Impact of hospital type and treatment on long-term survival among patients with FIGO Stage IIIC epithelial ovarian cancer: follow-up through two recurrences and three treatment lines in search for predictors for survival.

The purpose of this study was to investigate the impact of hospital type determined at primary treatment and find possible predictors of survival in a cohort of patients with advanced epithelial ovarian cancer (EOC) who recurred twice and received three lines of treatment during eight-year follow-up. Using the Norwegian Cancer Registry, the authors identified 174 women with FIGO Stage IIIC EOC diagnosed in 2002. First-line treatment consisted of up-front debulking surgery and chemotherapy, received in either a teaching hospital (TH, n = 84) or a non-teaching hospital (NTH, n = 90). After recurrence all patients in Norway are equally consulted at TH. Survival determined for three time intervals (TI): TI-1, from end date of first-line treatment to first recurrence or death, TI-2, from beginning of second-line treatment until second recurrence or death, and TI-3, from beginning of third-line treatment to death or end of follow-up. Extensive surgery carried out in TH followed by at least six cycles of platinol-taxan chemotherapy resulted in longer survival in the TH group during TI-1. Altogether, the majority of those who receive treatment for recurrences were primary better debulked with following platinol-taxane chemotherapy. Survival in TI-2 was influenced by platinol-sensitivity. During TI-3 the majority (96%) had good performance status and their mean age at primary diagnosis at either hospital type was 57 years. Extensive primary surgery at TH, platinol sensitivity, age, and performance status were predictors of survival in this cohort.

Interaction of IFN-γ with cholinergic agonists to modulate rat and human goblet cell function.

Goblet cells populate wet-surfaced mucosa including the conjunctiva of the eye, intestine, and nose, among others. These cells function as part of the innate immune system by secreting high molecular weight mucins that interact with environmental constituents including pathogens, allergens, and particulate pollutants. Herein, we determined whether interferon gamma (IFN-γ), a Th1 cytokine increased in dry eye, alters goblet cell function. Goblet cells from rat and human conjunctiva were cultured. Changes in intracellular [Ca(2+)] ([Ca(2+)](i)), high molecular weight glycoconjugate secretion, and proliferation were measured after stimulation with IFN-γ with or without the cholinergic agonist carbachol. IFN-γ itself increased [Ca(2+)](i) in rat and human goblet cells and prevented the increase in [Ca(2+)](i) caused by carbachol. Carbachol prevented IFN-γ-mediated increase in [Ca(2+)](i). This cross-talk between IFN-γ and muscarinic receptors may be partially due to use of the same Ca(2+)(i) reservoirs, but also from interaction of signaling pathways proximal to the increase in [Ca(2+)](i). IFN-γ blocked carbachol-induced high molecular weight glycoconjugate secretion and reduced goblet cell proliferation. We conclude that increased levels of IFN-γ in dry eye disease could explain the lack of goblet cells and mucin deficiency typically found in this pathology. IFN-γ could also function similarly in respiratory and gastrointestinal tracts.

Fertility and gonadal function after adjuvant therapy in women diagnosed with a malignant ovarian germ cell tumor (MOGCT) during the "cisplatin era".

PURPOSE: By self-report and serum levels of anti-Mullerian hormone (AMH) this study aims to assess post-treatment fertility after modern treatment of women with malignant ovarian germ cell tumors (MOGCT). PATIENTS AND METHODS: In 2013 a questionnaire-based survey was performed in 61 MOGCT patients diagnosed at age <40years from 1980-2009. Forty-nine of them also attended the out-patient clinic. The event of first post-treatment pregnancy ("fertility") was documented as cumulative estimates for all 61 patients and within each of 4 treatment groups: Group 1: Surgery only (n=10); Group 2: ≤3cycles of cisplatin-based chemotherapy (CBCT) (n=20); Group 3: >3cycles of CBCT (n=15) and Group 4: other adjuvant treatment (n=16). AMH was determined in 22 women <40years at survey. Statistics were based on Kaplan Meier procedure, log-rank test and a significance level p<0.05. RESULTS: At least one post-treatment pregnancy was reported by 34 of 39 MOGCT survivors who attempted motherhood after treatment. The 15-year cumulative post-treatment fertility estimate was 28% (95% CI: 26-30) for all 61 survivors and was significantly higher in patients treated with 3 or fewer cycles of CBCT (53% [95% CI: 50-55]) than those treated with more than 3cycles (20% [95% CI: 17-22]) (P=0.03). Of 22 AMH levels, two were <3pmol/l, with one women being pregnant at survey. CONCLUSION: After fertility-sparing surgery and modern cisplatin-based chemotherapy, fertility is preserved in most MOGCT survivors though dependent on the number of cycles. AMH's role as a biomarker of gonadal function seems promising but requires further research.

