Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.

Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy most frequently associated with OPA1 mutations. Most variants result in haploinsufficiency, and patient cells express roughly half of the normal levels of OPA1 protein. OPA1 is a mitochondrial GTPase that is essential for normal mitochondrial function. We identified and characterized STK-002, an antisense oligonucleotide (ASO) designed to prevent the incorporation of a naturally occurring alternatively spliced nonproductive exon in OPA1. STK-002 dose dependently reduced the inclusion of this exon, and increased OPA1 protein in human cells, including ADOA patient-derived fibroblasts. ADOA patient cells manifest reduced mitochondrial respiration, and treatment with STK-002 improved the parameters of mitochondrial respiratory function in these cells. Since STK-002 increases OPA1 through the wild-type allele, we assessed retinal OPA1 in wild-type cynomolgus monkeys and rabbits after intravitreal administration of STK-002 or a rabbit-specific surrogate. Increased OPA1 protein was produced in retinal tissue in both species at 4 weeks after ASO injection and persisted in monkeys at 8 weeks. STK-002 and enhanced OPA1 immunofluorescence were visualized in retinal ganglion cells of cynomolgus monkeys treated with the ASO. Cumulatively, these data support the progression of STK-002 toward the clinic as the first potential disease-modifying treatment for ADOA.

The Concizumab Pen-Injector is Easy to Use and Preferred by Hemophilia Patients and Caregivers: A Usability Study Assessing Pen-Injector Handling and Preference.

Introduction: Concizumab is a once-daily prophylactic treatment developed for patients with hemophilia A or B (HA/HB) with or without inhibitors. It is the first treatment for hemophilia patients to be delivered subcutaneously using a pre-filled, multi-dose pen-injector with a 4 mm, 32 G needle. Aim: To investigate patient and caregiver handling and preference for the concizumab pen-injector compared with current injection systems used to treat hemophilia. Methods: This preference and handling study was conducted in accordance with authority guidelines for approval of new devices and included adults and adolescents with HA/HB with or without inhibitors and caregivers currently administering factor replacement therapy or factor VIII mimetic (emicizumab) therapy. All participants underwent a training session, followed by a test session during which participants independently administered a single pen-injection into an injection pad or manikin. Time to train, time to prepare and inject, and number of complete independent injections handling the pen were assessed. Participants evaluated handling and preference via the Hemophilia Device Handling and Preference Assessment Questionnaire. Results: 80 participants (44 adults, 21 adolescents, 15 caregivers) currently using factor replacement therapy (n=41, 51%) or emicizumab (n=39, 49%) participated. Average training time and time to complete an injection were 7 min 49s and 1 min 21s. In total, 98% of independent complete injections were achieved at first attempt. 98% (n=78; 95% confidence interval [CI] 91-100%) of participants assessed the pen-injector as either "easy" or "very easy" to use. 88% of participants preferred the pen-injector (n=70; 95% CI 78-94%) over their current injection system, and 9% (n=7) reported "no preference". Conclusion: Participants found the concizumab pen-injector easy to learn and easy to use and preferred it over their current injection systems.

People with hemophilia lack clotting factors that help stop bleeding after an injury. If left untreated, it can lead to life-threatening bleeding episodes. Treatment such as replacement therapy with clotting factors needs to be administered at regular intervals to prevent bleeding. The administration of intravenous (inside the vein) medication can be challenging due to the required skills, injection pain and availability of a good vein to inject into. Factor VIII mimetic therapy now allows people to inject medication under the skin (subcutaneously). However, using vials and syringes still poses challenges with the time to prepare and inject medication. Pen-injectors have been developed to address these challenges and provide additional benefits, including increased dose accuracy, portability, reduced discomfort, and less administration time. Concizumab is a medication developed for once-daily subcutaneous injection for people with hemophilia A or hemophilia B, with or without inhibitors, using a pen-injector. The objective of this preference and handling study was to understand patient and caregiver pen-injector handling experiences, and device preferences compared to their existing devices. In this study, most participants found it easy to learn to use the pen-injector. 98% of participants reported that the pen-injector was easy or very easy to use compared with their current device. 88% of participants reported a preference for the concizumab pen-injector over their current device. This shows that the pen-injector can easily and effectively be used to inject concizumab, providing more control and independence in patients' treatment while reducing the burden caused by intravenous modes of administration.

