Frequency and prognosis of associated malignancies in 504 patients with lymphomatoid papulosis.

BACKGROUND: Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. OBJECTIVE: To evaluate the frequency and prognostic significance of associated HM and non-HM in LyP patients. METHODS: In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. RESULTS: After a median follow-up of 120 months (range, 6-585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large-cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B-cell (n = 14) or myeloid origin (n = 5). Even after a 25-year follow-up period, percentages of associated HM did not exceed 20%. Thirty-nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow-up, after a median of 68 months (range of 3-286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin-limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4-3.3) for non-HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. CONCLUSIONS: An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring.

[Psychedelics for existential distress in terminally ill patients]. / Psychedelica bij existentieel lijden bij patiënten met een terminale ziekte.

BACKGROUND: Existential distress in patients with a terminal illness is often associated with (symptoms of) anxiety and depression. Psychotherapeutic interventions seem effective but effects are short-lived. There are no proven effective pharmacological interventions.
AIM: To present an overview of literature on psychedelic treatment of existential distress in patients with terminal illness.
METHOD: Literature research in PubMed/Medline databases, supplemented with cross-references.
RESULTS: 14 clinical studies have been conducted: 6 with classic psychedelics between 1960 and 1980, and 8 with classic psychedelics and ketamine after 2000. Results of early pre-post studies are promising but have serious methodological limitations. Recent clinical research with LSD, psilocybin and ketamine are also promising although limited in terms of research design and generalizability. Overall, studies show a positive effect on existential and spiritual well-being, quality of life, acceptance and (symptoms of) anxiety and depression. Mystical experiences are correlated with positive outcomes. Few adverse effects are reported.
CONCLUSION: Treatment of existential distress using classical psychedelics or ketamine in patients with terminal illness seems auspicious. Larger clinical studies in a more diverse patient population with fewer methodological limitations are needed to draw conclusions about efficacy and generalizability.

[Psychedelics in the treatment of depression, anxiety, and obsessive-compulsive disorder]. / Psychedelica bij de behandeling van depressie, angst en obsessieve-compulsieve stoornis.

BACKGROUND: There is a need for new, effective treatments for patients with (treatment-resistant) depressive disorders, anxiety disorders and obsessive-compulsive disorder (ocd). At the same time, there is renewed interest in psychedelics for the treatment of psychiatric disorders.
AIM: To provide an overview of results from past and current research into psychedelics in the treatment of depression, anxiety disorders and ocd.
METHOD: Literature search in Medline and PubMed databases, supplemented with cross-references and results from recent studies.
RESULTS: There is a considerable evidence base for the atypical psychedelic ketamine. Ketamine has a rapid, beneficial effect on depression and suicidality; longer-term effects are less clear. Research into classical psychedelics for the treatment of depression and anxiety disorders is currently limited to a few small (open label) studies, although positive outcomes are reported even after a single administration, with potentially longer lasting benefits. Studies must be repeated in larger and more diverse groups of patients.
CONCLUSION: Further research into efficacy, therapeutic mechanisms and intervention models is very worthwhile; for the benefit of patients, but also to provide a deeper insight into the psychotherapeutic and neurobiological mechanisms that play a role in (the treatment of) common mental disorders.

[Ketamine as an anesthetic, analgesic and anti-depressant]. / Ketamine als anestheticum, analgeticum en als antidepressivum.

BACKGROUND: Treatment-resistance occurs in about 30% of patients with depression. Therefore, there is an urgent need to identify new treatment strategies. Ketamine, originally developed as an anesthetic, is studied and applied as treatment for patients with treatment-resistant depression.
AIM: A critical review of the current use of ketamine as an antidepressant.
METHOD: Literature study.
RESULTS: Ketamine is a proven effective acute antidepressant. However, limited information is available about maintenance of effect of ketamine, potential risks of repeated administration, and different routes of administration and treatment schedules.
CONCLUSION: Additional research on ketamine as an antidepressant is needed. Meanwhile, (off-label) treatment should only be applied after careful patient selection and under close monitoring.

Evaluation of treatment results in multifocal primary cutaneous anaplastic large cell lymphoma: report of the Dutch Cutaneous Lymphoma Group.

