A Plain Language Summary of "Dostarlimab for primary advanced or recurrent endometrial cancer".

What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).

Tumescent technique versus electrocautery mastectomy: A randomized controlled trial.

BACKGROUND: Breast cancer is the most common cancer in Danish women. In 2016 about 1450 (31%) Danish breast cancer patients had a mastectomy. The aim was to compare the frequency of postoperative complications in two methods of surgery, electrocautery dissection and tumescent technique, when performing a mastectomy. METHODS: Open randomized controlled trial of all consecutive primary breast cancer or DCIS female patients who underwent either a simple mastectomy or a modified radical mastectomy in Vejle Hospital, from January 2012 to October 2017. Primary outcomes were seroma production, bleeding, infection and necrosis. Secondary outcomes were duration of surgery and delay of adjuvant treatment caused by complications. Categorical outcome variables were compared between randomization groups using chi-square of Fisher exact test and continuous outcome variables by using Wilcoxon rank test. All analyses were performed at a 5% two-sided significance level. RESULTS: 357 patients met the inclusion criteria. 14 had bilateral mastectomy, i.e. 371 breasts. The two randomization groups consisted of 105 patients/107 breasts operated by tumescent technique and 98 patients/102 breasts operated by electrocautery technique. Tumescent technique produced more seroma though not significant (p = 0.631) (mean 605 vs. 630 ml). Bleeding in the tumescent group was 10.3% vs. 5.9% in the electrocautery group (p = 0.245). Infection (5.9% vs. 7.5% p = 0.645) and necrosis (4.9% vs. 4.7% p = 0.938) was uncommon with no difference between the intervention groups. Infection was most common cause of delay of adjuvant treatment; 3.9% in the electrocautery technique group. No significant difference in duration of surgery (p = 0.392). CONCLUSION: Both techniques are equally safe for simple and modified radical mastectomy.

A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer: NSGO AVANOVA1/ENGOT-OV24.

BACKGROUND: Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial. MATERIALS AND METHODS: In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D). RESULTS: Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21. CONCLUSIONS: There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.

The day of week of elective colorectal cancer surgery has no impact on mortality and morbidity.

INTRODUCTION: Recent studies have reported an asso-ciation between the day of week of surgery and post-operative mortality, meaning that patients undergoing surgery at the end of the week or during weekends may be at higher risk. The aim of this study was to investigate the influence of the day of week of surgery on mortality and morbidity rates in a national Danish cohort of patients undergoing major elective surgery for colorectal cancer. METHODS: In a register-based study design, all patients undergoing elective major surgery for colorectal cancer in Denmark during a ten-year period (2005-2014) were studied. Patients were identified in the National Colorectal Cancer Database. Any associations between short-time mortality and morbidity rates within 30 days after operation and the day of week of surgery, as well as patient characteristics, treatment data and socioeconomic data were analysed. RESULTS: We were unable to show that the day of week had a significant impact on short-term mortality or on surgical or medical complications. There was no evidence that patients undergoing surgery on Fridays had more risk factors or were more socioeconomically deprived than patients undergoing surgery from Monday to Thursday. CONCLUSIONS: The day of week of operation could not be shown to have any significant impact on the risk of post-operative surgical or medical complications or on short-term mortality in patients undergoing elective surgery for colorectal cancer in Denmark. FUNDING: none. TRIAL REGISTRATION: not relevant.

Predictive values of colorectal cancer alarm symptoms in the general population: a nationwide cohort study.