Improved 5-year disease-free survival for FIGO stage I epithelial ovarian cancer patients without tumor rupture during surgery.

OBJECTIVE: To investigate the impact of perioperative capsule rupture on disease-free survival (DFS) and cancer-specific survival (CSS) in patients with FIGO stage I epithelial ovarian cancer (EOC I). METHODS: This prospective population-based study enrolled all 279 patients with EOC I diagnosed in Norway between 2002 and 2004. All patients underwent primary surgery. The data were collected from notification reports to the Norwegian Cancer Registry and included medical, surgical and histopathological records. Kaplan-Meier plots were used to show differences in DFS and CSS. Cox regression analyses were used to show the effect of prognostic factors on survival, expressed as hazard ratios (HRs). RESULTS: Significantly more patients in the capsule rupture group (Cr group) had clear cell tumors (28%) than in the FIGO stage IA and IB (AB group: 14%) groups, and the FIGO stage IC (C group: 17%; p<0.05) group. Despite adjuvant chemotherapy (AC), these patients had a poor 5-year DFS, 94% in the non-AC group and 81% in the AC group (p<0.01). After five years of follow-up, there was a lower DFS among patients in the Cr group (79%) and the C group (81%), compared with patients in the AB group (91%; p<0.05). Independent prognostic factors at the time of diagnosis were grade, histological type, ascites, adhesions, performance status, CA125 and DNA ploidy. After correcting for the four most important prognostic factors (grade, histological type, ascites, and DNA ploidy), the HR for recurrence was 4.0 (95% CI 1.3-12.7; p<0.05) for the Cr group and 1.8 (95% CI 0.5-6.1; p=0.3) for the C group, compared with the AB group. CONCLUSIONS: Improvement was observed in the 5-year DFS for EOC I patients without tumor rupture during surgery compared with those with tumor rupture. Since AC did not improve the long-term DFS and CSS rates, it is of utmost importance that surgeons avoid tumor rupture during surgery.

Diagnosis and treatment of borderline ovarian neoplasms "the state of the art".

The 5-year survival for women with Stage-I borderline tumours (BOT) is favourable, about 95-97%, but the 10-year survival is only between 70 and 95%, caused by late recurrence. The 5-year survival for Stage II-III patients is 65-87%. Standard primary surgery includes bilateral SOEB, omentectomy, peritoneal washing and multiple biopsies. Second cytoreductive surgery is recommended for patients with recurrent disease. Adjuvant postoperative therapy is not indicated in Stage-I diploid tumors. Occasional responses to chemotherapy have been reported in advanced BOTs but no study has shown improved survival. Recently a new theory has been developed describing a subset of S-ovarian cyst adenomas that evolve through S-BOT to low-grade carcinoma. A more correct staging procedure, classification of true serous implants and agreement on the contribution to stage of the presence of gelatinous ascites in mucinous tumours may in the future change the distribution of stage and survival data by stage for women with BOT. Independent prognostic factors in patients with epithelial ovarian BOT without residual tumour after primary surgery are DNA-ploidy, international FIGO-stage, histologic type and patient age. Studies on other molecular markers have not yet uncovered a reliable prediction of biologic behaviour, however, there is hope that future studies of genetics and molecular biology of these tumours will lead to useful laboratory tests. Future questions to be addressed in this review include the following: Have patients with borderline tumours in general been over-treated and how should these patients be treated? How to define the high-risk patients? In which group of patients is fertility-sparing surgery advisable and, do patients with borderline tumours benefit from adjuvant treatment?

Obliquity-paced Pliocene West Antarctic ice sheet oscillations.