Antisense oligonucleotides restore excitability, GABA signalling and sodium current density in a Dravet syndrome model.

Dravet syndrome is an intractable developmental and epileptic encephalopathy caused by de novo variants in SCN1A resulting in haploinsufficiency of the voltage-gated sodium channel Nav1.1. We showed previously that administration of the antisense oligonucleotide STK-001, also called ASO-22, generated using targeted augmentation of nuclear gene output technology to prevent inclusion of the nonsense-mediated decay, or poison, exon 20N in human SCN1A, increased productive Scn1a transcript and Nav1.1 expression and reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy in a mouse model of Dravet syndrome. Here, we investigated the mechanism of action of ASO-84, a surrogate for ASO-22 that also targets splicing of SCN1A exon 20N, in Scn1a+/- Dravet syndrome mouse brain. Scn1a +/- Dravet syndrome and wild-type mice received a single intracerebroventricular injection of antisense oligonucleotide or vehicle at postnatal Day 2. We examined the electrophysiological properties of cortical pyramidal neurons and parvalbumin-positive fast-spiking interneurons in brain slices at postnatal Days 21-25 and measured sodium currents in parvalbumin-positive interneurons acutely dissociated from postnatal Day 21-25 brain slices. We show that, in untreated Dravet syndrome mice, intrinsic cortical pyramidal neuron excitability was unchanged while cortical parvalbumin-positive interneurons showed biphasic excitability with initial hyperexcitability followed by hypoexcitability and depolarization block. Dravet syndrome parvalbumin-positive interneuron sodium current density was decreased compared to wild-type. GABAergic signalling to cortical pyramidal neurons was reduced in Dravet syndrome mice, suggesting decreased GABA release from interneurons. ASO-84 treatment restored action potential firing, sodium current density and GABAergic signalling in Dravet syndrome parvalbumin-positive interneurons. Our work suggests that interneuron excitability is selectively affected by ASO-84. This new work provides critical insights into the mechanism of action of this antisense oligonucleotide and supports the potential of antisense oligonucleotide-mediated upregulation of Nav1.1 as a successful strategy to treat Dravet syndrome.

Prognostic impact of molecular profiles and molecular signatures in clear cell ovarian cancer.

OBJECTIVE: Ovarian Clear cell carcinomas (OCCC) are characterized by low response to chemotherapy and a poor prognosis in advanced stages. Several studies have demonstrated that OCCC are heterogenous entities. We have earlier identified four molecular profiles based on the mutational status of ARID1A and PIK3CA. In this study we aimed to examine the association between molecular profiles, Tumor Mutational Burden (TMB), and molecular signatures with the clinical outcome in OCCC METHODS: We identified 55 OCCC cases with corresponding data and biological tissue samples in the Danish Gynecological Cancer Database during 2005-2016. Mutational profiling and TMB were performed using the Oncomine Tumor Mutational Load Assay. Chi-square and Cox regression analyses were used. P-values < 0.05 were considered statistically significant. RESULTS: Mutations in the PIK3CA gene (p=0.04) and low TMB (p=0.05) were associated with disease progression. In multivariate analyses adjusted for stage, patients with tumor mutations in the ARID1A and/or PIK3CA genes had a significantly impaired Progression Free Survival (PFS) and Overall Survival (OS) compared to patients who were wildtype ARID1A and PIK3CA (undetermined subgroup) (HR= 5.42 and HR= 2.77, respectively). High TMB status was associated with an improved PFS (HR= 0.36) and OS (HR= 0.46). A trend towards an improved PFS in patients with APOBEC enrichment was observed (HR 0.45). CONCLUSION: TMB-High was associated with decreased risk of progression and with an improved PFS and OS. Furthermore, OCCC with mutations in either ARID1A and/or PIK3CA genes had a significantly impaired prognosis compared to the undetermined subgroup in stage adjusted analyses.

Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged ≥ 69 referred to colposcopy due to an HPV-positive screening test.