BACKGROUND: There is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). Radiotherapy (RT) and methotrexate (MTX) are the current treatment options, but their efficacy is unknown. Recently, targeted therapies showed promising results in C-ALCL, and may therefore be an attractive first choice of treatment. OBJECTIVES: To assess the efficacy of conventional treatment strategies for patients with multifocal C-ALCL, and to define which patients may require novel targeted therapies. METHODS: In this multicentre study, treatment was evaluated in patients initially presenting (n = 24) or relapsing with multifocal C-ALCL (n = 17; 23 relapses). Distinction was made between patients with five or less lesions (n = 36) and more than five lesions (n = 11). RESULTS: Treatments most commonly used were RT (n = 21), systemic chemotherapy (n = 9) and low-dose MTX (n = 7) with complete response rates of 100%, 78% and 43%, respectively, and an overall response rate of 100%, 100% and 57%, respectively. Four patients showed complete spontaneous regression. In total, 16 of 24 patients (67%) first presenting with multifocal C-ALCL relapsed, including all five patients initially treated with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone). Compared with patients presenting with two to five skin lesions, patients presenting with more than five lesions had a higher chance of developing extracutaneous relapse (56% vs. 20%) and more often died of lymphoma (44% vs. 7%). CONCLUSIONS: Patients with five or less lesions should be treated with low-dose RT (2 × 4 Gy). Maintenance low-dose MTX (20 mg weekly) is a suitable option in patients with more than five lesions. Targeted therapies may be considered in rare patients who are refractory to MTX or patients developing extracutaneous disease.

Recommendations for treatment in folliculotropic mycosis fungoides: report of the Dutch Cutaneous Lymphoma Group.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) and generally less responsive to standard skin-directed therapies (SDTs). Recent studies distinguished indolent (early-stage FMF) and more aggressive (advanced-stage FMF) subgroups. The optimal treatment for both subgroups remains to be defined. OBJECTIVES: To evaluate initial treatment results in patients with early- and advanced-stage FMF. METHODS: A study was undertaken of 203 patients (84 early-stage, 102 advanced-stage, 17 extracutaneous FMF) included in the Dutch Cutaneous Lymphoma Registry between 1985 and 2014. Type and results of initial treatment were retrieved from the Dutch Registry. Main outcomes were complete remission (CR); sustained complete remission; partial remission (PR), > 50% improvement; and overall response (OR; CR + PR). RESULTS: Patients with early-stage FMF were treated with nonaggressive SDTs in 67 of 84 cases resulting, respectively, in CR and OR of 28% and 83% for monotherapy topical steroids, 0% and 83% for ultraviolet B (UVB), and 30% and 88% for psoralen plus ultraviolet A (PUVA). In patients with advanced-stage FMF these SDTs were less effective (combined CR and OR 10% and 52%, respectively). In patients with advanced-stage FMF local radiotherapy (CR 63%; OR 100%), total skin electron beam irradiation (CR 59%; OR 100%) and PUVA combined with local radiotherapy (CR 5%, OR 75%) were most effective. CONCLUSIONS: The results of the present study demonstrate that not all patients with FMF should be treated aggressively. Patients with early-stage FMF may benefit very well from standard SDTs also used in early-stage classic MF and have an excellent prognosis.

Diffusion kurtosis imaging probes cortical alterations and white matter pathology following cuprizone induced demyelination and spontaneous remyelination.

Although MRI is the gold standard for the diagnosis and monitoring of multiple sclerosis (MS), current conventional MRI techniques often fail to detect cortical alterations and provide little information about gliosis, axonal damage and myelin status of lesioned areas. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) provide sensitive and complementary measures of the neural tissue microstructure. Additionally, specific white matter tract integrity (WMTI) metrics modelling the diffusion in white matter were recently derived. In the current study we used the well-characterized cuprizone mouse model of central nervous system demyelination to assess the temporal evolution of diffusion tensor (DT), diffusion kurtosis tensor (DK) and WMTI-derived metrics following acute inflammatory demyelination and spontaneous remyelination. While DT-derived metrics were unable to detect cuprizone induced cortical alterations, the mean kurtosis (MK) and radial kurtosis (RK) were found decreased under cuprizone administration, as compared to age-matched controls, in both the motor and somatosensory cortices. The MK remained decreased in the motor cortices at the end of the recovery period, reflecting long lasting impairment of myelination. In white matter, DT, DK and WMTI-derived metrics enabled the detection of cuprizone induced changes differentially according to the stage and the severity of the lesion. More specifically, the MK, the RK and the axonal water fraction (AWF) were the most sensitive for the detection of cuprizone induced changes in the genu of the corpus callosum, a region less affected by cuprizone administration. Additionally, microgliosis was associated with an increase of MK and RK during the acute inflammatory demyelination phase. In regions undergoing severe demyelination, namely the body and splenium of the corpus callosum, DT-derived metrics, notably the mean diffusion (MD) and radial diffusion (RD), were among the best discriminators between cuprizone and control groups, hence highlighting their ability to detect both acute and long lasting changes. Interestingly, WMTI-derived metrics showed the aptitude to distinguish between the different stages of the disease. Both the intra-axonal diffusivity (Da) and the AWF were found to be decreased in the cuprizone treated group, Da specifically decreased during the acute inflammatory demyelinating phase whereas the AWF decrease was associated to the spontaneous remyelination and the recovery period. Altogether our results demonstrate that DKI is sensitive to alterations of cortical areas and provides, along with WMTI metrics, information that is complementary to DT-derived metrics for the characterization of demyelination in both white and grey matter and subsequent inflammatory processes associated with a demyelinating event.