Thirty years after oxygen isotope records from microfossils deposited in ocean sediments confirmed the hypothesis that variations in the Earth's orbital geometry control the ice ages, fundamental questions remain over the response of the Antarctic ice sheets to orbital cycles. Furthermore, an understanding of the behaviour of the marine-based West Antarctic ice sheet (WAIS) during the 'warmer-than-present' early-Pliocene epoch ( approximately 5-3 Myr ago) is needed to better constrain the possible range of ice-sheet behaviour in the context of future global warming. Here we present a marine glacial record from the upper 600 m of the AND-1B sediment core recovered from beneath the northwest part of the Ross ice shelf by the ANDRILL programme and demonstrate well-dated, approximately 40-kyr cyclic variations in ice-sheet extent linked to cycles in insolation influenced by changes in the Earth's axial tilt (obliquity) during the Pliocene. Our data provide direct evidence for orbitally induced oscillations in the WAIS, which periodically collapsed, resulting in a switch from grounded ice, or ice shelves, to open waters in the Ross embayment when planetary temperatures were up to approximately 3 degrees C warmer than today and atmospheric CO(2) concentration was as high as approximately 400 p.p.m.v. (refs 5, 6). The evidence is consistent with a new ice-sheet/ice-shelf model that simulates fluctuations in Antarctic ice volume of up to +7 m in equivalent sea level associated with the loss of the WAIS and up to +3 m in equivalent sea level from the East Antarctic ice sheet, in response to ocean-induced melting paced by obliquity. During interglacial times, diatomaceous sediments indicate high surface-water productivity, minimal summer sea ice and air temperatures above freezing, suggesting an additional influence of surface melt under conditions of elevated CO(2).

Expression of matrix metalloproteinase-2 in serous borderline ovarian tumors is associated with noninvasive implant formation.

OBJECTIVE: To investigate matrix metalloproteinase (MMP) proteolytic and vascular endothelial growth factor (VEGF) and receptor (VEGFR-1, VEGFR-2) angiogenetic capacity in serous borderline ovarian tumors (S-BOTs) for women with and without noninvasive implants. METHODS: The population was made up of 99 patients with S-BOTs as the primary diagnosis between 1985 and 1995, 44 of whom had noninvasive implants and 55 without implants. MMP-2, MMP-14, the type-2 tissue inhibitor of MMPs (TIMP-2), and VEGF and receptors (VEGFR-1, VEGFR-2) were examined by immunhistochemistry. RESULTS: Strong positive (+++) MMP-2 staining was found more frequently in women with primary S-BOTs and noninvasive implants (76%) than in those without implants (53%; p < 0.05). In contrast, staining for MMP-14 and TIMP-2 was not significantly different in the two groups. Furthermore, expression of MMP-2, MMP-14, and TIMP-2 was similar in primary tumors and in their noninvasive implants. Most tumors in both groups had no VEGF expression (84% in the noninvasive implant group and 82% in the group without implants), while moderate (++) to strong (+++) expression of VEGFR-1 and VEGFR-2 was detected in 79% and 94% of the two tumor groups, with no significant difference between the groups. CONCLUSIONS: Enhanced MMP-2 was seen in primary S-BOT with noninvasive implants. The presence of noninvasive implants was prognostic for disease-free survival.

Improved short-term survival for advanced ovarian, tubal, and peritoneal cancer patients operated at teaching hospitals.

The aim of this study was to study the impact of hospital level and surgical skill on short-term survival of advanced ovarian, tubal, and peritoneal cancer patients in a prospective population-based study. All 198 women with a diagnosis of advanced epithelial invasive ovarian, tubal, and peritoneal cancer in Norway who underwent surgery during 2002 were included in this study. The data were derived from notifications to the Norwegian Cancer Registry and from medical, surgical, and histopathologic records. The hospitals were grouped into teaching and nonteaching hospitals (NTH), and the operating physicians were classified according to specialty (specialist gynecologist, gynecologist, and surgeon). The follow-up period was from 455 to 820 days. The short-term survival at 450 days was 79% for women operated at teaching hospitals (TH) and 62% at NTH (P= 0.02). After simultaneous adjustment for seven prognostic factors and residual disease, the risk of death within 600 days at NTH was unchanged compared to TH, hazard ratio 1.83. The women operated on by specialist compared to general gynecologists had a 20% increased short-term survival (P < 0.0001). TH and specialist gynecologists achieved better short-term survival of patients operated for advanced ovarian, tubal, and peritoneal cancer. Centralization and specialization of ovarian cancer surgery might improve the outcome for this patient group.

Symptoms and referral of women with epithelial ovarian tumors.

OBJECTIVE: To study referral to hospital units and the clinical characteristics of women with epithelial ovarian tumors in a prospective, population-based study. METHODS: Clinical information on all women diagnosed with epithelial invasive (n=486) and borderline ovarian tumors (n=137) in Norway during 2002 was derived from notifications to the Cancer Registry of Norway and medical, surgical and histopathological records. RESULTS: Sixty-one percent of women with invasive ovarian tumors were initially referred to gynecology units. The 38% of women referred to surgical and medical units were more likely to have symptoms as 'bowel irregularity', 'pain outside the abdominal cavity', 'persisting fatigue' and 'respiratory difficulties'. These women were older, had lower performance status and had a delay in treatment of 20 and 24 days respectively compared to 11 at gynecology units. CONCLUSION: Greater awareness of the symptoms of ovarian cancer might lead to earlier diagnosis and treatment and thus possibly improve survival.