BACKGROUND: Cervical cancer incidence and mortality rates are high in older women in many developed countries, including Denmark. Therefore, Danish women aged 69 and older were invited for one additional human papilloma virus (HPV) based screening test in 2017. Here, we describe the clinical management and detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) in screen-positive women referred for colposcopy. METHODS: We conducted an observational study in public gynecology departments in Central Denmark Region, Denmark. Women were eligible for enrolment if they were aged 69 + in 2017, HPV positive on a screening test taken between April 20th, 2017, and December 31st, 2017, and had been referred for direct colposcopy. Data on participants' characteristics, colposcopic findings, and histological outcomes were collected from medical records and the Danish Pathology Databank. We estimated the proportion of women with CIN2 + at the first colposcopy visit and at end of follow up including 95% confidence intervals (CIs). RESULTS: A total of 191 women were included with a median age of 74 years (IQR: 71-78). Most women (74.9%) did not have a fully visible transformation zone at colposcopy. At the first visit 170 women (89.0%) had a histological sample collected, 34 of whom (20.0%, 95% CI 14.3-26.8%) had CIN2 + diagnosed, 19 had CIN3 + , and two had cervical cancer). During follow-up additional CIN2 + were detected resulting in a total of 42 women (24.4%, 95% CI: 18.2-31.5%) being diagnosed with CIN2 + , 25 with CIN3 + , and three with cervical cancer. When restricting to women with paired histologic results (i.e., biopsies and a loop electrosurgical excision procedure (LEEP) specimen), we found that CIN2 + was missed in 17.9% (95% CI 8.9-30.4%) of biopsies compared to the LEEP. CONCLUSION: Our findings suggest a potential risk of underdiagnosis in older postmenopausal women referred to colposcopy. Future studies should explore potential risk-markers for discrimination of women at increased risk of CIN2 + from those at low risk, as this would reduce risk of underdiagnosis and overtreatment.

Insufficient training in colposcopy and loop electrosurgical excision procedure among residents.

INTRODUCTION: Colposcopy is an important tool in the diagnostic work-up of women with an abnormal cervical smear. Unlike in other countries where colposcopy is mostly performed by certified colposcopists, in Denmark, colposcopy may be performed by residents in obstetrics and gynaecology (OB/Gyn). We aimed to evaluate training in colposcopy and loop electrosurgical excision procedure (LEEP) among Danish OB/Gyn residents. METHODS: Two questionnaires were developed: one for OB/Gyn residents who are required to learn colposcopy and LEEP during their residency, and one for chief physicians who are responsible for providing their training. Questionnaires were distributed by e-mails and via social media from November to December 2021. RESULTS: Among 120 eligible residents, 93 completed the questionnaire. The median age was 36 (interquartile range: 34-39) years. Most received training in colposcopy (84.9%), but the majority considered training to be insufficient (76.3%) and had low self-efficacy in performing colposcopy (72.0%). With respect to LEEP, most received training (84.9%), but nearly half considered that their training had been insufficient (43.0%) and had low self-efficacy in performing LEEP (49.5%). CONCLUSIONS: Most Danish OB/Gyn residents receive insufficient training in colposcopy and LEEP, which demonstrates a need for a formal training programme for residents and their supervisors to ensure an appropriate level of training and adequate patient care. FUNDING: Danish Association of Younger Gynaecologists and Obstetricians (FYGO). TRIAL REGISTRATION: Not relevant.

High Intensity Aerobic exercise training and Immune cell Mobilization in patients with lung cancer (HI AIM)-a randomized controlled trial.

