RET proto-oncogene encodes a receptor tyrosine kinase whose ligand is glial cell line-derived neurotrophic factor (GDNF), and its polymorphism at G691S juxtamembrane region (RETp) is a germline polymorphism. Cutaneous melanomas, particularly the desmoplastic subtype, are highly neurotropic; thus we sought to determine the frequency of RETp in cutaneous melanoma and its functional responsiveness to GDNF. RETp was assessed in 71 non-desmoplastic cutaneous melanomas (non-DMs) and 70 desmoplastic melanomas (DMs). Melanoma cell lines with RETp, RET wild-type (RETwt), BRAF V600E mutation (BRAFmt) or BRAF wild-type (BRAFwt) were assessed for functional activity. RETp frequency was significantly higher in DMs (61%) than in non-DMs (31%, P<0.001). BRAFmt was detected in only 11% of DMs. GDNF stimulation significantly amplified cell proliferation, migration, and invasion in RETp, but not in RETwt melanoma cells. GDNF stimulation of RETp cell lines enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt of the RET-RAS-RAF-ERK and RET-phosphatidylinositol 3-kinase (PI3K)-Akt pathways, respectively. GDNF response of RETp cells in signal transduction and other functional studies were not affected by BRAFmt. The study demonstrates that RETp are frequently found in cutaneous melanoma, particularly desmoplastic subtypes, and responds to GDNF inducing events favorable for tumor progression.
Bacillus cereus is a growing concern as a cause of life-threatening infections in patients with hematologic malignancies. However, the risk factors for patients with unfavorable outcomes have not been fully elucidated. At our institution, we observed the growth of B. cereus in blood culture in 68 patients with (23) or without (45) hematologic malignancies treated from September 2002 to November 2009. We defined a case as having sepsis when more than two blood culture sets were positive for B. cereus or only a single set was positive in the absence of other microorganisms in patients who had definite infectious lesions. We determined 12 of 23 patients with hematologic malignancies as having sepsis, as well as 10 of 45 patients without hematologic malignancies (p = 0.012). Of the 12 patients with hematologic malignancies, four patients with acute leukemia died of B. cereus sepsis within a few days. In our cohort, risk factor analysis demonstrated that a neutrophil count of 0/mm(3), central venous (CV) catheter insertion, and the presence of central nervous system (CNS) symptoms were significantly associated with a fatal prognosis (p = 0.010, 0.010, and 0.010, respectively). Analysis of data from our cohort in conjunction with those from 46 previously reported patients with B. cereus sepsis identified similar risk factors, that is, acute leukemia, extremely low neutrophil count, and CNS symptoms (p = 0.044, 0.004, and 0.002, respectively). These results indicate that appropriate prophylaxis and early therapeutic intervention against possible B. cereus sepsis are crucially important in the treatment of hematologic malignancies.
A 64-year-old woman suffering from progressive amyloid A (AA) amyloidosis of the gastrointestinal (GI) tract, associated with active rheumatoid arthritis, was transferred to our hospital due to hypovolemic shock. Although intensive care, including treatment with prednisolone and methotrexate, improved the hypovolemic shock, paralytic ileus became dominant instead of the marked diarrhea, suggesting the terminal stage of AA amyloidosis of the GI tract. Thus, we administered tocilizumab, a humanized anti-interleukin 6 receptor antibody (8 mg/kg, repeated every 4 weeks). Two weeks after the first injection of tocilizumab, serum AA rapidly returned to their normal ranges in accordance with the amelioration of paralytic ileus and systemic joint pain. Surprisingly, after three courses of tocilizumab treatment, colon biopsy revealed no amyloid deposition. Tocilizumab is a promising agent to treat secondary AA amyloidosis by strongly suppressing serum AA levels.
The prognosis of follicular lymphoma (FL) is significantly associated with host immunity and tumor microenvironment. Lymphopenia has been identified as a negative prognostic factor for FL. The association between monocytosis and progression-free survival (PFS) in FL remains controversial. It is unknown whether the ratio of peripheral blood absolute lymphocyte count to absolute monocyte count (ALC/AMC) at diagnosis is associated with FL prognosis. We studied 99 consecutive patients with FL who were treated with rituximab-containing chemotherapy at Kitano Hospital or Kyoto University Hospital between 2000 and 2012. We analyzed individual variables associated with the ALC/AMC ratio before treatment, as well as known prognostic factors of FL, and found that an ALC/AMC ratio of 4.7 was the best cut-off value for PFS. Kaplan-Meier analysis showed that a decreased ALC/AMC ratio was associated with inferior PFS (P = 0.022). Multivariate analysis showed that a decreased ALC/AMC ratio was a significant poor prognostic factor independent of other variables (hazard ratio, 2.714; 95 % confidence interval, 1.060-6.948; P = 0.037). The ALC/AMC ratio before treatment may be a significant prognostic factor predicting PFS of FL.
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