BACKGROUND: Alarm symptoms are used in many cancer referral guidelines. The objectives were to determine the 1-year predictive values (PVs) of colorectal cancer (CRC) alarm symptoms in the general population and to describe the proportion of alarm symptoms reported prior to diagnosis. METHODS: A nationwide prospective cohort of 69,060 individuals ≥40 years randomly selected from the Danish population was invited to complete a survey regarding symptoms and healthcare-seeking in 2012. Information on CRC diagnoses in a 12-month follow-up came from the Danish Cancer Registry. PVs and positive and negative likelihood ratios were calculated. RESULTS: A total of 37,455 individuals participated (response rate 54.2%). Sixty-four individuals were diagnosed with CRC. The single symptom with the highest positive PVs (PPV) and LR+ was rectal bleeding. PPVs were generally higher among individuals aged ≥75 years and highest among those reporting at least one specific alarm symptom that led to a GP contact. CONCLUSION: In general, the PPVs of CRC alarm symptoms are low and the NPVs high, especially in the youngest age groups. The LR + show a relative association with specific symptoms like rectal bleeding. Future campaigns on early diagnosis of CRC should focus on healthcare-seeking when experiencing rectal bleeding and target older people with the highest incidence.

Screening history and FIGO-stages among Danish women with cervical cancer in 2012-2014: a register-based study.

The objective was to examine whether attendance in the mass cervical screening programme has implications for the prognosis when cervical cancer is diagnosed. We performed a retrospective analysis of all cases of cervical cancer between 1st of January 2012 and 31st of December 2014 in the Region of Southern Denmark. The cases were retrieved from the Danish National Pathology Registry, PatoBank. Odds ratios (OR) with confidence intervals (95% CI) were calculated for attendees versus non-attendees of the screening programme by using χ2-test. 216 patients were included in the study. 61.6% of the study population had not attended the screening programme. Patients who had attended the programme were characterised by disease in low stage (OR = 3.14, 95% CI; 1.66 to 5.92), treatment with surgery alone (OR = 2.63, 95% CI; 1.49 to 4.64) and a lower risk of death (OR = 0.36, 95% CI; 0.15 to 0.87). Adenocarcinomas were more often detected among attendees of the programme compared to squamous cell carcinomas (OR = 4.06, 95% CI; 2.03 to 8.14). Statistically significant results regarding relapse of cancer (OR = 0.62, 95% CI; 0.23 to 1.68, p = 0.47) and lymph node metastases (OR = 0.62, 95% CI; 0.32 to 1.21, p = 0.19) were not found. Cervical cancer detected in women who had attended the mass cervical screening programme prior to the diagnosis, was shown to have a statistically significant lower FIGO stage (p = 0.0004) and was therefore linked to less extensive treatment options. Continued focus on increasing the participation rate of the programme is of importance, as the nonattendance rate continues to be high.

Lifestyle, socioeconomic status and healthcare seeking among women with gynaecological cancer alarm symptoms: a combined questionnaire-based and register-based population study.

OBJECTIVES: To determine the proportion of contacts to general practitioner (GP) with recent onset gynaecological cancer alarm symptoms (pelvic pain, postmenopausal bleeding, bleeding during intercourse or pain during intercourse) and to analyse the associations between lifestyle factors, socioeconomic status and GP contact for these symptoms. DESIGN: Cross-sectional survey combined with data from national registers. SETTING: The general Danish population. PARTICIPANTS: A total of 25 866 non-pregnant women ≥20 years completed the survey. Women reporting at least one of four gynaecological alarm symptoms within the preceding 6 months form the study base (n=2957). RESULTS: The proportion of women reporting GP contact ranged from 21.1% (pain during intercourse) to 32.6% (postmenopausal bleeding). Women aged 60+ years had higher odds of reporting GP contact for at least one of the four gynaecological cancer alarm symptoms compared with those aged 20-39 years (OR 2.56, 95% CI 1.69 to 3.89), and immigrants had higher odds of reporting GP contact for at least one of the symptoms (OR 1.56, 95% CI 1.13 to 2.15) compared with ethnic Danish individuals. Among those reporting postmenopausal bleeding and/or bleeding during intercourse, women in the age group 60+ years had higher odds of reporting GP contact compared with those aged 20-39 years (OR 2.79, 95% CI 1.33 to 5.87). A high educational level (>12 years) was positively associated with reporting GP contact for postmenopausal bleeding and/or bleeding during intercourse compared with a low educational level (<10 years) (OR 2.23, 95% CI 1.19 to 4.19). No associations were found with lifestyle factors. CONCLUSIONS: Few women contacted their GP with recent onset gynaecological cancer alarm symptoms. Higher age, being immigrant and higher educational level increased the odds of GP contact. Future studies should explore the reasons for these findings as this may aid in prompting early diagnosis and thereby improve the prognosis of gynaecological cancer.