BACKGROUND: The increasing role of exercise training in cancer care is built on evidence that exercise can reduce side effects of treatment, improve physical functioning and quality of life. We and others have shown in mouse tumor models, that exercise leads to an adrenalin-mediated increased influx of T and NK cells into the tumor, altering the tumor microenvironment (TME) and leading to reduced tumor growth. These data suggest that exercise could improve immune responses against cancer cells by increase immune cell infiltration to the tumor and potentially having an impact on disease progression. Additionally, there are data to suggest that infiltration of T and NK cells into the TME is correlates with response to immune checkpoint inhibitors in patients. We have therefore initiated the clinical trial HI AIM, to investigate if high intensity exercise can mobilize and increase infiltration of immune cells in the TME in patients with lung cancer. METHODS: HI AIM (NCT04263467) is a randomized controlled trial (70 patients, 1:1) for patients with non-small cell lung cancer. Patients in the treatment arm, receive an exercise-intervention consisting of supervised and group-based exercise training, comprising primarily intermediate to high intensity interval training three times per week over 6 weeks. All patients will also receive standard oncological treatments; checkpoint inhibitors, checkpoint inhibitors combined with chemotherapy or oncological surveillance. Blood samples and biopsies (ultrasound guided), harvested before, during and after the 6-week training program, will form basis for immunological measurements of an array of immune cells and markers. Primary outcome is circulating NK cells. Secondary outcome is other circulating immune cells, infiltration of immune cells in tumor, inflammatory markers, aerobic capacity measured by VO2 max test, physical activity levels and quality of life measured by questionnaires, and clinical outcomes. DISCUSSION: To our knowledge, HI AIM is the first project to combine supervised and monitored exercise in patients with lung cancer, with rigorous analyses of immune and cancer cell markers over the course of the trial. Data from the trial can potentially support exercise as a tool to mobilize cells of the immune system, which in turn could potentiate the effect of immunotherapy. TRIAL REGISTRATION: The study was prospectively registered at ClinicalTrials.gov on February 10th 2020, ID: NCT04263467. https://clinicaltrials.gov/ct2/show/NCT04263467.

Assessment of recurrence rate and risk factors of relapse in stage in IA vulvar carcinoma.

OBJECTIVE: To evaluate recurrence rates and risk factors of relapse in stage IA vulvar squamous cell carcinoma (VSCC) patients. MATERIAL AND METHODS: Population-based prospectively collected data on stage IA VSCC was retrieved through the Danish Gynecological Cancer Database (DGCD) during 2011-2017. A central pathology review was performed on tumors from women with recurrent disease. RESULTS: 62 women diagnosed and treated for stage IA VSCC were identified. Nine (14.5%) of the included cases relapsed within the observation period. The recurrences were in the vulva, groins or both in 5 (8.1%), 3 (4.8%) and 1 (1.6%) of the women, respectively. At central pathology review, including all recurrent cases (n = 9), 5 out of 21 reviewed patients were upstaged to stage IB due to depth of invasion >1 mm and two were downstaged to Carcinoma in situ. Two of the upstaged women developed an isolated groin recurrence and one an isolated vulvar relapse. After exclusion of the seven cases the overall recurrence rate decreased to 10.9% (n = 6). Among these cases (n = 55) resection margin <8 mm and tumor size were associated with cancer recurrence. CONCLUSION: Pathological assessment of stage IA VSCC (depth of invasion ≤1 mm) may be difficult. This may result in under-staging, which impact the choice of treatment and possibly the prognosis. This suggests a need for further clarification of the FIGO measurement and may require a more radical approach when it comes to treatment and groin exploration in stage IA VSCC. Resection margins <8 mm and tumor size were associated with relapse of the disease.

Targeted Augmentation of Nuclear Gene Output (TANGO) of Scn1a rescues parvalbumin interneuron excitability and reduces seizures in a mouse model of Dravet Syndrome.

Dravet Syndrome (DS) is a severe developmental and epileptic encephalopathy typically caused by loss-of-function de novo mutations in the SCN1A gene which encodes the voltage-gated sodium channel isoform NaV1.1. Decreased NaV1.1 expression results in impaired excitability of inhibitory interneurons and seizure onset. To date, there are no clinically available treatments for DS that directly address the core mechanism of disease; reduced NaV1.1 expression levels in interneurons. Recently, Targeted Augmentation of Nuclear Gene Output (TANGO) of SCN1A by the antisense oligonucleotide (ASO) STK-001, was shown to increase Scn1a mRNA levels, increase NaV1.1 protein expression, reduce seizures, and improve survival in the Scn1a+/- mouse model of DS. However, it remains unknown whether STK-001 treatment rescues the reduced intrinsic excitability of parvalbumin-positive (PV) inhibitory interneurons associated with DS. In this study, we demonstrate that STK-001 treatment reduces seizures, prolongs survival, and rescues PV interneuron excitability in Scn1a+/- mice to levels observed in WT littermates. Together, these results support the notion that TANGO-mediated augmentation of NaV1.1 levels directly targets and rescues one of the core disease mechanisms of DS.

