A national study on conditional survival,excess mortality and second cancer after high dose therapy with autologous stem cell transplantation for non‐Hodgkin lymphoma

This national population‐based study aimed to investigate conditional survival and standardized mortality ratios (SMR) after high‐dose therapy with autologous stem‐cell transplantation (HDT‐ASCT) for non‐Hodgkin lymphoma (NHL), and to analyse cause of death, relapses and second malignancies. All patients ≥18 years treated with HDT‐ASCT for NHL in Norway between 1987 and 2008 were included (n = 578). Information from the Cause of Death Registry and Cancer Registry of Norway were linked with clinical data. The 5‐, 10‐ and 20‐year overall survival was 61% (95% confidence interval [CI] 56–64%), 52% (95%CI 48–56%) and 45% (95%CI 40–50%), respectively. The 5‐year survival conditional on having survived 2, 5 and 10 years after HDT‐ASCT was 81%, 86% and 93%. SMRs were 12·3 (95%CI 11·0–13·9), 4·9 (95%CI 4·1–5·9), 2·4 (95%CI 1·8–3·2) and 1·0 (95%CI 0·6–1·8) for the entire cohort and for patients having survived 2, 5 and 10 years after HDT‐ASCT respectively. Of the 281 deaths observed, 77% were relapse‐related. Treatment‐related mortality was 3·6%. The 10‐year cumulative incidence of second malignancies was 7·9% and standardized incidence ratio was 2·0 (95%CI 1·5–2·6). NHL patients treated with HDT‐ASCT were at increased risk of second cancer and premature death. The mortality was still elevated at 5 years, but after 10 years mortality equalled that of the general population.     

Air transport of the sick newborn infant: audit from a sparsely populated county in Norway

The aim of this study was to describe principal problems and to analyse transport times, stabilizing procedures, adverse events during transfer, outcome, effectiveness and the care of infants transferred by air from district general hospitals and maternity homes to a central hospital. Transfer times, equipment adverse events and clinical deterioration were recorded as they occurred. Data regarding clinical problems, diagnoses and outcome were collected retrospectively from hospital records. During the study period (1984-95) 275 infants (267 transports) were transferred by fixed-wing aircraft (233) or helicopter (34). Median time from request of transfer to arrival of the transport team (usually a neonatal nurse and a paediatrician) was 120 min, median stabilizing time 60 min. Ninety-six infants (35%) were intubated, 62 (22.5%) by the transport team. During 34 transports (12.7%), equipment-related adverse events occurred making six infants worse. Ten more infants deteriorated during transit. A significant correlation between birthweight and after-transfer temperature was recorded. After-transfer temperature for very low birthweight (<1500 g, VLBW) infants was significantly higher when the transport team attended the delivery than when they did not (35.9 degrees C vs 34.7 degrees C). All nine infants (3.2%) with after-transfer temperature <34.0 degrees C died, 15 infants (5.5%) died within 24 h after transfer and 20 (7.3%) died later. Adjusted OR for death among transported versus in utero transferred VLBW infants was 3.8 (1.4-10.4). Every effort should be taken to transfer VLBW infants in utero. If preterm deliveries at 26-28 weeks of gestation at district general hospitals is unavoidable, an early request for the neonatal transport team to be there at delivery is advisable. Transport of very immature infants <26 weeks gestational age is not recommended. An outreach educational program ("Team Pink Newborn") has been created. Staff training to combat hypothermia and regular inspection and control of the transport equipment by three neonatal intensive care nurses has now been implemented.     

Absence of microdeletions in the Y chromosome in patients with a history of cryptorchidism and azoospermia or oligospermia

OBJECTIVE: To determine if cryptorchidism is associated with microdeletions of interval 6 of the Y chromosome, we evaluated this locus in men with a history of cryptorchidism with and without azoospermia or oligospermia and in a control group. DESIGN: Clinical study. SETTING: Academic research environment. PATIENT(S): Men in whom surgical treatment of cryptorchidism had been performed in childhood and healthy control male subjects. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotyping of interval 6 of the Y chromosome. RESULT(S): Analysis of semen obtained from men treated for cryptorchidism in childhood showed azoospermia or oligospermia in 14 of 38 (37%) men. No microdeletions were identified with polymerase chain reaction amplification of 17 distinct sequence tagged sites located on the long arm of the Y chromosome and the sex determining region on Y (SRY) gene. CONCLUSION(S): Microdeletions of interval 6 of the Y chromosome were not detected in either the formerly cryptorchid or in the healthy subjects. Although we cannot exclude the possibility of point mutations, we conclude that cryptorchidism or cryptorchidism associated with azoospermia or oligospermia is not due to microdeletions involving interval 6 of the Y chromosome.     