Predictive values of upper gastrointestinal cancer alarm symptoms in the general population: a nationwide cohort study.

BACKGROUND: Survival rates for upper gastrointestinal (GI) cancer are poor since many are diagnosed at advanced stages. Fast track endoscopy has been introduced to prompt diagnosis for patients with alarm symptoms that could be indicative of upper GI cancer. However, these symptoms may represent benign conditions and little is known about the predictive values of alarm symptoms of upper GI cancer in the general population. METHODS: The study is a nationwide cohort study of 60,562 individuals aged 45 years or above randomly selected from the Danish general population. Participants were invited to complete a survey comprising of questions on several symptom experiences, including alarm symptoms for upper GI cancer within the past four weeks. The participants were asked about specific symptoms (repeated vomiting, difficulty swallowing, signs of upper GI bleeding or persistent and recent-onset abdominal pain) and non-specific symptoms (nausea, weight loss, loss of appetite, feeling unwell and tiredness). We obtained information on upper GI cancer diagnosed in a 12-month period after completing the questionnaire from the Danish Cancer Registry. We calculated positive predictive values and positive likelihood ratios for the association between alarm symptom and subsequent upper GI cancer. RESULTS: A total of 33,040 individuals above 45 years completed the questionnaire, yielding a response rate of 54.6%. Respondents were fairly respresentative of the study sample. During the follow-up period, 18 people were diagnosed with upper GI cancer. The number of incident cancers was similar among eligible non-respondents. Two thirds of the respondents with an upper GI malignancy had experienced one or more alarm symptoms. The positive predictive value for being diagnosed with upper GI cancer after reporting a least one alarm symptom was 0.1% (95% CI:0.0-0.1%). The positive likelihood ratio was 4.4 for specific alarm symptoms and 1.1 for non-specific alarm symptoms. CONCLUSIONS: We found that positive predictive values of alarm symptoms of upper GI cancer experienced in the general population are low. It is important knowledge that despite denoted alarm symptoms even patients with specific alarm symptoms of upper GI cancer have a low risk of being diagnosed with upper GI cancer.

Identification of Associations Between Prescribed Medications and Cancer: A Nationwide Screening Study.

PURPOSE: We present a systematic screening for identifying associations between prescribed drugs and cancer risk using the high quality Danish nationwide health registries. METHODS: We identified all patients (cases) with incident cancer in Denmark during 2000-2012 (n=278,485) and matched each case to 10 controls. Complete prescription histories since 1995 were extracted. Applying a two-phased case-control approach, we first identified drug classes or single drugs associated with an increased or decreased risk of 99 different cancer types, and further evaluated potential associations by examining specificity and dose-response patterns. FINDINGS: 22,125 drug-cancer pairs underwent evaluation in the first phase. Of 4561 initial signals (i.e., drug-cancer associations), 3541 (78%) failed to meet requirements for dose-response patterns and specificity, leaving 1020 eligible signals. Of these, 510 signals involved the use of single drugs, and 33% (166 signals) and 67% (344 signals) suggested a reduced or an increased cancer risk, respectively. While a large proportion of the signals were attributable to the underlying conditions being treated, our algorithm successfully identified well-established associations, as well as several new signals that deserve further investigation. CONCLUSION: Our results provide the basis for future targeted studies of single associations to capture novel carcinogenic or chemopreventive effects of prescription drugs.