Adherence to the EAT-Lancet Diet and Risk of Stroke and Stroke Subtypes: A Cohort Study.

BACKGROUND AND PURPOSE: We investigated the association between adherence to the EAT-Lancet diet, a sustainable and mostly plant-based diet, and risk of stroke and subtypes of stroke in a Danish population. For comparison, we also investigated the Alternate Healthy Eating Index-2010 (AHEI). METHODS: We used the Danish Diet, Cancer and Health cohort (n=55 016) including adults aged 50 to 64 years at baseline (1993-1997). A food frequency questionnaire was used to assess dietary intake and group participants according to adherence to the diets. Stroke cases were identified using a national registry and subsequently validated by review of medical records (n=2253). Cox proportional hazards models were used to estimate hazard ratios and 95% CIs for associations with the EAT-Lancet diet or the AHEI and risk of stroke and stroke subtypes. RESULTS: Adherence to the EAT-Lancet diet was associated with a lower risk of stroke, although not statistically significant (highest versus lowest adherence: hazard ratio, 0.91 [95% CI, 0.76-1.09]). A lower risk was observed for AHEI (0.75 [95% CI, 0.64-0.87]). For stroke subtypes, we found that adherence to the EAT-Lancet diet was associated with a lower risk of subarachnoid hemorrhage (0.30 [95% CI, 0.12-0.73]), and the AHEI was associated with a lower risk of ischemic stroke (0.76 [95% CI, 0.64-0.90]) and intracerebral hemorrhage (0.58 [95% CI, 0.36-0.93]). CONCLUSIONS: Adherence to the EAT-Lancet diet in midlife was associated with a lower risk of subarachnoid stroke, and the AHEI was associated with a lower risk of total stroke, mainly ischemic stroke and intracerebral hemorrhage.

Genomic Sub-Classification of Ovarian Clear Cell Carcinoma Revealed by Distinct Mutational Signatures.

Ovarian clear cell carcinoma (OCCC) is characterized by dismal prognosis, partially due to its low sensitivity to standard chemotherapy regimen. It is also well-known for presenting unique molecular features in comparison to other epithelial ovarian cancer subtypes. Here, we aim to identify potential subgroups of patients in order to (1) determine their molecular features and (2) characterize their mutational signature. Furthermore, we sought to perform the investigation based on a potentially clinically relevant setting. To that end, we assessed the mutational profile and genomic instability of 55 patients extracted from the Gynecologic Cancer Database (DGCD) by using a panel comprised of 409 cancer-associated genes and a microsatellite assay, respectively; both are currently used in our routine environment. In accordance with previous findings, ARID1A and PIK3CA were the most prevalent mutations, present in 49.1% and 41.8%, respectively. From those, the co-occurrence of ARID1A and PIK3CA mutations was observed in 36.1% of subjects, indicating that this association might be a common feature of OCCC. The microsatellite instability frequency was low across samples. An unbiased assessment of signatures identified the presence of three subgroups, where "PIK3CA" and "Double hit" (with ARID1A and PIK3CA double mutation) subgroups exhibited unique signatures, whilst "ARID1A" and "Undetermined" (no mutations on ARID1A nor PIK3CA) subgroups showed similar profiles. Those differences were further indicated by COSMIC signatures. Taken together, the current findings suggest that OCCC presents distinct mutational landscapes within its group, which may indicate different therapeutic approaches according to its subgroup. Although encouraging, it is noteworthy that the current results are limited by sample size, and further investigation on a larger group would be crucial to better elucidate them.

Relative Quantification of NaV1.1 Protein in Mouse Brains Using a Meso Scale Discovery-Electrochemiluminescence (MSD-ECL) Method.

