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ABSTRACT: Oral chronic graft-versus-host disease (cGVHD) is a frequent, clinically significant sequela of allogeneic hematopoietic stem cell transplantation (HSCT). This study was designed to elucidate relationships among clinical characteristics of oral cGVHD and related oral pain and oral dryness, salivary proinflammatory cytokine interleukin (IL)-6 and IL-1alpha concentrations, and health-related quality of life (HRQL). An understanding of the characteristics and correlates of oral cGVHD manifestations and related symptoms, such as oral dryness, is fundamental to the development of therapeutic interventions. Oral cGVHD severity was assessed with the Oral Mucositis Rating Scale (OMRS). Oral pain and perceived intensity of oral dryness were self-reported via a visual analog scale and a numeric rating scale, respectively. HRQL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G). Salivary IL-1alpha and IL-6 concentrations were measured by enzyme-linked immunosorbent assay. All 42 adult subjects (59% males) had clinician-assessed oral cGVHD by the OMRS scale (mean score, 18.38 +/- 12.99; range, 2-46). Oral dryness (in 43% of subjects; mean OMRS score, 2.56 +/- 3.45; range, 0-10) was more prevalent than oral pain (8%; mean score, 0.13 +/- 0.47). Salivary IL-6 was associated with oral cGVHD severity (r = 0.49; P < .01), oral ulceration (r = 0.38; P = .04), and erythema (r = 0.63; P < .01). FACT-G total score and physical and emotional well-being subscale scores were meaningfully lower than U.S. population normative values. Participants with more severe oral cGVHD manifestations had significantly inferior social/family well being (r = -0.49; P < .01). Oral dryness was associated with higher salivary IL-1alpha (r = 0.41; P = .04) and, controlling for cGVHD severity, with lower HRQL (r = -0.41; P = .03). Subjects with moderate to severe oral dryness tended to report the poorest overall HRQL. This study provides preliminary evidence of the relationship between oral dryness and HRQL, the contribution of oral cGVHD to inferior HRQL, and the association between IL-6 and oral cGVHD severity, ulceration, and erythema. The high prevalence of oral dryness and its relationship to HRQL in a sample of subjects with oral cGVHD underscores the importance of improving our evaluation and management of this symptom in long-term survivors of allogeneic HSCT. The positive associations between IL-6 and oral cGVHD severity and erythema, as well as the positive trend with oral ulceration, warrant further exploration of this cytokine as a potential biomarker of active oral cGVHD.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2010; 16(7):948-56. · 3.15 Impact Factor
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ABSTRACT: Oral mucositis is the most common sequela of conditioning chemotherapy (CT) for hematopoietic stem cell transplantation (HSCT) and is the principal cause of most of the associated pain. Tumor necrosis factor-alpha (TNF-alpha) is a key pathogenic component of oral mucositis.
The primary purpose of this study was to describe oral mucositis-related oropharyngeal pain in the setting of HSCT. A secondary purpose was to assess the effectiveness of molecular biology methods for measuring TNF-alpha concentrations in plasma, saliva, and buccal epithelial cells in patients with oral mucositis undergoing HSCT. Methods: This descriptive, correlative study recruited subjects aged >or= 18 years who were scheduled to receive HSCT with CT. Subjects assessed their pain at baseline and 9 days (+/-24 hours) after CT using a pain visual analog scale (VAS) from 0=no pain to 10=worst possible pain, as well as word descriptors of sensory and affective pain. The extent and severity of oral mucositis were evaluated using the Oral Mucositis Assessment Scale. Saliva and blood samples and buccal brush biopsies were obtained at the same time points. Salivary and plasma TNF-alpha concentrations were measured using an enzyme-linked immunosorbent assay. Quantitative real-time polymerase chain reaction testing was used to measure buccal TNF-alpha gene expression. To determine the optimal method of RNA isolation, samples were extracted using 3 different methods: TRIzol, RNeasy, and RLT/TRIzol.
