Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high‐risk patients: the first involves the combination of 2‐chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high‐risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant‐related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3‐year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.     

Long term morbidity and health related quality of life after multi-system Langerhans cell histiocytosis

Background:Langerhans’ cell histiocytosis, a clonal multisystem disorder, can affect children or adults resulting in long term sequelae. However, the overall morbidity for survivors has not been formally determined.Patients and Methods:We performed a cross-sectional study of 40 unselected long term survivors of childhood multisystem Langerhans cell histiocytosis, involving clinical examination, health–related quality of life assessment, brain imaging, neuropsychometry, endocrine assessment, respiratory function tests and audiometry. A specific ‘morbidity score’ was devised to measure outcome.Results:Seventyfive percent of patients had detectable long term sequelae, hypothalamic-pituitary dysfunction (50%), cognitive dysfunction (20%) and cerebellar involvement (17.5%) being the most common. Half had moderate to severe morbidity, and the worst-affected patients were unable to lead an independent adult life. Health-related quality of life, which correlated well with the morbidity score (p < 0.001), was adversely affected in >50% of patients.Conclusion:Organ damage from multisystem Langerhans cell histiocytosis causes long term morbidity extending into adult life. Carefully planned, multidisciplinary follow up is essential to ensure early recognition of problems with appropriate interventions to reduce the impact on patients’ ‘quality of life’.     

Significant allelic loss of ANX7region (10q21) in hormone receptor negative breast carcinomas

Loss of heterozygosity (LOH) in the 10q21 region that harbors the tumor suppressor gene ANX7-GTPase gene have been found in 35% of prostate tumors. Therefore, the rationale for this study is that this gene could also be implicated in breast pathogenesis as well. We investigated allelic losses in microsatellites of the 10q21 region, and their correlations with ANX7 status, estrogen receptor (ER) status, progesterone receptor (PR) status, Ki-67 status and pathological phenotype in 30 breast carcinomas with matched control specimens. The LOH analysis was performed by amplifying DNA by PCR, using four markers of the 10q21 region (AFMa299ya5, AFM220xe5, AFM 063xc5, AFM200wf4). LOH in at least one marker of the 10q21 region (AFM220xe5 marker close to ANX7) was found in 66% of the first set of informative tumors containing 10 pairs of specimens. Subsequent comparison between 20 carcinomas using AFM220xe5, with and without LOH in terms of pathological parameters showed significant associations with differences in age (P=0.04), ER (P=0.05), Ki-67 (P=0.04) and PR (P=0.01); a trend toward significance was found for tumor size (P=0.06) and histological grade III (P=0.14). These results suggest that the ANX7 gene, or other genes of the 10q21 region, could be functionally related to breast cancer, probably influencing the hormone receptor expression associated with poor prognosis during development.     

Cognitive outcome of long-term survivors of multisystem langerhans cell histiocytosis: a single-institution, cross-sectional study.

PURPOSE: Damage to the CNS, including the cerebellum, and to the hypothalamopituitary axis, is documented in Langerhans cell histiocytosis (LCH). Neuropsychologic deficits have been recognized, but this is the first study in which cognitive function has been systematically assessed in a cohort of patients. PATIENTS AND METHODS: Twenty-eight long-term survivors of multisystem LCH (mean age, 15.1 years) were investigated for intelligence, memory and learning, language, and academic attainments. RESULTS: The mean intelligence quotient (IQ) of the entire group was not significantly different from the mean of the population (ie, mean +/- SD, 100 +/- 1), but there were wide ranges (Full-Scale IQ [FSIQ]: mean, 93.6; range, 61.7 to 134; Performance IQ [PIQ]: mean, 92.2; range, 46 to 136; and Verbal IQ [VIQ]: mean, 93.7; range, 64.2 to 126). CNS involvement was a significant risk factor for lower scores, but sex, diabetes insipidus, and cranial radiotherapy were not. The CNS group had lower VIQ, PIQ, and FSIQ than patients with no CNS involvement (no CNS group: mean +/- SD FSIQ, 102.3 +/- 15.6; CNS group: mean +/- SD FSIQ, 73.6 +/- 7.7; P <.001). A similar pattern of results was obtained for all other cognitive measures. Even when effects of reduction in FSIQ were taken into account, specific deficits were found in patients in the CNS group. CONCLUSION: Long-term survivors of multisystem LCH, particularly patients with CNS involvement, may develop significant cognitive deficits. All patients should have formal, repeated neuropsychologic assessment as part of long-term follow-up, which will enable abnormalities to be detected early so that appropriate supportive measures can be offered.     