Densitometric analysis is often used to quantify NaV1.1 protein on immunoblots, although the sensitivity and dilution linearity of the method are usually poor. Here we present a protocol for quantification of NaV1.1 in mouse brain tissues using a Meso Scale Discovery-Electrochemiluminescence (MSD-ECL) method. MSD-ECL is based on ELISA (enzyme-linked immunosorbent assay) and uses electrochemiluminescence to produce measurable signals. Two different antibodies are used in this assay to capture and detect NaV1.1 respectively in brain tissue lysate. The specificity of the antibodies is confirmed by Scn1a gene knock-out tissue. The calibration curve standards used in this assay were generated with mouse liver lysate spiked with mouse brain lysate, instead of using a recombinant protein. We showed that this method was qualified and used for quantification of NaV1.1 in mouse brain tissues with specificity, accuracy and precision.

Comparison of the three-level and the five-level versions of the EQ-5D.

EQ-5D is a generic instrument to measure health-related quality of life. In 2009, a new version, EQ-5D-5L, was introduced as an attempt to reduce ceiling effects and improve sensitivity to small changes over time. The objective of this study was to assess the measurement properties of the EQ-5D-5L instrument compared to the EQ-5D-3L instrument in an elderly general population with a moderate to a high degree of comorbidity. A subgroup of participants in a large clinical trial completed the EQ-5D-3L and the EQ-5D-5L questionnaires. Based on the collected data, we tested for feasibility and ceiling and floor effects. Furthermore, we assessed the redistribution properties of the responses and examined the level of inconsistency, informativity, and convergent validity. A total of 1002 persons diagnosed with hypertension, diabetes, heart failure, and/or previous stroke completed both the EQ-5D-3L and the EQ-5D-5L questionnaires. The overall ceiling effect decreased from 46% with the EQ-5D-3L to 30% with the EQ-5D-5L and absolute and relative informativity were higher for EQ-5D-5L, and there was a stronger correlation between EQ-5D-5L and EQ VAS. The EQ-5D-5L seemed to perform better than the EQ-5D-3L in terms of feasibility, ceiling effect, discriminatory power, and convergent validity. The overall ceiling effect was higher than that found in patient samples in previous studies but lower than the one found in population studies.

Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome.

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in the SCN1A gene, resulting in haploinsufficiency of the voltage-gated sodium channel α subunit NaV1.1. Here, we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human cell lines, as well as in mouse brain. We show that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy (SUDEP) in the F1:129S-Scn1a +/- × C57BL/6J mouse model of DS. Increased expression of productive Scn1a transcript and NaV1.1 protein was confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of DS.

Increased mortality in patients with porphyria cutanea tarda-A nationwide cohort study.

BACKGROUND: Porphyria cutanea tarda (PCT) is a rare hepatocutaneous disease for which the prognosis is largely unknown. OBJECTIVE: To compare all-cause and cause-specific mortality between a nationwide cohort of patients with PCT and a matched population sample. METHODS: We included all Danish patients who received a diagnosis of PCT from 1989 through 2012. Each patient was matched by age and sex to 10 random population control individuals. We compared survival and cause-specific mortality between patients and control individuals and adjusted for confounding from alcohol-related diseases, hepatitis, hemochromatosis, HIV, diabetes, acute myocardial infarction, stroke, cancer, chronic obstructive pulmonary disease, and cirrhosis. RESULTS: The 20-year survival was 42.9% (95% confidence interval [CI], 36.9-48.7) for patients with PCT compared with 60.5% (95% CI, 58.6-62.4) for matched control individuals. All-cause mortality hazard ratio (HR) was 1.80 (95% CI, 1.56-2.07) before adjustment and 1.22 (95% CI, 1.04-1.44) after adjustment. The cause-specific mortality was markedly increased for nonmalignant gastrointestinal diseases (HR, 5.32; 95% CI, 2.71-10.43) and cancers of the gut (HR, 2.05; 95% CI, 1.24-3.39), liver/gallbladder (HR, 11.24; 95% CI, 4.46-28.29), and lungs (HR, 2.17; 95% CI, 1.41-3.33). LIMITATIONS: We had no data on lifestyle factors. CONCLUSIONS: Patients with PCT have increased mortality, primarily explained by an increased mortality from gastrointestinal diseases and from cancers of the gut, liver/gallbladder, and lungs.

[Workup, treatment and follow-up of vulva cancer].

