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Dietary cholesterol is known to raise total and low density lipoprotein cholesterol concentrations in humans and experimental animals, but the response among individ- uals varies greatly. Here we describe a mouse strain, C57BL/ 6ByJ (B6By), that is resistant to diet-induced hypercholes- terolemia, in contrast to the phenotype seen in other com- mon strains of mice including the closely related C57BL/6J (B6J) strain. Compared to B6J, B6By mice exhibit some- what lower basal cholesterol levels on a chow diet, and show a relatively modest increase in absolute levels of total and LDL/VLDL cholesterol in response to an atherogenic diet containing 15% fat, 1.25% cholesterol, and 0.5% cholate. Correspondingly, B6By mice are also resistant to diet- induced aortic lesions, with less than 15% as many lesions as B6J. Food intake and cholesterol absorption are similar be- tween B6By and B6J mice. To investigate the gene(s) un- derlying the resistant B6By phenotype, we performed ge- netic crosses with the unrelated mouse strain, A/J. A genome-wide scan revealed a locus, designated Diet1 , on chromosome 2 near marker D2Mit117 showing highly sig- nificant linkage (lod 5 9.6) between B6By alleles and hypo- response to diet. Examination of known genes in this region suggested that this locus represents a novel gene affecting plasma lipids and atherogenesis in response to diet. — Mouzeyan, A., J. Choi, H. Allayee, X. Wang, J. Sinsheimer, J. Phan, L. W. Castellani, K. Reue, A. J. Lusis, and R. C. Davis. A locus conferring resistance to diet-induced hypercholes- terolemia and atherosclerosis on mouse chromosome 2. J. Lipid Res. 2000. 41: 573-582.

The fatty liver dystrophy (fld) mutation is manifested in abnormalities of lipid and glucose metabolism and peripheral neuropathy. To identify the gene affected by this mutation, we generated a genetic map of the fld region on chromosome 12 by the analysis of F2 offspring from an intersubspecific cross between strains BALB/cByJ-fld and CAST/EiJ. The results localize fld to the 0.42-cM interval between the microsatellite markers D12Mit170 and D12Mit184. A contig of YACs and BACs covering the nonrecombinant genomic region has been constructed and used for the identification of genes. Expressed sequence tag mapping and exon trapping identified three transcripts within the critical interval: Ctla2b, which encodes a cysteine protease inhibitor, and mouse homologs of KIAA0188 and KIAA0575, two long human transcripts of unknown function. Expression analysis revealed that Kiaa0188 is expressed in wildtype but not in fld liver, implicating this gene as a candidate for harboring the fld mutation.

We performed this study to define the incidence of radiographic retropharyngeal lymph node (RPLN) involvement in oropharyngeal cancer (OPC) and its impact on clinical outcomes, neither of which has been well established to date.Our departmental database was queried for patients irradiated for OPC between 2001 and 2007. Analyzable patients were those with imaging data available for review to determine radiographic RPLN status. Demographic, clinical, and outcome data were retrieved and analyzed.The cohort consisted of 981 patients. The median follow-up was 69 months. The base of the tongue (47%) and the tonsil (46%) were the most common primary sites. The majority of patients had stage T1 to T2 primary tumors (64%), and 94% had stage 3 to 4B disease. Intensity-modulated radiation therapy was used in 77% of patients, and systemic therapy was administered in 58% of patients. The incidence of radiographic RPLN involvement was 10% and was highest for the pharyngeal wall (23%) and lowest for the base of the tongue (6%). RPLN adenopathy correlated with several patient and tumor factors. RPLN involvement was associated with poorer 5-year outcomes on univariate analysis (P.001 for all) for local control (79% vs 92%), nodal control (80% vs 93%), recurrence-free survival (51% vs 81%), distant metastases-free survival (66% vs 89%), and overall survival (52% vs 82%) and maintained significance on multivariate analysis for local control (P = .023), recurrence-free survival (P = .001), distant metastases-free survival (P = .003), and overall survival (P = .001).In this cohort of nearly 1000 patients investigating [corrected] radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends [corrected] a negative influence on disease recurrence, distant relapse, and survival. In this cohort of nearly 1000 patients investigating radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends a negative influence on disease recurrence, distant relapse, and survival.