[The type of agent auto-intoxication and the degree of suicidal intent]. / Type geneesmiddel en suïcidale intentie na auto-intoxicatie.

BACKGROUND: The type of the agent used for auto-intoxication may increase or decrease the degree of suicidal intent. AIM: To find out whether the type of agent used for auto-intoxication is linked to the degree of suicidal intent at the moment when a patient is given a psychiatric assessment in a general hospital. METHOD: We studied the files of 211 patients who had been assessed following auto-intoxication. The files provided us with information about the type of agent used, the suicidal intent of the patient at the time and about other recent, relevant risk factors. RESULTS: At the time of the assessment, benzodiazepines were the only auto-intoxication agents used which seemed to predict suicidal intent. CONCLUSION: Although the results need to be verified in further studies, it can be concluded that auto-intoxication induced only by benzodiazepines can be seen as a serious expression of an individual's wish to die.

Repeated oral esketamine in patients with treatment resistant depression and comorbid posttraumatic stress disorder.

Introduction: Ketamine and its S-enantiomer esketamine are novel pharmacotherapeutic options for treatment resistant depression (TRD). There is growing evidence on the efficacy for other psychiatric disorders, including posttraumatic stress disorder (PTSD). It is hypothesized that psychotherapy may further potentiate the effects of (es)ketamine in psychiatric disorders. Methods: Repeated oral esketamine was prescribed once or twice weekly in five patients suffering from TRD and comorbid PTSD. We describe the clinical effects of esketamine and report data from psychometric instruments and patients' perspectives. Results: Esketamine treatment duration ranged from six weeks to a year. In four patients, we observed improvement in depressive symptoms, increased resilience and more receptiveness to psychotherapy. One patient experienced symptom worsening in response to a threatening situation during esketamine treatment, highlighting the need for a safe setting. Discussion: (Es)ketamine treatment within a psychotherapeutic framework appears promising in patients with treatment resistant symptoms of depression and PTSD. Controlled trials are warranted to validate these results and to elucidate the optimal treatment methods.

Randomized clinical trial of ultrasound-guided foam sclerotherapy versus surgery for the incompetent great saphenous vein.

BACKGROUND: New minimally invasive treatment modalities, such as ultrasound-guided foam sclerotherapy (UGFS), are becoming more popular. In a multicentre randomized controlled non-inferiority trial, the effectiveness and costs of UGFS and surgery for treatment of the incompetent great saphenous vein (GSV) were compared. METHODS: Patients with primary great saphenous varicose veins were assigned randomly to either UGFS or surgical stripping with high ligation. Recurrence, defined as reflux combined with venous symptoms, was determined on colour duplex scans at baseline, 3 months, 1 year and 2 years after initial treatment. Secondary outcomes were presence of recurrent reflux (irrespective of symptoms), reduction of symptoms, health-related quality of life (EQ-5D(™)), adverse events and direct hospital costs. RESULTS: Two hundred and thirty patients were treated by UGFS and 200 underwent GSV stripping. The 2-year probability of recurrence was similar in the UGFS and surgery groups: 11·3 per cent (24 of 213) and 9·0 per cent (16 of 177) respectively (P = 0·407). At 2 years, reflux irrespective of venous symptoms was significantly more frequent in the UGFS group (35·0 per cent) than in the surgery group (21·0 per cent) (P = 0·003). Mean(s.d.) hospital costs per patient over 2 years were €774(344) per patient for UGFS and €1824(141) for stripping. CONCLUSION: At 2-year follow-up, UGFS was not inferior to surgery when reflux associated with venous symptoms was the clinical outcome of interest. UGFS has the potential to be a cost-effective approach to a common health problem. Registration numbers: NCT01103258 (http://www.clinicaltrials.gov) and NTR654 (http://www.trialregister.nl).