This review summarises the current guidelines for vulva cancer in Denmark. Vulva cancer is a rare disease. The diagnosis is often delayed, which results in large tumours and regional spread. The most important prognostic factor is inguinal lymph node metastases. Staging and treatment is centralised to two hospitals. Primary treatment is wide local excision combined with removal of either inguinal sentinel nodes or lymphadenectomy. Treatment is associated with considerable morbidity, and supportive care is often necessary. Local curable recurrences are common. Relapses in the groin are associated with a poor prognosis. Thus, long term follow-up is essential. *) On behalf of Dansk Gynækologisk Cancer Gruppe for vulvacancer.

[Acute abdominal pain caused by lead poisoning].

This case report describes a 55-year-old man, who was admitted to hospital with acute abdominal pain. The only positive finding was elevated levels of bilirubin and alanine transaminase and dilation of the intrahepatic bile ducts. Due to the nature of the abdominal pain acute porphyria was suspected. A urinalysis for porphyria indicated intoxication with a heavy metal, in this case lead. Lead poisoning is a rare cause of acute abdominal pain, and in this case further workup was left for the occupational health specialists, who have experience in metal intoxication.

Nonspecific Symptoms in a Rare Case of Urethral Adenocarcinoma in a 58-Year-Old Female.

Cancer of the urethra is very rare with an age-adjusted incidence of only 0.6 per million women in Europe. The etiology is multifactorial and the incidence increases with age, with the highest rates in patients 75 years or older. We herein describe a 58-year-old woman referred to our unit due to pollakisuria and repeated lower urinary tract infections. The gynecological examination revealed a suspect area in the anterior wall of vagina. Subsequently, ultrasound examination, MRI, and PET-CT scan followed by vaginal biopsies revealed a urethral adenocarcinoma.

Safety and feasibility of home-based chemotherapy.

INTRODUCTION: The purpose of this study was to evaluate the safety and feasibility of home-based chemotherapy and to compare chemotherapy given at home with chemotherapy given as an outpatient treatment in relation to toxicity, quality of life and patient's preference. METHODS: Patients who had undergone radical surgery for colon cancer and who were eligible to receive adjuvant treatment with capecitabine and oxaliplatin could be included. To ensure patient safety, the first infusion was given at an outpatient clinic. Patients with adverse events graded ≤ 2 on the Common Terminology Criteria for Adverse Events version 3.0 were randomised to either group A continuing with four treatments at home followed by three in an outpatient clinic, or to group B continuing with three treatments in an outpatient clinic followed by four at home. To assess quality of life, the EuroQol-5 Domain was used at baseline and before each treatment. Preference cards were used at baseline and at end of treatment. RESULTS: A total of 51 patients were included between 2007 and 2010. Forty-two patients continued in either group A or B. The nurse found that the treatment was safe and acceptable in all cases. In 145 cycles (99.3%), patients answered that they felt secure; only one patient answered: "Do not know". The highest-ranking preferences for patients were transportation time followed by waiting time. CONCLUSIONS: Our study demonstrates that home-based chemotherapy is feasible and safe and that it might be a valuable alternative to treatment at an outpatient clinic. FUNDING: This study was supported by a grant from Roche. TRIAL REGISTRATION: not relevant.

Diagnosing diabetes mellitus in patients with porphyria cutanea tarda.

The prevalence of diabetes mellitus is increased in patients with porphyria cutanea tarda. Different tests are available for diagnosing and screening for type II diabetes mellitus, however choosing the most suitable test is challenging. The pitfalls in the different tests along with the interfering comorbidities and treatments concerning patients with porphyria cutanea tarda complicate diagnosing these patients with diabetes mellitus. HbA1c, fasting glucose, or oral glucose tolerance are the current available tests, with HbA1c as first choice. Measuring HbA1c requires no fasting, however HbA1c can be false low if the patient is treated with phlebotomy or has liver cirrhosis or chronic hepatitis. Instead fasting glucose and oral glucose tolerance tests can be used if the patient is not acutely ill. If either of the tests give a result in the diagnostic range, the test should be repeated if the patient has no clinical symptoms of diabetes. Diagnosing diabetes mellitus is important for the purpose of early intervention, and this review provides the knowledge needed to diagnose this special patient group properly.