Purpose: Treatment planning for Head and Neck(HN) re-irradiation is a challenge because of ablative doses to target volume and strict critical structure constraints. PlanIQ(Sun Nuclear Corporation) can assess the feasibility of clinical goals and quantitatively measure plan quality. Here, we assess whether incorporation of PlanIQ in our SBRT treatment planning process can improve plan quality and planning efficiency. Methods: From 2013–2015, 35 patients (29 retrospective, 6 prospective) with recurrent HN tumors were treated with SBRT using VMAT treatment plans. The median prescription dose was 45 Gy in 5 fractions. We retrospectively reviewed the treatment plans and physician directives of our first 29 patients and generated score functions of the dosimetric goals used in our practice and obtained a baseline histogram. We then re-optimized 12 plans that had potential to further reduce organs-at-risk (OAR) doses according to PlanIQ feasibility DVH and plan quality analysis and compared them to the original plans. We applied our new PlanIQ-assisted planning process for our 6 most recently treated patients and evaluated the plan quality and planning efficiency. Results: The mean plan quality metric(PQM) and feasibility adjusted PQM(APQM) scores of our initial 29 treatment plans were 77.1±13.1 and 88.7±11.9, respectively (0–100 scale). The PQM and APQM scores for the 12 optimized plans improved from 75.9±11.0 and 85.1±10.2 to 80.7±9.3 and 90.2±8.0, respectively (p

Objectives To evaluate acute and long-term urinary morbidity after permanent prostate brachytherapy at a single tertiary care center. To minimize the risk of long-term urinary morbidity, it is important for clinicians to be able to distinguish acute urinary side effects after prostate brachytherapy from longer-term treatment-related urinary complications. Methods The medical records of 351 consecutive patients who underwent prostate brachytherapy at the MD Anderson Cancer Center between 1998 and 2006 were analyzed. To evaluate the short-term urinary side effects, the Expanded Prostate Cancer Index Composite questionnaire was administered at baseline and at 1, 4, 8, and 12 months. Long-term urinary complications were scored using a modified Radiation Therapy Oncology Group scale. Results All 4 urinary subdomain scores evaluating acute urinary side effects after treatment (bother, function, incontinence, and irritation or obstruction) had returned to baseline levels by 8 months after implantation. At 5 years, the cumulative risks of late urinary complications by grade were 8.6% for grade 1 complications, 6.5% for grade 2, 1.7% for grade 3%, and 0.5% for grade 4. The most common grade 2 late urinary complications were urethral stricture (4 patients), incontinence requiring daily pads (3 patients), and intermittent hematuria (3 patients). Grade 3 complications were urinary retention requiring self-catheterization (2 patients) and severe frequency with dysuria (2 patients). The only grade 4 event was severe hemorrhagic cystitis. Conclusions Short-term urinary side effects after prostate brachytherapy are common, follow a predictable course, and typically resolve within 1 year. Conservative management of short-term urinary side effects is recommended to minimize the risk of long-term urinary complications.

Purpose: Multi-field optimization intensity modulated proton therapy (MFO-IMPT) for oropharyngeal tumors has been established using robust planning, robust analysis, and robust optimization techniques. While there are inherent uncertainties in proton therapy treatment planning and delivery, outcome reporting are important to validate the proton treatment process. The purpose of this study is to report the first 50 oropharyngeal tumor patients treated de-novo at a single institution with MFO-IMPT. Methods: The data from the first 50 patients with squamous cell carcinoma of the oropharynx treated at MD Anderson Cancer Center from January 2011 to December 2014 on a prospective IRB approved protocol were analyzed. Outcomes were analyzed to include local, regional, and distant treatment failures. Acute and late toxicities were analyzed by CTCAE v4.0. Results: All patients were treated with definitive intent. The median follow-up time of the 50 patients was 25 months. Patients by gender were male (84%) and female (16%). The average age was 61 years. 50% of patients were never smokers and 4% were current smokers. Presentation by stage; I–1, II–0, III– 9, IVA–37 (74%), IVB–3. 88% of patients were HPV/p16+. Patients were treated to 66–70 CGE. One local failure was reported at 13 months following treatment. One neck failure was reported at 12 months. 94% of patients were alive with no evidence of disease. One patient died without evidence of disease. There were no Grade 4 or Grade 5 toxicities. Conclusion: MFO-IMPT for oropharyngeal tumors is robust and provides excellent outcomes 2 years after treatment. A randomized trial is underway to determine if proton therapy will reduce chronic late toxicities of IMRT.