Role dilemmas among health-workers in cross-cultural patient encounters around dietary advice

AIM: The aim of this paper is to explore Norwegian health workers' experiences from cross-cultural patient encounters, and how they understand and enact their role when meeting patients with Pakistani background to whom they give dietary advice related to type 2 diabetes. METHODS: Qualitative in-depth interviews have been performed with six hospital dietitians and six general practitioners in Oslo. RESULTS: The health workers consider themselves to be patient-centred and stress the importance of the two dimensions, empathy and equality. However, they often experience that patients want them to be more authoritarian, a way of acting that would be totally in disagreement with their convictions, although some occasionally do adopt an authoritarian style. More striking is that some health workers' moral engagement to involve and empower patients actually leads them to be authoritarian. For others, a fear of insulting the patient results in their advice being too diffuse. CONCLUSIONS: A possible explanation for such ways of responding to the patient may be that the health workers, in their articulation of patient-centredness, draw on a repertoire of social conduct that involves an effort to level out, or tacitly deny, hierarchic structures, and that this becomes more pronounced in cross-cultural encounters. Patient-centredness and empowerment are results of long ongoing processes in Western countries, based on ideals of equality and individual freedom. The results from this study indicate that these approaches may pose intricate dilemmas for the health workers in their cross-cultural encounters, and need further attention.     

No association between body mass index and beta(3)-adrenergic receptor variant (W64R) in children with premature pubarche and adolescent girls with hyperandrogenism

OBJECTIVE: To determine if the Trp(64)Arg (W64R) variant of the beta(3)-adrenergic receptor (ADRB3) could be used as a genetic marker to define risk for polycystic ovary syndrom (PCOS) and/or obesity in children and adolescents. DESIGN: Association study. SETTING: Academic research environment. PATIENT(s): Children referred for evaluation of premature pubic hair (n = 63), adolescent girls referred for evaluation of hirsutism and/or oligomenorrhea (n = 33), and healthy adult controls (n = 67). INTERVENTION(s): None. MAIN OUTCOME MEASURE(s): Relationship of body mass index (BMI) to presence or absence of W64R variant and frequency of W64R variant in our patient population. RESULT(s): Body mass index (kg/m(2)) was determined for 63 children (55 girls and 8 boys) and 33 adolescent girls. Presence or absence of the W64R variant was assayed by polymerase chain reaction (PCR) amplification followed by allele-specific restriction fragment digest. Twelve subjects and 11 healthy controls were found to be heterozygous for the W64R variant. One subject was found to be homozygous for the W64R variant. Allele frequency for the W64R variant was comparable between patients and controls. Among the patients, mean BMI values were not different between carriers and noncarriers. CONCLUSION(s): Although other studies suggest that the W64R variant is associated with the development of obesity and insulin resistance, we cannot demonstrate that it has a major effect on BMI in children with premature pubarche or in adolescent girls with hyperandrogenism. Serial observations are necessary to determine if this variant predicts the development of obesity and/or PCOS in adulthood.     

Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-escalating induction and introducing temozolomide maintenance: results from a phase II study by The Nordic Lymphoma Group

The Nordic Lymphoma Group has conducted a phase ll trial in newly diagnosed primary central nervous system lymphoma patients applying an age-adjusted multi-agent immunochemotherapy regimen, which in elderly patients included temozolomide maintenance treatment. Patients aged 18–75 years were eligible. Thirty-nine patients aged 18–65 years and 27 patients aged 66–75 years were enrolled. The median age of the two age groups was 55 and 70 years, respectively. The overall response rate was 73.8% for the entire cohort: 69.9% in the younger and 80.8% in the elderly subgroup. With a median follow up of 22 months, the 2-year overall survival probability was 60.7% in patients aged 65 years or under and 55.6% in patients aged over 65 years (P=0.40). The estimated progression-free survival at two years was 33.1% (95%CI: 19.1%–47.9%) in patients aged under 65 years and 44.4% (95%CI: 25.6%–61.8%) in the elderly subgroup (P=0.74). Median duration of response was ten months in the younger subgroup, and not reached in the elderly patient subgroup (P=0.33). Four patients aged 64–75 years (6%) died from treatment-related complications. Survival in the two age groups was similar despite a de-escalation of induction treatment in patients aged over 65 years. Duration of response in elderly patients receiving maintenance temozolomide was longer than in the younger age subgroup. While toxicity during induction is still of concern, especially in the elderly patients, we conclude from these data that de-escalation of induction therapy in elderly primary central nervous system lymphoma patients followed by maintenance treatment seems to be a promising treatment strategy. (clinicaltrials.gov identifier:01458730)     