Association between sexually transmitted disease and church membership. A retrospective cohort study of two Danish religious minorities.

OBJECTIVES: Studies comprising Danish Seventh-day Adventists (SDAs) and Danish Baptists found that members have a lower risk of chronic diseases including cancer. Explanations have pointed to differences in lifestyle, but detailed aetiology has only been sparsely examined. Our objective was to investigate the incidence of sexually transmitted diseases (STDs) among Danish SDAs and Baptists as a proxy for cancers related to sexual behaviour. METHODS: We followed the Danish Cohort of Religious Societies from 1977 to 2009, and linked it with national registers of all inpatient and outpatient care contacts using the National Patient Register. We compared the incidence of syphilis, gonorrhoea and chlamydia among members of the cohort with the general population. RESULTS: The cohort comprised 3119 SDA females, 1856 SDA males, 2056 Baptist females and 1467 Baptist males. For the entire cohort, we expected a total of 32.4 events of STD, and observed only 9. Female SDAs and Baptists aged 20-39 years had significant lower incidence of chlamydia (both p<0.001). Male SDAs and Baptists aged 20-39 years also had significant lower incidence of chlamydia (p<0.01 and p<0.05, respectively). No SDA members were diagnosed with gonorrhoea, when 3.4 events were expected, which, according to Hanley's 'rule of three', is a significant difference. No SDA or Baptist was diagnosed with syphilis. CONCLUSIONS: The cohort shows significant lower incidence of STD, most likely including human papillomavirus, which may partly explain the lower incidence of cancers of the cervix, rectum, anus, head and neck.

Point-of-care ultrasonography in patients admitted with respiratory symptoms: a single-blind, randomised controlled trial.

BACKGROUND: When used with standard diagnostic testing, point-of-care ultrasonography might improve the proportion of patients admitted with respiratory symptoms who are correctly diagnosed 4 h after admission to the emergency department. We therefore assessed point-of-care ultrasonography of the heart, lungs, and deep veins in addition to the usual initial diagnostic testing in this patient population. METHODS: In a prospective, parallel-group trial in the emergency department at Odense University Hospital, Odense, Denmark, patients (≥18 years) with a respiratory rate of more than 20 per min, oxygen saturation of less than 95%, oxygen therapy, dyspnoea, cough, or chest pain were randomly assigned in a 1:1 ratio with a computer-generated list to a standard diagnostic strategy (control group) or to standard diagnostic tests supplemented with point-of-care ultrasonography of the heart, lungs, and deep veins (point-of-care ultrasonography group). The primary endpoint was the percentage of patients with a correct presumptive diagnosis 4 h after admission to the emergency department. Only the physicians doing the primary clinical assessment and the auditors were masked. Analyses were by intention to treat. The study is registered with ClinicalTrials.gov, number NCT01486394. FINDINGS: Between Dec 7, 2011, and March 15, 2013, 320 patients were randomly assigned to the control group (n=160) and point-of-care ultrasonography group (n=160). 158 patients in the point-of-care ultrasonography group and 157 in the control group were analysed. 4 h after admission to the emergency department, 139 patients (88·0%; 95% CI 82·8-93·1) in the point-of-care ultrasonography group versus 100 (63·7%; 56·1-71·3) in the control group had correct presumptive diagnoses (p<0·0001). The absolute and relative effects were 24·3% (95% CI 15·0-33·1) and 1·38 (1·01-1·31), respectively. No adverse events were reported. INTERPRETATION: Point-of-care ultrasonography is a feasible, radiation free, diagnostic test, which alongside standard diagnostic tests is superior to standard diagnostic tests alone for establishing a correct diagnosis within 4 h. It should therefore be considered for routine use as part of the standard diagnostic tests in the emergency department for patients admitted with respiratory symptoms. FUNDING: University of Southern Denmark, Odense University Hospital, and Højbjerg Fund.

Primary non-adherence in general practice: a Danish register study.