6065 Background: The benefits of adding chemotherapy to radiation, combined with the ability to spare more normal tissue with conformal radiation techniques have led to an increased interest in rei...

Fatty liver is a common feature of both obesity and lipodystrophy, reflecting compromised adipose tissue function. The lipin-deficient fatty liver dystrophy (fld) mouse is an exception, as there is lipodystrophy without a fatty liver. Using a combination of indirect calorimetry and stable-isotope flux phenotyping, we determined that fld mice exhibit abnormal fuel utilization throughout the diurnal cycle, with increased glucose oxidation near the end of the fasting period and increased fatty acid oxidation during the feeding period. The mechanisms underlying these alterations include a twofold increase compared with wild-type mice in tissue glycogen storage during the fed state, a 40% reduction in hepatic glucose production in the fasted state, and a 27-fold increase in de novo fatty acid synthesis in liver during the fed state. Thus, the inability to store energy in adipose tissue in the fld mouse leads to a compensatory increase in glycogen storage for use during the fasting period and reliance upon hepatic fatty acid synthesis to provide fuel for peripheral tissues during the fed state. The increase in hepatic fatty acid synthesis and peripheral utilization provides a potential mechanism to ameliorate fatty liver in the fld that would otherwise occur as a consequence of adipose tissue dysfunction.

Lipin-alpha and -beta are the alternatively spliced gene products of the Lpin1 gene, whose product lipin is required for adipocyte differentiation. Lipin deficiency causes lipodystrophy, fatty liver, and insulin resistance in mice, whereas adipose tissue lipin overexpression results in increased adiposity but improved insulin sensitivity. To assess lipin expression and its relation to insulin resistance in humans, we examined lipin-alpha and -beta mRNA levels in subjects with normal or impaired glucose tolerance. We found higher expression levels of both lipin isoforms in lean, insulin-sensitive subjects. When compared with normal glucose-tolerant subjects, individuals with impaired glucose tolerance were more insulin resistant, demonstrated higher levels of intramyocellular lipids (IMCLs), and expressed approximately 50% lower levels of lipin-alpha and -beta. In addition, there was a strong inverse correlation between adipose tissue lipin expression and muscle IMCLs but no evidence for an increase in muscle lipid oxidation. After treatment of the impaired glucose-tolerant subjects with insulin sensitizers for 10 weeks, pioglitazone (but not metformin) resulted in a 60% increase in the insulin sensitivity index (Si) and a 32% decrease in IMCLs (both P < 0.01), along with an increase in lipin-beta (but not lipin-alpha) expression by 200% (P < 0.005). Lipin expression in skeletal muscle, however, was not related to obesity or insulin resistance. Hence, high adipose tissue lipin expression is found in insulin-sensitive subjects, and lipin-beta expression increases following treatment with pioglitazone. These results suggest that increased adipogenesis and/or lipogenesis in subcutaneous fat, mediated by the LPIN1 gene, may prevent lipotoxicity in muscle, leading to improved insulin sensitivity.

Recent studies in the mouse have demonstrated that variations in lipin expression levels in adipose tissue have marked effects on adipose tissue mass and insulin sensitivity. In the mouse, lipin deficiency prevents normal adipose tissue development, resulting in lipodystrophy and insulin resistance, whereas excess lipin levels promote fat accumulation and insulin sensitivity. Here, we investigated the effects of genetic variation in lipin levels on glucose homeostasis across species by analyzing lipin transcript levels in human and mouse adipose tissues. A strong negative correlation was observed between lipin mRNA levels and fasting glucose and insulin levels, as well as an indicator of insulin resistance (HOMA-IR), in both mice and humans. We subsequently analyzed the allelic diversity of the LPIN1 gene in dyslipidemic Finnish families, as well as in a case-control sample of obese (n = 477) and lean (n = 821) individuals. Alleles were defined by genotyping seven single nucleotide polymorphisms (SNPs) of the critical DNA region over the LPIN1 gene. Intragenic SNPs and corresponding allelic haplotypes exhibited associations with serum insulin levels and body mass index (P = 0.002-0.04). Both the expression levels in adipose tissue across species and genetic data in human study samples highlight the importance of lipin in glucose homeostasis and imply that allelic variants of this gene have significance in human metabolic traits.