[Examination, treatment and follow-up of ovarian cancer in Norway]. / Utredning, behandling og etterkontroll av eggstokkreft i Norge.

BACKGROUND: In order to improve our knowledge about the medical examination, treatment and follow of cancer patients, suggestions have been put forward for a system for quality assurance of clinical data on cancer in Norway (Government White Paper 20: 1997). MATERIAL AND METHODS: In spring 2000, a questionnaire was sent to 41 gynaecological departments with focus on ovarian cancer patients. Four of the departments were regional cancer centres. RESULTS: All gynaecological departments answered the questionnaire. Standard gynaecological examination, vaginal ultrasonography and CA-125 determination were included in the diagnostic procedures in all departments. Some differences were detected: Cytological examination of pleural effusions as part of the staging procedure was not performed by all hospitals. In one health region, hospitals used a Risk of Malignancy Index for referring women with suspected malignant pelvic masses to a centralised gynaecologic oncology unit for primary surgery. Sixteen hospitals out of 37 operated on patients with FIGO stage I disease without performing lympadenectomy. When operating on suspected FIGO stage II-IV disease, three out of 22 local hospitals never performed surgery of the intestines in order to achieve optimal tumour reduction. All regional hospitals gave adjuvant chemotherapy to high-risk FIGO stage I patients. Standard treatment in advanced stages was paclitaxel/carboplatinum. Some hospitals participated in randomized trials on chemotherapy. Third-line treatment depended on the patient's condition, earlier toxicity and response. One regional centre preferred not to give any third-line chemotherapy. Only a few hospitals recorded the patient's performance status (WHO or Karnofsky's grading table) during the treatment and follow-up. Most of the gynaecological departments referred the patients to the regional hospital at the time of recurrence. About half of the outpatient departments gave a written report to the regional hospital. INTERPRETATION: There are differences between the hospitals in how they handle ovarian cancer patients. One cannot, however, determine from this inquiry what kind of medical examination, treatment and follow-up is best. An extended registration of ovarian cancer organised by the Cancer Registry of Norway will be started with the aim of providing reliable population-based data (the OVANOR project).

Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer.

Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers.

[Controversies in surgical treatment of advanced ovarian cancer]. / Kontroverser ved kirurgisk behandling av avansert ovarialcancer.

Cytoreductive surgery has traditionally been regarded as a cornerstone in the primary treatment of advanced ovarian cancer. Both five year survival and median survival are better for patients with small residual masses. Despite many similar reports showing the prognostic significance of postoperative residual tumour, the survival benefits of cytoreductive surgery still remain scientifically unproven and controversial. There have been no prospective controlled clinical trials. The question remains as to whether the observed survival benefits for patients subjected to primary cytoreductive surgery are an effect of surgery skills or tumour biology. The proponents of tumour biology claim that cytoreductive surgery is a selective procedure and that patients with better prognosis are selected. Therefore a randomized study between primary cytoreduction and neoadjuvant chemotherapy in patients that cannot be optimally cytoreduced seems warranted, though one problem with such a study is how to select eligible patients. During chemotherapy and after relapse several types of operations are used in ovarian cancer: secondary cytoreductive surgery, interval cytoreductive surgery, second-look surgery and palliative secondary surgery. So far interval cytoreductive surgery during chemotherapy is the only type of operation which in a prospective randomized study showed significant improvement in long-term survival. This paper discusses indirect evidence in the literature in support of or in contradiction to the primary debulking hypotheses and also indications and impact of surgical procedures during chemotherapy.

Effects of paclitaxel on CA-125 serum levels in ovarian cancer patients.

OBJECTIVE: As in vitro activation of ovarian carcinoma cells in terms of CA-125 secretion by taxanes has been demonstrated, we were interested in whether taxanes also modulate CA-125 expression in vivo. METHODS: Serum CA-125 was determined immediately before and 24 h after paclitaxel-containing chemotherapy in 53 ovarian carcinoma patients. To test the quality of the analysis methods and the biological variation of untreated patients, serum CA-125 levels of two control groups were analyzed. RESULTS: Median CA-125 concentration was 107 kU/liter 24 h after chemotherapy treatment compared with 99 kU/liter the day before paclitaxel treatment. Changes in CA-125 serum levels observed immediately after paclitaxel treatment were not correlated to treatment response. However, overall change in CA-125 serum concentration was a good predictor of response to paclitaxel containing treatment. Patients achieving a complete or partial response had a significant reduction of median CA-125 levels, whereas tumor progression was associated with increased CA-125 levels. Only for the group of patients obtaining a complete response was a decrease in the median relative CA-125 value observed. CONCLUSION: Paclitaxel-induced modulation of CA-125 expression could not be confirmed in vivo.