PURPOSE: The aim of this study was to describe primary non-adherence (PNA) in a Danish general practitioner (GP) setting, i.e. the extent to which patients fail to fill the first prescription for a new drug. We also assessed the length of time between the issuing of a prescription by the GP and the dispensing of the drug by the pharmacist. Lastly, we sought to identify associations between PNA and the characteristics of the patient, the drug and the GP. METHODS: By linking data on issued prescriptions compiled in the Danish General Practice Database with data on redeemed prescriptions contained in the Danish National Prescription Registry, we calculated the rate of PNA among Danish patients from January 2011 through to August 2012. Characteristics associated with PNA were analysed using a mixed effects logistic regression model. RESULTS: A total of 146,959 unique patients were started on 307,678 new treatments during the study period. The overall rate of PNA was 9.3 %, but it varied according to the major groups of the Anatomical Therapeutic Chemical (ATC) Classification System, ranging from 16.9 % for "Blood and bloodforming organs" (ATC group B) to 4.7 % for "Cardiovascular system" (ATC group C). Most of the patients redeemed their prescriptions within the first week. Older age, high income and a diagnosis of chronic obstructive pulmonary disease were found to be significantly associated with lower rates of PNA, while polypharmacy and a diagnosis of ischaemic heart disease were associated with higher rates of PNA. CONCLUSIONS: The overall rate of PNA among Danish residents in a GP setting was 9.3 %. Certain drug classes and patient characteristics were associated with PNA.

Influence of comorbidity on cancer patients' rehabilitation needs, participation in rehabilitation activities and unmet needs: a population-based cohort study.

PURPOSE: This study aims to investigate possible associations between cancer survivors' comorbidity status and their (1) need for rehabilitation, (2) participation in rehabilitation activities and (3) unmet needs for rehabilitation in a 14-month period following date of diagnosis. METHODS: We performed a population-based cohort study including incident cancer patients diagnosed from 1 October 2007 to 30 September 2008 in two regions in Denmark. Fourteen months after diagnosis, participants completed a questionnaire measuring different aspects and dimensions of rehabilitation. Individual information on comorbidity was based on hospital contacts from 1994 and until diagnosis, subsequently classified according to the Charlson comorbidity index. Logistic regression analyses were used to explore the association between comorbidity and outcomes for rehabilitation. Analyses were conducted overall and stratified for gender, age and cancer type. RESULTS: A total of 3,439 patients responded (70%). Comorbidity at all levels was statistically significant associated with a physical rehabilitation need, and moderate to severe comorbidity was statistically significant associated with a need in the emotional, family-oriented and financial areas as well as participation in physical-related rehabilitation activities. Stratified analyses showed that significant results in most cases were related to being older than 65 years or having colorectal or prostate cancer. CONCLUSIONS: Comorbidity at all levels was significantly associated with needs for physical rehabilitation. Moderate to severe comorbidity was further associated with other areas of need and participation in physical area activities. This should be taken into account when planning rehabilitation interventions for cancer survivors. Differences among subgroups could help target interventions and should be explored further.

Unmet needs in cancer rehabilitation during the early cancer trajectory--a nationwide patient survey.

