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.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

Carcinoma of the cervix in the young patient.

Two thousand and two cases of cervical carcinoma were studied, and the patients were divided into 3 age groups specifically to study the prognosis of the young patient. The distribution of histologic tumor types was the same in all age groups. The young patients had a more favorable stage distribution and as a group a better prognosis than the older ones, but within each stage the same 5-year survival was found for all age groups. The period studied was relatively short (6 years), and modern therapy was available to all patients.

Carcinoembryonic antigen levels in patients with squamous cell carcinoma of the cervix.

A modified CEA-Roche kit was used to determine the pretreatment value of carcinoembryonic antigen (CEA) in patients with intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. A positive correlation between tumor volume and CEA levels was found in patients with invasive disease, and patients with intraepithelial neoplasia also had elevated levels compared with a reference material of blood donors. Pre- and posttreatment levels were measured in 156 patients with invasive lesions, and a significant response to treatment was seen in 80%. The resutls of this study indicate that any pretreatment level can be of interest in the followup of patients with squamous cell carcinoma of the cervix.

Stage IB carcinoma of the cervix, the Norwegian Radium hospital. II. Results when pelvic nodes are involved.

From 1967 through 1972, 562 patients with squamous cell carcinoma of the cervix, stage IB (FIGO), underwent radical hysterectomy with pelvic lymphadenectomy. The patients with pelvic metastases were treated with external beam supervoltage irradiation of 4000 or 5000 rads to the pelvis. Metastases in the pelvic lymph nodes were found in 21.3%. In this study the authors analyzed in detail which nodes were involved with metastases and the relationship with survival and with recurrence. The overall 5-year survival for patients with pelvic lymph node metastases was 53%; for patients without metastases it was 92%. The site of recurrence in patients without demonstrable pelvic lymph node metastases was also examined. The main conclusion drawn from the study is that patients with pelvic node metastases below the common iliac group have a much better prognosis than patients in whom metastases are located in the common iliac nodes; in addition, when nodal involvement is below the common iliac level, patients with disease limited to one node or one group of nodes do not have a better prognosis than patients with multiple metastatic nodes.

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.

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.

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.

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.

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.

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.

Antibiotic prophylaxis for radical abdominal hysterectomy.

Records of 35 patients with cervical cancer Stage IB operated with radical abdominal hysterectomy and pelvic lymphadenectomy were surveyed retrospectively for incidence of febrile morbidity and site-related infections. Febrile morbidity was observed in 6 patients (17%). No surgical site-related infections were observed. It is concluded that radical abdominal hysterectomy in our hospital does not carry any significant risk of postoperative site-related infections and that prophylactic antibiotics cannot be recommended.

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.

Stage IB adenocarcinoma of the cervix: metastatic potential and patterns of dissemination.

The metastatic potential patterns of dissemination have been investigated in 150 patients with Stage 1B adenocarcinoma of the cervix treated during a 20-year period from 1956 to 1977. All cases with the exception of one were treated with a combination of intracavitary radium implants followed by a radical surgical procedure with pelvic lymph node dissection. It was found that the incidence of pelvic metastases and distant recurrences and the survival rates were the same as in previously published reports for squamous cell carcinomas treated in the same manner. In one respect adenocarcinomas showed a significant difference when compared with squamous cell cancers: The incidence of residual tumor in the hysterectomy specimens after intracavitary treatment was much higher (30% versus 11%). This is considered a strong argument for surgical treatment of patients with early stages of adenocarcinoma of the cervix.

The prognostic significance of carcinoembryonic antigen determinations in patients with adenocarcinoma of the cervix.

Pretreatment levels of carcinoembryonic antigen (CEA) correlate well with the extent of disease in squamous cell and adenocarcinoma of the cervix. These two tumor types, however, have significantly different capacities for CEA release. The prognostic significance of pretreatment CEA determinations in squamous cell cancers is restricted to a subpopulation of these tumors and low values are equivocal. The present paper reports a long-term follow-up of 54 patients with adenocarcinoma of the cervix, all stages. It was found that no patient, regardless of stage, with an initial value over 15 micrograms/liter survived the disease. In the range between 5 and 15 micrograms/liter the recurrence rate was 67%. Patients with initial values under 5.0 micrograms/liter had an estimated 5-year survival of 90% in contrast to 11% if pretreatment values were over this limit. In Stage I, only 1 out of 8 patients with pelvic lymph node metastasis had a pretreatment value under 5.0 micrograms/liter. CEA determinations are of definite value in the planning of treatment and follow-up of patients with adenocarcinoma of the cervix.

Endometrial squamous cell carcinoma: report of three cases and review of the literature.

A histopathologic review of 1993 cases of confirmed endometrial carcinoma produced two cases of primary squamous cell carcinoma. A third possible case is included to illustrate the diagnostic problems in this type of tumor. All patients presented with advanced disease and died within a year. The literature is reviewed and the criteria for acceptance of a diagnosis of endometrial squamous cell carcinoma are discussed.

Studies on carcinoembryonic antigen levels in patients with adenocarcinoma of the uterus.

Carcinoembryonic antigen was determined before treatment in 101 patients with adenocarcinoma of the uterus. If 2.5 ng/ml is accepted as the upper normal value, 34% of the patients with cancer of the corpus had elevated levels. Only 7% had values exceeding 5 ng/ml. The highest recorded value in endometrial carcinoma was 8.5 ng/ml. In adenocarcinoma of the cervix 68% had values over 2.5 ng/ml and a direct correlation between nodal metastases and plasma elevation of CEA was found. The highest recorded value for endocervical cancer was 108 ng/ml. No patient with localized disease had a value over 4.0 ng/ml. It is concluded that adenocarcinomas of the cervix and corpus have different biological properties, and that in adenocarcinoma of the cervix determination of CEA is a reliable indicator of the extent of disease.

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.

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.