We recently identified mutations in the Lpin1 (lipin) gene to be responsible for lipodystrophy in the fatty liver dystrophy (fld) mouse strain. Previous studies revealed that lipin plays a critical role in adipogenesis, explaining the adipose-deficient phenotype of the fld mouse. In the current study, we demonstrate that alternative mRNA splicing generates two lipin isoforms, lipin-alpha and lipin-beta, which are differentially expressed during adipocyte differentiation. Lipin-alpha expression peaks at day 2 of 3T3-L1 cell differentiation, after which its levels gradually decrease. In contrast, lipin-beta expression is transiently elevated at 10 h, followed by a drop to background levels at 20 h and a gradual increase between days 2 and 6 of differentiation. The two lipin isoforms also exhibit differences in subcellular localization. Lipin-alpha is predominantly nuclear, whereas lipin-beta is primarily located in the cytoplasm of 3T3-L1 adipocytes, suggesting distinct cellular functions. Using primary mouse embryonic fibroblasts expressing either lipin-alpha or lipin-beta, we demonstrate functional differences between the two isoforms. Whereas lipin-alpha is required for adipocyte differentiation, the predominant effect of lipin-beta expression is the induction of lipogenic genes. In vivo, overexpression of lipin-beta specifically in mature adipocytes leads to elevated expression of lipogenic genes and adipocyte hypertrophy, confirming a role of lipin-beta in the regulation of lipogenesis. In conclusion, our data suggest that the two lipin isoforms have distinct, but complementary, functions in adipogenesis, with lipin-alpha playing a primary role in differentiation and lipin-beta being predominantly involved in lipogenesis.

We recently identified mutations in the lipin gene, Lpin1, as the cause of lipodystrophy in the fatty liver dystrophy (fld) mouse. Here we identify impaired adipocyte differentiation as the basis for lipodystrophy in lipin-deficient mice and demonstrate that lipin is required for normal induction of the adipogenic gene transcription program. We found that the reduced adiposity in chow fed fld mice and resistance to obesity in fld mice fed a high-fat diet is associated with reduced adipogenic gene expression. Using primary mouse embryonic fibroblasts isolated from fld mice, we confirmed that lipin deficiency prevents normal lipid accumulation and induction of key adipogenic genes, including peroxisome proliferator-activated receptor (PPAR)gamma and CCAAT enhancer-binding protein (C/EBP)alpha. However, our previous studies of daily gene expression in differentiating 3T3-L1 preadipocytes indicated that lipin expression is undetectable until about day 3 of differentiation, at a point after PPARgamma and C/EBPalpha gene expression is established. This paradox was resolved by examining gene expression at 10-h intervals during 3T3-L1 cell differentiation, leading to detection of transient lipin expression at 10 h into the differentiation program, prior to the induction of PPARgamma and C/EBPalpha. Consistent with a requirement for lipin expression upstream of PPARgamma, differentiation of lipin-deficient mouse embryonic fibroblasts could be rescued by ectopic expression of PPARgamma. Thus, we conclude that lipin expression is required prior to PPARgamma during adipocyte differentiation.

The overall goal of this project was to develop reliable methods for resolving macroscopic properties important for describing the flow of one or more fluid phases in reservoirs from formation measurements. During this reporting period, the determination of surface relaxivity from NMR data was investigated. A new method for determining the surface relaxivity from measured data was developed and tested with data obtained from an Exxon sample. The new method avoids the use of a certain mathematical short-time approximation in the data analysis, which has been shown to be unsuitable.

9585 Background: Remote monitoring of patients outside of the clinic setting during critical periods of care is an emerging paradigm in oncology. CYCORE (CYberinfrastructure for COmparative effecti...

6040 Background: Local and systemic symptoms during radiation therapy (RT) may be exacerbated by dysregulated inflammation and its downstream toxic effects. Minocycline (mino) can suppress pro-infl...