BACKGROUND: A cancer diagnosis may lead to psychosocial problems and physical symptoms that can be relieved during rehabilitation. The aim of this study was to analyse patient-perceived unmet needs of rehabilitation close to time of diagnosis, i.e. frequencies of unmet needs and the association with sociodemographic characteristics, cancer type and treatment. MATERIAL AND METHODS: All adult residents of Denmark diagnosed with cancer for the first time from 1 May to 31 August 2010 were mailed a patient questionnaire two to five months following diagnosis. The study population was identified by use of national administrative registers. Data on rehabilitation, family situation, education, and cancer treatment were obtained from the questionnaire, while sex, birth year and cancer type were obtained from the Danish National Patient Registry. The association between each type of unmet needs and the variables sex, age, cancer diagnosis, treatment, education, cohabitation status, and children (living at home and away from home) was analysed using multiple logistic regression. RESULTS: Among the 4346 participants (64.7%) unmet needs were reported with regard to talking to patients in the same situation (24.1%), counselling with a psychologist (21.4%), physical rehabilitation (18.8%), practical help (17.3%), and counselling related to work or education (14.8%). Differences were observed with regard to type of unmet needs, sociodemographic and clinical characteristics, but generally, young age, male sex, low educational level and living alone increased the adjusted odds ratios of unmet needs. Breast cancer and to some extent melanoma cancer decreased the odds. CONCLUSION: Unmet needs of rehabilitation are frequent during the early cancer trajectory and sociodemographic and clinical inequalities exist. The results support guideline recommendations of integration of cancer rehabilitation from the beginning of the cancer trajectory. Early interventions tailored to men, patients with low educational level, living alone, or treated with chemotherapy may help counterbalancing social and clinical inequalities in the long run.

The predictive value of single nucleotide polymorphisms in the VEGF system to the efficacy of first-line treatment with bevacizumab plus chemotherapy in patients with metastatic colorectal cancer: results from the Nordic ACT trial.

PURPOSE: Bevacizumab and chemotherapy is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). So far, no predictive markers have been identified. The aim was to investigate the possible predictive value of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor (VEGF) system in this setting. METHODS: Pre-treatment blood samples and response evaluations were available from 218 of the 249 included patients. All patients received bevacizumab and chemotherapy comprising fluorouracil and leucovorin or capecitabine combined with either oxaliplatin (FOLFOX or XELOX, n = 183) or irinotecan (FOLFIRI or XELIRI, n = 66). Germline DNA was isolated from whole blood, and five SNPs in the VEGF-A gene, one SNP in the VEGF receptor 1 (VEGFR-1) gene and three SNPs in the VEGFR-2 gene were analysed by polymerase chain reaction. Response was evaluated according to RECIST version 1.0, and the association to genotypes was analysed using Fisher's exact test. RESULTS: The VEGFR-1 319 C/A SNP was significantly associated with response. Objective response was observed in 36% of the patients with CC genotype, 40% with CA and 56% with AA, p = 0.048. The response rates also differed significantly between patients with C-allele containing genotypes (CC + CA) (39%) and patients homozygous for the A-allele (AA) (56%), p = 0.015. There was no correlation between response rates and the remaining SNPs. CONCLUSIONS: The VEGFR-1 319 C/A SNP is a potential predictive marker for bevacizumab plus chemotherapy in patients with mCRC. Patients with the A allele appeared to have increased response rates. The results call for validation.

Reasons for diagnostic delay in gynecological malignancies.

INTRODUCTION: To describe the different delay types in women with gynecological cancer and to analyze the relationship between diagnostic delay and a number of characteristics for patients, cancers, and the health care system. METHOD: Data were obtained from 4 different questionnaires, the Electronic Patient Journal (EPJ), and the Danish Gynecological Cancer Database (DGCD). A total of 161 women with ovarian cancer (63), endometrial cancer (50), cervical cancer (34), and vulvar cancer (14) were included. Outcome measures were different delay types counted in days and 4 clinically important variables' impact on the diagnostic delay: presence of alarm symptoms, age (divided into 2 groups: ≤60 or >60 years), performance of gynecological examination by the general practitioner (GP), and notification of cancer suspicion on first referral from GP. RESULTS: Across cancer types, median total delay was 101 days. Some 10% of women experienced the longest delay with a total delay of 436 days or more. Vulva cancer had the longest delay, whereas women with ovarian cancer had the shortest delay. More than one third (39%) of the women consulted their GP for reasons other than the predefined alarm symptoms. Gynecological examination by the GP was less likely to be performed if the woman did not present with vaginal bleeding. The length of the delay was shortened by performance of a gynecological examination by the GP and a primary referral from the GP raising the receiver's suspicion of cancer. CONCLUSION: Reducing diagnostic delays should be achievable, particularly for those most delayed, and interventions aimed at reducing delays need to be developed. Creation of new valid instruments for measuring delay is essential in future research.