Novel missense mutations in the FOXC2 gene alter transcriptional activity.

Mutations in the FOXC2 gene that codes for a forkhead transcription factor are associated with primary lymphedema that usually develops around puberty. Associated abnormalities include distichiasis and, very frequently, superficial and deep venous insufficiency. Most mutations reported so far either truncate the protein or are missense mutations in the forkhead domain causing a loss of function. The haplo-insufficient state is associated with lymphatic hyperplasia in mice as well as in humans. We analyzed the FOXC2 gene in 288 patients with primary lymphedema and found 11 pathogenic mutations, of which 9 are novel. Of those, 5 were novel missense mutations of which 4 were located outside of the forkhead domain. To examine their pathogenic potential we performed a transactivation assay using a luciferase reporter construct driven by FOXC1 response elements. We found that the mutations outside the forkhead domain cause a gain of function as measured by luciferase activity. Patient characteristics conform to previous reports with the exception of distichiasis, which was found in only 2 patients out of 11. FOXC2 mutations causing lymphedema-distichiasis syndrome reported thus far result in haplo-insufficiency and lead to lymphatic hyperplasia. Our results suggest that gain-of-function mutations may also cause lymphedema. One would expect that in this case, lymphatic hypoplasia would be the underlying abnormality. Patients with activating mutations might present with Meige disease.

Erysipelas as a sign of subclinical primary lymphoedema: a prospective quantitative scintigraphic study of 40 patients with unilateral erysipelas of the leg.

BACKGROUND: Erysipelas is a common skin infection that is usually caused by beta-haemolytic group A streptococci. After having had erysipelas in an extremity, a significant percentage of patients develops persistent swelling or suffers from recurrent erysipelas. We hypothesize that in cases of erysipelas without a clear precipitating agent, subclinical pre-existing congenital or acquired disturbances in the function of the lymphatic system are present. The persistent swelling after erysipelas is then most likely caused by lymphoedema. OBJECTIVES: We designed a study to examine if erysipelas of unknown origin is associated with a pre-existent insufficiency of the lymphatic system. If our hypothesis is correct, patients with erysipelas of unknown cause without previously evident lymphoedema should have evidence of disturbed lymphatic transport in the unaffected extremity. METHODS: A prospective study, in which lymphoscintigraphy of both legs was performed in patients 4 months after presenting with an episode of erysipelas only in one leg. No patient had any known risk factor for erysipelas, such as diabetes mellitus, chronic venous insufficiency or clinical signs of lymphoedema. Lymphoscintigraphy was performed in 40 patients by subcutaneous injection of Tc-99m-labelled human serum albumin in the first web space of both feet. After 30 and 120 min, quantitative and qualitative scans were performed using a computerized gamma camera. During the lymphoscintigraphy, the patients performed a standardized exercise programme. Lymph drainage was quantified as the percentage uptake of Tc-99m-labelled human serum albumin in the groin nodes at 2 h after injection. Groin uptake of < 15% is pathological; uptake between 15-20% is defined as borderline, and uptake of > 20% as normal. RESULTS: The mean +/- SD percentage uptake in the groin nodes in the affected limbs was 9.6 +/- 8.5% vs. 12.1% +/- 8.9% in the nonaffected limbs. The mean paired difference in uptake between the nonaffected vs. affected side was 2.5% (95% confidence interval 1.1-3.9%). This indicates that lymphatic drainage in the nonaffected limb was only slightly better than in the affected limb despite the infectious event in the latter. Of 33 patients with objective impairment of lymph drainage in the affected limb, 26 (79%) also had impaired lymph drainage in the nonaffected limb. Agreement in qualitative measurements between affected and nonaffected leg was less pronounced: 21 patients had abnormal qualitative results in the affected leg of whom nine also had impairment of the nonaffected leg (43%). CONCLUSIONS: Erysipelas is often presumed to be purely infectious in origin, with a high rate of recurrence and a risk of persistent swelling due to secondary lymphoedema. In this study, we show that patients presenting with a first episode of erysipelas often have signs of pre-existing lymphatic impairment in the other, clinically nonaffected, leg. This means that subclinical lymphatic dysfunction of both legs may be an important predisposing factor. Therefore, we recommend that treatment of erysipelas should focus not only on the infection but also on the lymphological aspects, and long-standing treatment for lymphoedema is essential in order to prevent recurrence of erysipelas and aggravation of the pre-existing lymphatic impairment. Our study may change the clinical and therapeutic approach to erysipelas as well as our understanding of its aetiology.