The C57BL/6ByJ (B6By) mouse strain is resistant to diet-induced hypercholesterolemia and atherosclerosis, despite its near genetic identity with the atherosclerosis-susceptible C57BL/6J (B6J) strain. We previously identified a genetic locus, Diet1, which is responsible for the resistant phenotype in B6By mice. To investigate the function of Diet1, we compared mRNA expression profiles in the liver of B6By and B6J mice fed an atherogenic diet using a DNA microarray. These studies revealed elevated expression levels in B6By liver for key bile acid synthesis proteins, including cholesterol 7alpha-hydroxylase and sterol-27-hydroxylase, and the oxysterol nuclear receptor liver X receptor alpha. Expression levels for several other genes involved in bile acid metabolism were subsequently found to differ between B6By and B6J mice, including the bile acid receptor farnesoid X receptor, oxysterol 7alpha-hydroxylase, sterol-12alpha-hydroxylase, and hepatic bile acid transporters on both sinusoidal and canalicular membranes. The overall expression profile of the B6By strain suggests a higher rate of bile acid synthesis and transport in these mice. Consistent with this interpretation, fecal bile acid excretion is increased 2-fold in B6By mice, and bile acid levels in blood and urine are elevated 3- and 18-fold, respectively. Genetic analysis of serum bile acid levels revealed co-segregation with Diet1, indicating that this locus is likely responsible for both increased bile acid excretion and resistance to hypercholesterolemia in B6By mice.

Lipodystrophy and obesity are opposite ends of the spectrum of adiposity. They generally have been ascribed to changes in the expression or function of distinct sets of genes. Previous studies have shown that a deficiencyof lipin impedes the differentiation of adipocytes and causes lipodystrophy in mice. Although some forms of congenital lipodystrophy in humans result from defects in genes that are involved in adipogenesis (eg, PPARG) and in the synthesis and storage of fat (AGPAT2), it is not clear whether such genes-which act in fat tissue-an also cause obesity. The present studies were designed to assess whether lipin, which is expressed mainly in peripheral tissues, promotes obesity when present at high levels as well as lipodystrophy in its absence. Observations in 2 tissue-specific lipin transgenic mouse strains demonstrated that increased expression of lipin in either adipose tissue or skeletal muscle promotes obesity. The mice used in the studies either had enhanced lipin expression specifically in -adipose tissue (P2-lipin Tg) or were muscle-specific lipin transgenic mice (Mck-lipin Tg). Obesity developed in Tg mice that overexpressed lipin in either fat tissue or muscle. In addition to the increased fat tissue mass noted in Mck-lipin Tg mice, increased insulin sensitivity was associated with increased lipin expression, specifically in adipose tissue. Expression of fat synthesis/storage genes was not increased in fat tissue from Mck-lipin Tg mice. Lipin deficiency led to an increase in the utilization of fatty acid compared with glucose substrates for oxidation. Enhanced lipin levels in skeletal muscle had the opposite effect, decreasing fatty acid utilization. Lipin replacement in muscle tissue of lipin-deficient mice normalized energy expenditure and fuel utilization, but not the accumulation of adipose tissue. These findings indicate that modulation of lipid levels by itself is sufficient to cause marked shifts in adiposity. The result is either lipodystrophy, in the absence of lipin, or obesity secondary to enhanced lipin expression in either fat tissue or skeletal muscle. It is possible that more subtle genetic variations in lipin expression contribute to the range of adiposity seen in humans. Because lipin is expressed chiefly in peripheral tissues, where it acts, it may be a worthwhile peripheral target for treating obesity and/or lipodystrophy.

