MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

MYC alterations influence the survival of patients with diffuse large B-cell lymphoma. Most studies have focused on MYC translocations but there is little information regarding the impact of numerical alterations and protein expression. We analyzed the genetic alterations and protein expression of MYC, BCL2, BCL6, and MALT1 in 219 cases of diffuse large B-cell lymphoma. MYC rearrangement occurred as the sole abnormality (MYC single-hit) in 3% of cases, MYC and concurrent BCL2 and/or BCL6 rearrangements (MYC double/triple-hit) in 4%, MYC amplifications in 2% and MYC gains in 19%. MYC single-hit, MYC double/triple-hit and MYC amplifications, but not MYC gains or other gene rearrangements, were associated with unfavorable progression-free survival and overall survival. MYC protein expression, evaluated using computerized image analysis, captured the unfavorable prognosis of MYC translocations/amplifications and identified an additional subset of patients without gene alterations but with similar poor prognosis. Patients with tumors expressing both MYC/BCL2 had the worst prognosis, whereas those with double-negative tumors had the best outcome. High MYC expression was associated with shorter overall survival irrespectively of the International Prognostic Index and BCL2 expression. In conclusion, MYC protein expression identifies a subset of diffuse large B-cell lymphoma with very poor prognosis independently of gene alterations and other prognostic parameters.     

Burden of osteoporotic fractures in primary health care in Catalonia (Spain): a population-based study

ABSTRACT: BACKGROUND: Knowledge on the epidemiology of non-hip fractures in Spain is limited and somewhat outdated. Using computerized primary care records from the SIDIAP database, we derived age and sex-specific fracture incidence rates for the region of Catalonia during the year 2009. METHODS: The SIDIAP database contains quality-checked clinical information from computerized medical records of a representative sample of >5,800,000 patients (80% of the population of Catalonia). We conducted a retrospective cohort study including all patients aged [greater than or equal to]50 years, and followed them from January 1 to December 31, 2009. Major osteoporotic fractures registered in SIDIAP were ascertained using ICD-10 codes and validated by comparing data to hospital admission and patient-reported fractures records. Incidence rates and 95% confidence intervals were calculated. RESULTS: In total, 2,011,430 subjects were studied (54.6% women). Overall fracture rates were 10.91/1,000 person-years (py) [95%CI 10.89-10.92]: 15.18/1,000 py [15.15-15.21] in women and 5.78/1,000 py [5.76-5.79] in men. The most common fracture among women was wrist/forearm (3.86/1,000 py [3.74-3.98]), while among men it was clinical spine (1.25/1,000 py [1.18-1.33]). All fracture rates increased with age, but varying patterns were observed: while most of the fractures (hip, proximal humerus, clinical spine and pelvis) increased continuously with age, wrist and multiple rib fractures peaked at age 75-80 and then reached a plateau. CONCLUSIONS: Our study provides local estimates of age, sex and site-specific fracture burden in primary health care, which will be helpful for health-care planning and delivery. A proportion of fractures are not reported in primary care records, leading to underestimation of fracture incidence rates in these data.     

Phase II trial of temozolomide in patients with pretreated cutaneous T-cell lymphoma

Between July 2003 and March 2004, nine patients with pretreated mycosis fungoides were enrolled into a phase II trial and were treated with temozolomide. The overall response rate was 33%. Further studies are needed to test the efficacy of temozolomide, alone or in combination in earlier stages of this disease.     

Liver mitochondrial function in familial amyloidotic polyneuropathy

The objective of the present study was to analyze hepatic mitochondrial function in patients with familial amyloidotic polyneuropathy (FAP) undergoing cadaveric donor orthotopic liver transplantation. From February 2005 to May 2007, eight patients with FAP, ranging in age from 34 to 41 years and with Model for End-Stage Liver Disease scores ranging from 24 to 29. Underwent orthotopic transplantation using a liver from a deceased donor by the piggyback method. Immediately before beginning the recipient hepatectomy in a patient with FAP, a biopsy was obtained for analysis of mitochondrial function (FAP group). The control group consisted of 15 patients undergoing hepatic surgery to treat small tumors of the liver. Mitochondrial respiration was determined on the basis of oxygen consumption by energized mitochondria using a polarographic method. The membrane potential of the mitochondria was determined spectrofluorometrically. Data were analyzed statistically by the Mann-Whitney test, with the level of significance set at 5%. State 3 and 4 values, respiratory control ratio, and membrane potential were 47 +/- 8 versus 28 +/- 10 natoms O/min/mg protein (P < .05); 14 +/- 3 vs 17 +/- 7 nat.O/min/mg.prot.mit. (P > .05); 3.6 +/- .5 vs 1.7 +/- 0.7 (P < .05); and 135 +/- 5.2 vs 135 +/- 6 mV (P > .05) for control versus FAP patients, respectively, demonstrating a decreased energy status of the liver in FAP.     

