge about the cellular biokinetics of cGMP (synthesis, metabolic conversion and export). In the present study the transport of cGMP in human erythrocytes has been further characterized. The uptake of cGMP was dependent on a concentration gradient and was temperature-sensitive, compatible with passive diffusion. The cGMP export was temperature-sensitive, saturable (Km = 3.4 +/- 1.0 mu mol l-1), inhibited by probenecid and verapamil and stimulated by progesterone. The results show that human erythrocytes possess a cGMP transport system similar to that found in other cells and that extracellular levels of cGMP are dependent on intracellular levels, membrane transport and influenced by physiological factors and pharmacological agents.

Progesterone and beta-estradiol influence the cell density-dependent distribution of cyclic nucleotides across the cell membrane of human C4-I cells (squamous carcinoma of the uterine cervix) by a non-genomic mechanism.

The ratio between extracellular levels of cGMP and cAMP (cGMPex/cAMPex) has been proposed as diagnostic tool in many forms of malignancies. In vitro and in vivo studies have shown that sex steroids effect extracellular levels of cyclic nucleotides. Cyclic changes of these hormones in premenopausal women may disturb the interpretation of the diagnostic marker. C4-I cells grew in the presence of beta-estradiol and progesterone in a chemically defined medium. Cells were sampled during the logarithmic growth phase. Cyclic nucleotide levels were determined by RIA. Receptor status was evaluated by immunocytochemistry. Progesterone increased the cGMPex/cAMPex at all cell densities tested. This effect resulted from increased cGMP and reduced cAMP extrusion. Estradiol had no clear effect on cGMPex/cAMPex even when inhibition of cAMP extrusion was observed at low cell density. Receptors for steroids were not detectable. Sex steroids interact with cyclic nucleotides in C4-I cells in a non-genomic manner.

Small cell carcinoma of the cervix. A clinicopathologic study of 26 patients.

BACKGROUND: Small cell carcinoma of the cervix is a rare and aggressive tumor. Most gynecologic oncology centers have little experience with this tumor, and only small series have been published. METHODS: Twenty-six patients with small cell carcinoma of the uterine cervix were treated at the Norwegian Radium Hospital. Clinical data, immunohistochemical characteristics, and infection with human papillomavirus were studied. RESULTS: Twelve tumors were of oat cell type and 14 of intermediate cell type. Twelve tumors were associated with other forms of carcinoma: squamous cell carcinoma (6 tumors), adenocarcinoma (5 tumors), and adenocarcinoma in situ (1 tumor). Neuroendocrine differentiation was expressed in 79% of the tumors. Human papillomavirus (HPV)-18 was detected in 40% of the tumors and HPV-16 in 28%. Fifteen patients had Stage I disease, 7 had Stage II, 2 had Stage III, and 3 had Stage IV. Fourteen patients with Stage I and II disease underwent radical hysterectomy with pelvic lymph node dissection. In four, the operation was preceded by intracavitary radiation treatment. The patients with Stage II, III, and IV disease were treated with a combination of intracavitary radium, external beam radiation therapy, and chemotherapy. The 5-year survival rate was 14%. Four patients are alive, one with recurrent disease 50 months after diagnosis. Three patients free of disease have been followed up 26, 54, and 101 months, respectively. CONCLUSIONS: Small cell carcinoma of the cervix is an aggressive tumor with a propensity for rapid recurrence; it is associated with high mortality.

Leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS) of the uterus. A survey of patients treated in the Norwegian Radium Hospital 1976-1985.

One hundred and twenty-seven patients with leiomyosarcoma (LSS) or endometrial stromal sarcoma (ESS) were treated at the Norwegian Radium Hospital during the 10-year period 1976-1985. After a review of the histologic slides 14 of the original tumors were reclassified, three as carcinomas and in 11 cases no malignant criteria were found. Five-year survival was 67% and 39% for ESS and LSS, respectively. Malignancy grade was the most powerful prognostic criterion in patients who were considered radically treated with surgery. Patients with grade 1 and 2 tumors had a prognosis similar to patients with endometrial carcinoma in contrast to the very gloomy outlook for patients with grade 3 and 4 (5-year survival 33%). For ESS the mitotic index also influenced the outcome. Despite widespread use of chemotherapy there is no clear indication that the prognosis for patients with the more aggressive types of sarcoma has improved in the period studied.