[A verrucous plaque on the lower leg]. / Een wratachtige afwijking op het onderbeen.

A 10-year-old boy presented with an asymptomatic, congenital, dark brown coloured, well circumscribed, verrucous, hyperkeratotic plaque on his left leg. This was diagnosed as verrucous haemangioma.

[Aggression and restlessness following baclofen overdose: the narrow line between intoxication and withdrawal symptoms]. / Agressie en onrust na overdosis baclofen.

BACKGROUND: Baclofen is increasingly prescribed for alcohol dependency. Subsequently, the risk of self-intoxication with this medicinal product is increasing. CASE DESCRIPTION: A 23-year-old man with a history of alcohol dependence was admitted to our hospital after self-intoxication with 2700 mg baclofen and 330 mg mirtazapine. Respiratory insufficiency as a result of the baclofen intoxication required intubation and admission to the ICU. During the first day, despite the use of sedatives, the patient became intermittently agitated and aggressive. In the following days, he developed severe delirium, probably due to baclofen withdrawal. The reintroduction of baclofen quickly resolved these symptoms. CONCLUSION: In the case of baclofen, in practice it is difficult to differentiate between intoxication and withdrawal. To prevent potentially severe withdrawal symptoms, we recommend reintroduction of baclofen when the first signs of restlessness and agitation arise following intoxication.

Comparison of unsupervised classification methods for brain tumor segmentation using multi-parametric MRI.

Tumor segmentation is a particularly challenging task in high-grade gliomas (HGGs), as they are among the most heterogeneous tumors in oncology. An accurate delineation of the lesion and its main subcomponents contributes to optimal treatment planning, prognosis and follow-up. Conventional MRI (cMRI) is the imaging modality of choice for manual segmentation, and is also considered in the vast majority of automated segmentation studies. Advanced MRI modalities such as perfusion-weighted imaging (PWI), diffusion-weighted imaging (DWI) and magnetic resonance spectroscopic imaging (MRSI) have already shown their added value in tumor tissue characterization, hence there have been recent suggestions of combining different MRI modalities into a multi-parametric MRI (MP-MRI) approach for brain tumor segmentation. In this paper, we compare the performance of several unsupervised classification methods for HGG segmentation based on MP-MRI data including cMRI, DWI, MRSI and PWI. Two independent MP-MRI datasets with a different acquisition protocol were available from different hospitals. We demonstrate that a hierarchical non-negative matrix factorization variant which was previously introduced for MP-MRI tumor segmentation gives the best performance in terms of mean Dice-scores for the pathologic tissue classes on both datasets.

A novel pyrroleninone cross-link from bovine dentine.

The aim was to identify suspect collagen cross-links in dentine, eluting close to known cross-links in ion-exchange HPLC. Bovine tooth roots as source of dentine were powdered, demineralised, reduced, and acid-hydrolysed. Cross-linking amino acids were isolated from the acid hydrolysate by size exclusion, adsorption, and sequential ion exchange chromatography. In addition to dihydroxylysinonorleucine and hydroxylysylpyridinoline, an unknown cross-link was isolated (V-2). The ultraviolet, mass, and nuclear magnetic resonance spectra support the proposed structure of V-2, a trimeric amino acid with a pyrroleninone nucleus.

Dialysis-solid-phase extraction combined on-line with non-aqueous capillary electrophoresis for improved detectability of tricyclic antidepressants in biological samples.

Dialysis-solid-phase extraction (SPE) sample pretreatment is combined on-line with non-aqueous capillary electrophoresis for the determination of tricyclic antidepressants in urine and serum. After clean-up and enrichment, the water is removed from the sample matrix and the analytes are eluted from the cartridge by means of an organic solvent. Next, the eluate is transported to the capillary and the injection is performed electrokinetically. This injection, which does not suffer from an adverse sample matrix effect because of the SPE step, results in further analyte concentration. The detection limits are in the 0.02-0.1 microg/ml range and the day-to-day repeatabilities are between 2.5 and 9.5%, which is quite satisfactory.