A phase II study of combination chemotherapy in early relapsed epithelial ovarian cancer using gemcitabine and pegylated liposomal doxorubicin.

OBJECTIVE: Treatment of epithelial ovarian cancer patients relapsing with a short treatment-free interval (TFI) after prior chemotherapy is unsatisfactory. This phase II trial evaluated the activity and feasibility of pegylated liposomal doxorubicin (PLD) plus gemcitabine in this setting. METHODS: Patients who had received prior platinum and paclitaxel with a TFI 0-12 months received PLD 25 mg/m(2)day 1 plus gemcitabine 800 mg/m(2)day 1, 8 every 21 days. Gemcitabine was dose escalated to 1000 mg/m(2)day 1, 8 from course 2 in the absence of grade 3/4 toxicity. The primary endpoint was progression-free survival (PFS). Patients were stratified according to response to primary chemotherapy. RESULTS: Seventy-nine patients (n=26 with CR on prior chemotherapy and TFI 6-12 months; n=20 with CR and TFI 0-6 months; n=33 with PR/SD and TFI 0-12 months) were enrolled. The median age was 59 years (range 31-77 years), and 33 patients had received ≥ 2 prior treatments. A median of five courses was delivered per patient (total 389 courses). Gemcitabine was dose escalated in 124 courses and reduced in 105 courses. No PLD dose reductions occurred. Grade 3/4 toxicities were febrile neutropenia (n=4), PPE (n=2), and mucositis (n=2). One toxic death occurred (pneumonitis/alveolitis). Responses were complete in 5.1%, partial in 27.9%, and stable disease in 55.7%. Median OS and PFS were 12.5 and 6.4 months, respectively. CONCLUSIONS: The PLD-gemcitabine combination is an effective and well-tolerated salvage treatment for relapsed epithelial ovarian cancer and is a valid candidate for evaluation in a phase III trial.

Reproducibility of serum protein profiling by systematic assessment using solid-phase extraction and matrix-assisted laser desorption/ionization mass spectrometry.

Protein profiling of human serum by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) is potentially a new diagnostic tool for early detection of human diseases, including cancer. Sample preparation is a key issue in MALDI MS and the analysis of complex samples such as serum requires optimized, reproducible methods for handling and deposition of protein samples. Data acquisition in MALDI MS is also a critical issue, since heterogeneity of sample deposits leads to attenuation of ion signals in MALDI MS. In order to improve the robustness and reproducibility of MALDI MS for serum protein profiling we investigated a range of sample preparation techniques and developed a statistical method based on repeated analyses for evaluation of protein-profiling performance of MALDI MS. Two different solid-phase extraction (SPE) methods were investigated, namely custom-made microcolumns and commercially available magnetic beads. Using these two methods, nineteen different sample preparation methods for serum profiling by MALDI MS were systematically tested with regard to matrix selection, stationary phase, selectivity, and reproducibility. Microcolumns were tested with regard to chromatographic properties; reversed phase (C8, C18, SDB-XC), ion-exchange (anion, weak cation, mixed-phase (SDB-RPS)) and magnetic beads were tested with regard to chromatographic properties; reversed phase (C8) or affinity chromatography (Cu-IMAC). The reproducibility of each sample preparation method was determined by enumeration and analysis of protein signals that were detected in at least six out of nine spectra obtained by three triplicate analyses of one serum sample.A candidate for best overall performance as evaluated by the number of peaks generated and the reproducibility of mass spectra was found among the tested methods. Up to 418 reproducible peaks were detected in one cancer serum sample. These protein peaks can be part of a possible diagnostic profile, suggesting that this sample preparation method and data acquisition approach is suitable for large-scale analysis of serum samples for protein profiling.