Laser excision of the transformation zone as treatment of cervical intraepithelial neoplasia with satisfactory colposcopy.

A series of 123 patients with histologically confirmed cervical intraepithelial neoplasia (CIN) with satisfactory colposcopy were treated with outpatient laser excision of the transformation zone. Punch biopsy and/or endocervical curettage proved CIN III in 111 patients (90%). Histology of the laser excision specimen showed microinvasive disease in 3 patients. Operative hemorrhage occurred in 2 patients. The follow-up ranged from 12 to 59 months (median, 30 months). Four patients were found to have residual/recurrent CIN during the observation period, resulting in a cure rate of 97%. All patients with recurrence are free of disease after a second laser treatment. Only 1 patient out of 26 with involved resection margins relapsed. Laser excision of the transformation zone is proposed as a suitable replacement for laser vaporization in patients with CIN with satisfactory colposcopy, offering the major advantage of providing a histological specimen without an increase in morbidity.

Randomized trial comparing cisplatin with radioactive phosphorus or whole-abdomen irradiation as adjuvant treatment of ovarian cancer.

In this study, 347 patients with epithelial ovarian cancer without residual tumor after primary laparotomy, were assigned randomly to receive either intraperitoneal instillation of radioactive phosphorus (32P) or six courses of cisplatin (50 mg/m2). Patients randomized to receive 32P with extensive intraperitoneal adhesions were treated with whole-abdomen irradiation instead of 32P (n = 28). The median follow-up was 62 months. Crude and disease-free survival were similar in all groups. Late bowel complications occurred more often in patients treated with 32P compared with the cisplatin group. The estimated 5-year crude survival rate was as high as 95% in patients with borderline or well-differentiated tumors in Stage I. It is suggested that these patients can be treated adequately by operation alone. Patients with moderately or poorly differentiated cancers in Stage I disease had a 5-year crude survival rate of 75%. In these patients, the relapse risk was high enough to warrant postoperative treatment. The efficacy of adjuvant treatment in this subgroup of patients can only be established in a prospective randomized study comparing postoperative adjuvant treatment with a no-treatment arm. Because of the high number of late bowel complications after 32P treatment, it was recommended that cisplatin be used as standard adjuvant treatment for subsequent controlled studies.

Endometrial adenocarcinoma with squamous cell differentiation.

In a histopathologic review of all cases of endometrial carcinoma diagnosed in Norway between 1970 and 1978, 255 cases of adenocarcinoma with squamous cell differentiation were found among the 1985 cases reviewed. One hundred eighty-one (9.1%) were adenoacanthoma and 74 (3.7%) adenosquamous carcinoma. The mean age for patients with adenoacanthoma was 57.7 years (range, 32 to 85 years) and for adenosquamous carcinoma, 62.8 years (range, 43 to 84 years). Five-year and 10-year survival rates for all patients were 83.5% and 71.8%, respectively. For patients with adenosquamous carcinoma, corresponding figures were 64.9% and 52.7%, and for those with adenoacanthoma, the figures were 91.2% and 79.6%, respectively. When stratified for grade and depth of myometrial infiltration, there was no difference in survival rates between patients with adenoacanthoma and adenosquamous carcinoma, provided hysterectomy was part of the primary treatment. In patients who had surgery, myometrial infiltration was the most important single prognostic factor. It is recommended that the terms adenoacanthoma and adenosquamous carcinoma be replaced by the descriptive term adenocarcinoma with squamous cell differentiation.

Carcinoma of the endometrium in Norway: a histopathological and prognostic survey of a total population.