c‐Met signaling promotes IL‐6‐induced myeloma cell proliferation

Objectives: Hepatocyte growth factor (HGF) is a constituent of the myeloma microenvironment and is elevated in sera from myeloma patients compared to healthy individuals. Increased levels of serum HGF predict a poor prognosis. It has previously been shown by us and others HGF can act as a growth factor to myeloma cells in vitro although these effects have been moderate. We therefore wanted to investigate if HGF could influence the effects of interleukin (IL)‐6. Methods: Myeloma cell lines and primary samples were tested for the combined effects of IL‐6 and HGF in inducing DNA synthesis and migration. Expression levels of c‐Met protein were analysed by Western blotting and flow cytometry. Signaling pathways were examined by Western blotting using phosphospecific antibodies and a Ras‐GTP pull down assay. Results: HGF potentiated IL‐6‐induced growth in human myeloma cell lines and in purified primary myeloma cells. There was also cooperation between HGF and IL‐6 in induction of migration. There seemed to be two explanations for this synergy. IL‐6‐treatment increased the expression of c‐Met making cells HGF responsive, and IL‐6 was dependent on c‐Met signaling in activating both Ras and p44/42 MAPK by a mechanism involving the tyrosine phosphatase Shp2. Conclusions: The results indicate that besides from being a myeloma growth factor alone, HGF can also potentiate the effects of IL‐6 in myeloma proliferation and migration. Thus, c‐Met signaling could be a target for therapy of multiple myeloma.     

Immunohistochemical analysis of hepatocyte growth factor and c-Met in plasma cell disease

Wader K F, Fagerli U‐M, Børset M, Lydersen S, Hov H, Sundan A, Bofin A & Waage A
(2012) Histopathology 60 ,443–451
Immunohistochemical analysis of hepatocyte growth factor and c‐Met in plasma cell disease Aims: Interaction with the bone marrow microenvironment is important for homing and survival of myeloma cells. One cytokine involved in this process is hepatocyte growth factor (HGF). HGF, by binding to the receptor tyrosine kinase c‐Met, mediates a broad range of tumour progression activities. Our aims were to investigate whether HGF and c‐Met are present in bone marrow and extramedullary tumours from patients with monoclonal plasma cell disease, and whether c‐Met is activated. Methods and results: Expression of HGF, c‐Met and phospho‐c‐Met was studied by immunohistochemistry in biopsies from 80 patients with monoclonal plasma cell disease. Cytoplasmic staining for HGF in plasma cells was demonstrated in 58 of 68 biopsies from multiple myeloma patients (85%), but also in biopsies from nine of 10 healthy individuals. Membranous staining for c‐Met was found in 25 of 63 multiple myeloma patients (40%) and in none of 10 healthy individuals. Membranous staining for phospho‐c‐Met was found in biopsies from 15 of 21 c‐Met‐positive myeloma patients (71%). Conclusions: Our data point to c‐Met expression as one of the factors that distinguishes normal from malignant plasma cells, and indicate that the HGF/c‐Met system is activated in multiple myeloma patients.     

Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells

Multiple myeloma (MM) is characterized by accumulation and dissemination of malignant plasma cells (PCs) in the bone marrow (BM). Gene expression profiling of 2 MM cell lines (OH-2 and IH-1) indicated that expression of PRL-3, a metastasis-associated tyrosine phosphatase, was induced by several mitogenic cytokines. Cytokine-driven PRL-3 expression could be shown in several myeloma cell lines at both the mRNA and protein levels. There was significantly higher expression of the PRL-3 gene in PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and myeloma than in PCs from healthy persons. Among 7 MM subgroups identified by unsupervised hierarchical cluster analysis, PRL-3 gene expression was significantly higher in the 3 groups denoted as "proliferation," "low bone disease," and "MMSET/FGFR3." PRL-3 protein was detected in 18 of 20 BM biopsies from patients with MM. Silencing of the PRL-3 gene by siRNA reduced cell migration in the MM cell line INA-6, but had no detectable effect on proliferation and cell-cycle phase distribution of the cells. In conclusion, PRL-3 is a gene product specifically expressed in malignant plasma cells and may have a role in migration of these cells.