Twenty-five adult men and women (mean age, 46 years; age range, 32-68 years; 64% white) underwent HSCT with CT. Significant differences from baseline to day 9 were observed in the severity of oral mucositis (P<0.001), the overall intensity of oral pain (P<0.05), the overall intensity of oral pain with swallowing (P<0.01), the sensory dimension of oral pain with swallowing (P<0.05), and the sensory and affective dimension of oral pain with swallowing (P<0.05). The severity of oral mucositis was significantly associated with the overall intensity of oral pain (P<0.05). Although mean scores for oral pain were low, 8 subjects had clinically unacceptable pain VAS scores (>3) while receiving opioids. Fourteen subjects had measurable increases in buccal TNF-alpha RNA expression at day 9 (P=0.027 vs baseline), as measured using the TRIzol method, which was found to be the best method for measuring this variable. TNF-alpha RNA content in buccal samples was significantly associated with the worst intensity of oral pain with swallowing (partial R(2)=0.19; P<0.05).
Despite the use of opioids, oropharyngeal pain remained a treatment challenge in approximately one third of these subjects after CT with HSCT. The sensitive assay used to measure TNF-alpha gene expression in buccal cells may be useful in investigating molecular events in oral mucositis-related pain, as well as in evaluating the therapeutic response to investigational agents.
Clinical Therapeutics 01/2007; 29 Suppl:2547-61. · 2.32 Impact Factor
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ABSTRACT: Susceptibility to mouse plasmacytomagenesis is a complex genetic trait controlled by several Pctr loci (Pctr1, Pctr2, etc). Congenic strain analysis narrowed the genetic interval surrounding the Pctr2 locus, and genes identified in the interval were sequenced from susceptible BALB/c and resistant DBA/2 mice. Frap (FKBP12 rapamycin-associated protein, mTOR, RAFT) was the only gene differing in amino acid sequence between alleles that correlated with strain sensitivity to tumor development. The in vitro kinase activity of the BALB/c FRAP allele was lower than the DBA/2 allele; phosphorylation of p53 and PHAS1/4EBP1 (properties of heat and acid stability/eukaryotic initiation factor 4E-binding protein) and autophosphorylation of FRAP were less efficient with the BALB/c allele. FRAP also suppressed transformation of NIH 3T3 cells by ras, with DBA/2 FRAP being more efficient than BALB/c FRAP. Rapamycin, a specific inhibitor of FRAP, did not inhibit growth of plasmacytoma cell lines. These studies identify Frap as a candidate tumor suppressor gene, in contrast to many reports that have focused on its prooncogenic properties. Frap may be similar to Tgfb and E2f in exerting both positive and negative growth-regulatory signals, depending on the timing, pathway, or tumor system involved. The failure of rapamycin to inhibit plasma cell tumor growth suggests that FRAP antagonists may not be appropriate for the treatment of plasma cell tumors. Pctr2 joins Pctr1 in possessing alleles that modify susceptibility to plasmacytomagenesis by encoding differences in efficiency of function (efficiency alleles), rather than all-or-none, gain-of-function, or loss-of-function alleles. By analogy, human cancer may also result from the combined effects of several inefficient alleles.
Proceedings of the National Academy of Sciences 01/2004; 100(25):14982-7. · 9.68 Impact Factor
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ABSTRACT: BALB/c mice are susceptible to the development of pristane-induced plasma cell tumors, and have a rare allelic variant in the coding region of the p16(INK4a) (p16) tumor suppressor gene that produces a protein with impaired activity. We have now found that the BALB/c p16 promoter has an allelic variant that may also compromise p16 activity. Following pristane treatment, BALB/c p16 mRNA levels in B cells were lower than that in DBA/2 or C.D2-Pctr1, a resistant BALB/c congenic strain that harbors DBA/2 chromatin surrounding the p16 locus. Four sequence variants were found between BALB/c and DBA/2 in the p16 promoter region. In reporter assays, the DBA promoter was at least four times more active in driving luciferase expression than the BALB/c promoter. Most of the difference in activity was localized to a single nucleotide deletion in BALB/c. This deletion created a consensus binding site for RREB, a ras-responsive transcriptional element with zinc-finger binding motifs. Transient transfections with RREB confirmed that the p16 promoter can be downregulated by RREB, in a Ras- or Mek-dependent manner, and that the BALB/c promoter is more sensitive than DBA/2 to regulation by RREB. BALB/c mice have both regulatory and coding region defects that may contribute to the impairment of p16 gene function.
Oncogene 05/2003; 22(15):2285-95. · 6.37 Impact Factor