In a histopathological review of a total population, 1974 cases of endometrial carcinoma were found from 1970 to 1977. Of these 1566 (79.3%) were adenocarcinomas of the endometrioid type, 181 (9.2%) adenoacanthomas, 97 (4.9%) clear cell carcinomas, 74 (3.7%) adenosquamous carcinomas, 31 (1.6%) undifferentiated carcinomas, 22 (1.1%) serous papillary carcinomas and 3 (0.1%) squamous cell carcinomas. Thirty percent of the tumors were well differentiated, 44% moderately and 25.9% poorly differentiated. The mean age at diagnosis was 62.0 years (range 32-93 years). Age was clearly related to histologic type, grade and extent of myometrial infiltration. Crude 5- and 10-year survival rates for the entire group were 73.1 and 61%. For the different subtypes of endometrial carcinoma the 5- and 10-year crude survival rates were as follows: adenoacanthoma 91.2 and 79.6%, adenocarcinoma of the endometrioid type 74.1 and 62.2%, adenosquamous carcinoma 64.9 and 52.7%, undifferentiated carcinoma 58 and 48%, clear cell carcinoma 42.3 and 30.9% and serous papillary carcinoma 27 and 14%. All three patients with squamous cell carcinoma died within a year. The 5- and 10-year survival rates were 87.8 and 79.7% for grade 1 tumors, 76.6 and 62.1% for grade 2, and 60.1 and 48.6% for grade 3. The extent of myometrial infiltration was a string predictor of prognosis. The 5- and 10-year survival rates of patients with intramucosal tumors and tumors infiltrating the inner half of the myometrium were, respectively 89.6 and 82.5%, and 84.7 and 72.7%. Only 48.3 and 29.3% of the patients with tumors reaching the serosa survived, respectively 5 and 10 years. Patients without demonstrable vessel invasion had a significantly better prognosis than those with vessel invasion with a survival rate of 83.5 and 61.1% at 5- and 10-years, compared with 64.5 and 53.8%, respectively. Age at the time of diagnosis was an important prognostic factor for crude survival. Surgico-pathological staging was significantly better than clinical staging in predicting prognosis only in advanced stages.

Cardiac left ventricular function before and during early thyroxine treatment in severe hypothyroidism.

In some patients with severe hypothyroidism, thyroxine replacement therapy precipitates or aggravates angina pectoris, whereas in other patients angina pectoris is ameliorated or even cured. Cardiac function in eight severely hypothyroid patients was studied by means of radionuclide ventriculography (RNV) at rest and during supine bicycle exercise before thyroxine treatment, and repeated during treatment before and after administration of 160 mg of oral verapamil. There was an exercise-induced fall in left ventricular ejection fraction (LVEF) in two patients before therapy, and in two additional subjects after 17 d on suboptimal doses of thyroxine. Verapamil attenuated the fall and induced a significant increase in LVEF during exercise (P less than 0.014). No abnormal regional cardiac wall movement (RWM) was observed. After 2 months of thyroxine treatment, LVEF increased significantly during exercise both before and after verapamil (P less than 0.012 and P less than 0.005). These findings are indicative of reversible coronary artery dysfunction. We recommend that, if feasible, thyroxine should be supplemented with verapamil during the early phase of treatment.

Undifferentiated carcinoma of the endometrium. A histopathologic and clinical study of 31 cases.

A histopathologic review of 1985 cases of endometrial carcinoma yielded 31 undifferentiated carcinomas (1.6%). Forty-eight percent were large cell type and 52%, intermediate/small cell type. Twenty-one tumors were examined immunohistochemically. All stained for keratin. Eleven tumors reacted with vimentin antibodies, two with carcinoembryonic antigen antibodies, and ten with neuron-specific enolase (NSE) antibodies (four of which stained for bombesin, two for beta-endorphin, one for prealbumin, five for Leu7, and four for synaptophysin). The mean age at diagnosis was 63.9 years (range, 45 to 86). The crude 5-year and 10-year survival was 58% and 48%, respectively. Seventy-nine percent of the patients in surgicopathologic Stage I and 33% in Stage II survived 5 years. The intermediate/small cell types had a somewhat better prognosis than the large cell type, but the difference was not statistically significant. The presence or absence of NSE and vimentin immunoreactivity had no influence on survival. All patients with tumors infiltrating less than one half of the myometrium survived 5 years in contrast with 46% of the patients with deep infiltrating tumors. Fifty-four percent of the patients with demonstrable vessel invasion survived 5 years in contrast with 89% not so affected.

Endometrial adenocarcinoma in Norway. A study of a total population.