Natural history of complex fractures of the proximal humerus using a three-dimensional classification system

We studied the nonoperative treatment of proximal humeral fractures in severe injuries usually treated surgically. The natural history of 63 patients was followed prospectively for 2 to 9 years (mean, 42 months) with a nonrandomized protocol. A 3-dimensional classification system based on computed tomography scans was used to categorize the fractures. Assessment was made for range of motion, function via a validated testing instrument (Simple Shoulder Test), analog pain score, avascular necrosis (AVN), and fracture union. Magnetic resonance imaging for early signs of AVN was done in 16 cases. After conservative treatment of complex fractures of the shoulder, motion is considerably compromised but pain is minimal and functional status is acceptable to most individuals in this predominantly older patient population. Status comparable to a successful surgical shoulder fusion is achieved in most cases-Nature's fusion. Contrary to common belief, AVN, even in severely displaced injuries, is rare. Future randomized studies based on a 3-dimensional classification need to be done to compare these natural history results with various types of surgical interventions.     

Interleukin-21 (IL-21) controls inflammatory pathways in the gut

In both Crohn's disease (CD) and ulcerative colitis (UC), the major forms of inflammatory bowel diseases (IBD) in humans, the pathologic process consists of an aberrant local immune response to components of the bacterial microflora, due to abnormally strong effector cell activity that is poorly controlled by counter-regulatory mechanisms. There is also evidence that mucosal immune cells actively interact with non-immune cells to promote tissue damage, and that cytokines are essential mediators of this cross-talk. Interleukin-21 (IL-21), the latest member of the common gamma-chain-dependent cytokine family, is a product of activated CD4+ T cells and natural killer T cells. IL-21 is produced in excess in CD tissue, where it helps sustain the ongoing Th1 inflammation. High IL-21 production occurs also in the inflamed colon of most patients with UC, a disease that is not associated with a marked Th1 cell response. This suggests that, in the gut, IL-21 can modulate additional inflammatory pathways other than enhancing Th1 cell immunity. Indeed, IL-21 stimulates the secretion of extracellular matrix degrading enzymes by fibroblasts, and of the T cell chemoattractant, MIP-3 alpha, by epithelial cells. These data collectively indicate that IL-21 is a mediator of the chronic inflammatory response in CD and UC, and suggest that IL-21 may be an emerging therapeutic target in IBD.     

RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis

Paracrine signaling through receptor activator of NF-κB (RANK) pathway mediates the expansion of mammary epithelia that occurs during pregnancy, and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and show that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation, including mammary gland reconstitution, epithelial-mesenchymal transition (EMT), increased migration, and anchorage-independent growth. In addition, spheroids of RANK overexpressing MCF10A cells display disrupted acinar formation, impair growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with nonfunctional BRCA1 enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathologic grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings show that RANK promotes tumor initiation, progression, and metastasis in human mammary epithelial cells by increasing the population of CD44(+)CD24(-) cells, inducing stemness and EMT. These results suggest that RANK expression in primary breast cancer associates with poor prognosis.     

VNCOP-B plus rituximab in the treatment of diffuse large B-cell lymphoma in the elderly

The conventional treatment included CHOP and several age-adapted regimens, from first to third generation, designed and tested for their feasibility and efficacy in elderly patients. Recently, some trials demonstrated that CHOP-rituximab was superior to CHOP alone. Between February 2003 and November 2005, 24 untreated patients 60 years and older with DLBCL were treated with a combination therapy including cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (VNCOP-B) plus four rituximab administrations. Nineteen of the 24 patients (80%) obtained a CR, four achieved a PR, and the remaining patient had a disease progression. The overall response rate was 96%. Sixteen of the 19 complete responders remain in continuous CR at a median of 24 months (range 12 - 42). Three CRs relapsed within 12 months from the completion of treatment. Clinical and hematological toxicity was moderate. This regimen was effective in inducing a good remission rate with moderate toxic effects in elderly DLBCL patients.