Diagnostic omission errors in acute paediatric practice: impact of a reminder system on decision-making

Background  

Diagnostic error is a significant problem in specialities characterised by diagnostic uncertainty such as primary care, emergency medicine and paediatrics. Despite wide-spread availability, computerised aids have not been shown to significantly improve diagnostic decision-making in a real world environment, mainly due to the need for prolonged system consultation. In this study performed in the clinical environment, we used a Web-based diagnostic reminder system that provided rapid advice with free text data entry to examine its impact on clinicians' decisions in an acute paediatric setting during assessments characterised by diagnostic uncertainty.     

Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group

BACKGROUND: Permanent consequences (PC) are often described among subjects with Langerhans cell histiocytosis (LCH) but data on the real incidence are scarce. Within the Histiocyte Society (HS), and in order to design a definitive late effects study, a retrospective survey was organized to describe the prevalence of PC among long-term survivors of LCH. METHODS: Nine institutions contributed with their LCH patients having a minimum follow-up of 3 years. Information was collected on their disease-history, and on type and date of onset of any PC. Because of the retrospective type of this study, it was accepted that each institution might have used different criteria to assess PC. RESULTS: One hundred eighty-two subjects were registered and in 95 (52%) at least 1 PC was reported. For some specific PC (e.g., anterior pituitary dysfunction) information was too scarce to provide reliable data. PC were more frequent among subjects with multisystem (MS) disease (71%), compared to those with single system (SS) disease (24%); P < 0.0001. The most frequently reported PC were diabetes insipidus (DI) (24%) orthopedic abnormalities (20%), hearing loss (13%), and neurological consequences (11.0%). Analysis of cumulative risk showed that some types of PC may become manifest more than 10 years from diagnosis. CONCLUSIONS: This survey on selected cases of LCH survivors has confirmed that late sequels are frequent, and that they are even more common among those with MS LCH. Our findings highlight the need for long-term and patient-oriented follow-up in children with LCH.     

Intraocular Langerhans cell histiocytosis in a neonate resulting in bilateral loss of vision

Intraocular involvement in Langerhans cell histiocytosis (LCH) is rare. We describe the case of a neonate with congenital disseminated LCH involving skin, liver, spleen, and intraocular structures including uvea and retina. Early and aggressive treatment according to the LCH-II treatment protocol was administered and resulted in remission of the disease. However, despite close follow-up and additional local treatment, involvement of intraocular structures resulted in severe long-term ophthalmological sequelae including complete bilateral loss of vision.     

Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant,AR-V7, in prostate cancer cells

Metastatic prostate cancer (PCa) is primarily an androgen-dependent disease, which is treated with androgen deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain androgen receptor (AR) dependent. Numerous mechanisms for AR-dependent resistance have been identified including expression of constitutively active AR splice variants lacking the hormone-binding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether AR-V7 is simply a constitutively active substitute for AR or has novel gene targets that cause unique downstream changes is unresolved. Several studies have shown that AR activation alters cell metabolism. Using LNCaP cells with inducible expression of AR-V7 as a model system, we found that AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. However, further analyses using metabolomics and metabolic flux assays revealed several differences. Whereas AR increased citrate levels, AR-V7 reduced citrate mirroring metabolic shifts observed in CRPC patients. Flux analyses indicate that the low citrate is a result of enhanced utilization rather than a failure to synthesize citrate. Moreover, flux assays suggested that compared to AR, AR-V7 exhibits increased dependence on glutaminolysis and reductive carboxylation to produce some of the TCA (tricarboxylic acid cycle) metabolites. These findings suggest that these unique actions represent potential therapeutic targets.     

Advances in the management of histiocytic disorders 2011

Childhood histiocytoses span a range of illnesses that can present with a small skin or single bony lesion that may spontaneously regress or a systemic disease resulting in multiorgan failure and death. For practical purposes they can be classified into four groups: Langerhans cell histiocytosis (LCH), Non-Langerhans cell histiocytoses (Non-LCH), Haemophagocytic lymphohistiocytoses (HLH) and Histiocyte lineage-related malignancies. The establishment of diagnostic, staging and response criteria for LCH has enabled a series of international randomized clinical trials to be conducted that are the basis of current evidence based treatment. However, as with non-LCH, individual cases are often difficult to manage and require expert advice. Although in most cases the disease responds to treatment many children are left with significant permanent consequences commonly affecting the skeleton and endocrine system. Familial HLH is an inherited disease in which initial remission can be gained by chemotherapeutic or immunological strategies, but then requires allogeneic stem cell transplant for cure. There are a variety of leukaemias and sarcomas that are phenotypically derived from the histiocytic lineage. Treatment and outcomes for these are generally similar to those of the wider malignant spectrum.