Fifteen hundred sixty-six patients with adenocarcinoma of the endometrioid type (AC) were studied. These accounted for 78.9% of all 1985 patients with confirmed endometrial carcinoma diagnosed in Norway in the period 1970 through 1978. Four hundred and sixty-nine patients (29.9%) had well-differentiated tumors, 677 (43.2%) were moderately and 420 (26.8%) poorly differentiated. Eighty-one percent of the patients had surgicopathologic Stage I disease, 11% Stage II, 6% Stage III, and 2% Stage IV. Mean age at diagnosis was 62.1 years (range, 36 to 91). The crude 5-year and 10-year survival rates for all patients were 74.1% and 62.2%, respectively. Five-year crude survival was 86.8% for Grade 1 and 58.3% for Grade 3 tumors. The 5-year crude survival for patients with intramucosal tumors was 88.7% as opposed to 46.9% for patients with tumors infiltrating to the serosa. Sixty-six percent of the patients with vessel invasion survived for 5 years in contrast to 88.6% for patients without vessel invasion. Histologic grade, myometrial infiltration, vessel invasion, and lymphocyte reaction surrounding the tumor were strongly interrelated. Multivariate analysis showed that the age of the patient at the time of diagnosis was the most important single prognostic factor. Disregarding age, survival in operated patients was more dependent on the depth of myometrial invasion than on grade and stage of disease.

The prevalence of human papillomavirus type 16 and 18 DNA in cervical cancer in different age groups: a study on the incidental cases of cervical cancer in Norway in 1983.

In a study carried out to estimate the prevalence of genital Human Papilloma Virus (HPV) infection among cervical cancer patients in Norway, the following values were recorded using the southern blot hybridization method: 54.1% HPV 16, 9.5% HPV 18, 0% HPV 11, and 1.4% HPV 16 and 18 coinfection, yielding a total of 62.2% HPV positive cases in the study. An attempt to include a normal biopsy as "internal control" from each patient failed, as macroscopically normal tissue was often histologically abnormal. HPV infection did not relate to stage of disease, age, or 5-year survival, whereas the classic relationship between stage and survival was observed. A very high percentage of HPV positive cases occurred among older women, a fact which does not support the existence of a new HPV epidemic. The studied population is unique, as it represents 75 cases which comprise a representative sample of the 372 incidental cases of cervical cancer in Norway in 1983. To our knowledge this is the first study of its kind.

Clear cell carcinoma of the endometrium: a histopathological and clinical study of 97 cases.

In a histopathologic review of 1985 cases of endometrial carcinoma 97 patients (4.9%) had clear cell carcinoma (CCC). Mean age at diagnosis was 65.3 years. The crude 5- and 10-year survivals for all stages were 42.3 and 30.9%, respectively. Fifty-nine percent of the patients in surgicopathological stage I and 27% in stage II survived 5 years. Myometrial infiltration and vessel invasion were important prognosticators. Ninety percent of the patients with intramucosal tumors survived 5 years, in contrast to only 15% of the patients with deep myometrial infiltration. Seventeen percent of the patients with vessel invasion survived 5 years, in contrast to 49% of the patients without this finding. CCC is one of the most aggressive subtypes of endometrial carcinoma.

Serous papillary carcinoma of the endometrium: a histopathological study of 22 cases.

In a histological review of all 1985 cases of endometrial carcinoma in Norway diagnosed in the period 1970 through 1977, 22 patients (1.1%) with serous papillary carcinoma (ESPC) were identified. Mean age at diagnosis was 72 years, which was significantly higher than for patients with ordinary adenocarcinoma. All patients were followed at least 10 years. The crude 5- and 10-year survival rates were 27 and 14%. Only three patients survived longer than 10 years and all of these had had stage I tumors. In 19 available curettage specimens ESPC could be identified in 18. This could have implications regarding choice of therapy because this subtype of endometrial carcinoma is very aggressive. It is most often found in elderly women.

Management of malignant ovarian immature teratoma. Role of adriamycin.

Sixteen consecutive patients with pure ovarian immature teratoma have been treated at The Norwegian Radium Hospital between 1975 and 1987. The median age was 22 years. Thirteen patients had International Federation of Gynecology and Obstetrics (FIGO) Stage I disease and three had Stage III disease. None of the patients with Stage I disease had bilateral disease. In nine patients at least one ovary was conserved. Four cases were Grade 1, seven cases Grade 2, and five cases Grade 3. Adjuvant treatment consisted mainly of Adriamycin (Adria Laboratories, Columbus, OH). The chemotherapy regimen appeared to be highly effective because all patients are alive without evidence of disease (median follow-up, 85 months). No severe toxicity was observed. In patients without residual tumor after primary surgery, the authors prefer the adjuvant treatment with Adriamycin because this treatment has a lower toxicity and is as effective as combination chemotherapy (vincristine, dactinomycin, and cyclophosphamide or cisplatin, vinblastine and bleomycin). Some comments on initial surgery and second-look surgery are also given.