Carboplatin/5-fluorouracil treatment of recurrent cervical carcinoma: a phase II study with long-term follow-up.

OBJECTIVE: To evaluate the response rate, progression-free (PFS) and overall survival in patients with recurrent carcinoma of the cervix (RCC) treated with carboplatin (CBDCA; cis-diamine-1, 1-cyclobutane dicarboxylate platinum II) 300 mg/m2 or according to Calverts formula, CBDCA dose [(GFR + 25) x AUC = 51 mg intravenous (iv) day 1 and 5-FU (5-fluorouracil) 1000 mg/m2 iv day 1 to 5, every 4 weeks. METHODS: From June 1989 to October 1992, 25 patients were enrolled in this phase II study. All patients were evaluated for toxicity, response and survival data. RESULTS: No patients obtained objective response. Eleven patients had stable disease. The median progression-free survival for these patients was 9 months (range 2 to 38), and the median survival was 17 months (range 3 - 50). For all patients the median overall survival was 11 months (range 2 - 50). Four patients survived for more than 1 year. Two of these patients survived for more than 4 years. The toxicity was tolerable with bone marrow suppression as the major problem. CONCLUSION: Eleven patients (44%) with RCC obtained stable disease and four patients (16%) survived for more than one year. These poor results make this combination regimen insufficient and it should not be used in treating RCC.

Primary systemic treatment with weekly doxorubicin monotherapy in women with locally advanced breast cancer; clinical experience and parameters predicting outcome.

Sixty-three patients (median age 64 years) with locally advanced breast cancer (T3, T4 and/or N2) were treated with primary 'neoadjuvant' chemotherapy given as weekly doxorubicin monotherapy (14 mg/m2 per dose). Seven patients had solitary distant metastasis at the time of diagnosis. Twenty-eight patients (45%) achieved 'partial response' to primary chemotherapy. Twenty-nine patients (46%) had 'stable disease', and 6 patients (9%) had 'progressive disease' during treatment. Following chemotherapy, 52 patients were subjected to surgery and another 4 patients had surgery performed after radiotherapy. Surgery was considered impossible in only three patients. After a median observation time of 23 months, local recurrences were observed in 2 patients, one with progressive disease and one with stable disease during chemotherapy. Univariate analyses revealed that large tumour size, high histological grade and high mitotic frequency were associated with poor primary response to chemotherapy. Recent studies have demonstrated a correlation between p53-mutations and chemotherapy response.

Field homogeneity of bevelled intraoperative electron beam cones: the influence of virtual focus surface distance.

Field flatness of bevelled intraoperative electron therapy cones were evaluated from dose profiles, taken at dmax, both in the longitudinal plane (long axis direction) and the transversal plane (short axis direction), and were found to depend strongly on the setting of the x-ray collimators. Dose gradients in the longitudinal plane of 10-12% were found for collimator settings of 5 mm larger than the cone diameter for low energies, while the dose gradient were smaller for higher energies, both decreasing with larger collimator setting. The dose increase, relative to the central dose, of the hot spots observed in the profile of the transversal plane were in the range of 5-10% for high energies and large collimator settings, decreasing to less than 3% for low electron beam energies and smaller collimator setting. A decrease in virtual focus to surface distance (VFSD) was found to accompany the increasing dose gradient in the longitudinal plane with decreasing collimator setting, this due to increased scatter of electrons at collimator level. Increasing scatter with smaller collimator setting is also indicated by the increase in photon contamination ranging from 1-2.5% for low energies and 3.5-5% for high energies.

The labelling index is not always reliable. Discrepancies between the labelling index and the mitotic rate in the rat corneal epithelium after intraperitoneal and topical administration of tritiated thymidine and colcemid.

Many cell kinetic studies are based on the assumption that tritiated thymidine injected into an animal is available for incorporation into DNA for only a short time, and that it labels all cells in the S phase. The present study indicates that this is not the fact for the rat corneal epithelium. The labelling index (LI) declines considerably from the limbal area to the central cornea, while the mitotic rate is almost constant all over the corneal epithelium. The LI should therefore not be used as the only criterion in the assessment of proliferation rate.