Purpose Head and neck (H&N) cancers arising in previously irradiated volumes were rarely treated with radiotherapy due to concerns of toxicity. With improved precision in planning and delivery, reirradiation has been increasingly used. We reviewed our institutional experience using IMRT in the management of previously irradiated H&N carcinoma. Materials and methods The records of 136 patients treated with IMRT reirradiation at U.T. M.D. Anderson Cancer Center for H&N cancer between 1999 and 2012 were retrospectively reviewed. Reirradiation was defined as any overlap between the two radiation treatment volumes. Severe toxicity related to reirradiation included events requiring hospitalization, urgent intervention, or death. Survival estimates were calculated using the Kaplan–Meier algorithm, excluding those patients treated with palliative intent. Results Thirty-three (24%) patients underwent surgical resection and 70 (51%) patients received chemotherapy. Twenty of these patients received radiation with palliative intent. Median time interval between initial radiation and reirradiation was 23 months. Median follow-up after reirradiation was 33 months. Median reirradiation dose was 60 Gy (range 15–70 Gy), while the median cumulative radiation dose was 120 Gy. The 2- and 5-year overall survival and locoregional control rates were 58% and 63%, and 39% and 51%, respectively. Re-treatment doses ⩾66 Gy trended towards improved LRC ( p = 0.14). Severe reirradiation related toxicity occurred in 35 patients (26%), including three treatment-related deaths. Severe toxicity did not correlate with total or re-treatment dose but was associated with retreatment volumes >150 cc. Conclusions IMRT yields promising local control and survival outcomes in select patients receiving reirradiation for H&N cancer. However, treatment related toxicity continues to be significant despite the increased conformality of IMRT over 3D conformal radiation. Alternative treatment strategies, including the possible use of stereotactic radiotherapy, to further improve conformality and thereby increase the therapeutic ratio, may be explored in the future.

Abstract 2695 Purpose: To evaluate potential differences in overall survival (OS) and progression-free survival (PFS) according to PET and CT disease status at completion of chemotherapy for patients with Diffuse Large B-cell lymphoma. Patients and Methods: Subjects were 303 patients with histologically confirmed DLBCL treated between January 2001 and December 2007; no patient received radiation therapy. We evaluated: age, sex, Ann Arbor stage, bulky disease, International Prognostic Index score, Ki-67 expression, PET standardized uptake values (SUVs), disease status after chemotherapy and at last follow-up. Results: Median age was 61 years; 149 men; 81 (27%) had stage I-II, 242 (73%) stage III-IV. A total of 248 patients (82%) completed 6–8 cycles of doxorubicin-based therapy. On multivariate analysis, both OS and PFS were significantly influenced by: the presence of PET negative residual mass on CT at completion of therapy (P < 0.001 for OS and P < 0.001 for PFS) (Figure 1); number of cycles and type of chemotherapy (P < 0.001 for OS and P < 0.001 for PFS); Combined presence (p=0.01 for OS and P=0.003 for PFS) of high Ki 67, high PET SUV, and bulky disease; and IPI score (P = 0.001 for OS and P < 0.001 for PFS). Same factors remained significant when replacing response to therapy with size of the residual mass on CT (Figure 2), or number of residual sites (Figure 3) (p Conclusion: Presence of a residual mass on CT at the completion of chemotherapy has both prognostic and predictive value in patients with DLBCL. These patients should be considered for biopsy and further consolidative therapy. Disclosures: No relevant conflicts of interest to declare.

6577 Background: Central nervous system (CNS) disease in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) is an infrequent occurrence. This study aimed to asses the cytogenetic profi...

e18512 Background: Solitary plasmacytoma is a rare plasma-cell neoplasm. We wanted to assess the outcome and prognostic factors in patients with solitary plasmacytoma. Methods: The data from 79 pat...

Abstract 4635 Purpose ABVD-based chemotherapy alone is a standard treatment for stage III Hodgkin's disease. The role for radiotherapy in this patient population remains controversial. In this study, we evaluated factors such as initially involved site or size of disease that could predict for local recurrence and thus may guide consolidative radiotherapy use and design of future prospective studies. Methods and Materials We retrospectively reviewed the medical records of 118 Stage III Hodgkin's Disease patients diagnosed and treated at the University of Texas M.D. Anderson Cancer Center from 1993-2006. We evaluated patterns of failure, site and size of initial involvement, image-verified bulky disease, and site-specific consolidative RT on rate and site of recurrence and survival. We defined local failure (LF) as failure at initial site of involvement, loco-regional failure (LRF) as any failure above the diaphragm and freedom from failure (FFF) as any failure event, including below diaphragm and extralymphatic spread. We used descriptive statistics to summarize the demographic and clinical characteristics of the patients. We used the Kaplan-Meier method to estimate LRF, FFF, disease free survival (DFS) and overall survival (OS) and comparisons of potential prognostic factors by log-rank tests. Chi-square analysis was used to compare differences in proportions for LF. Multivariate analysis was performed using Cox proportional hazards regression model to determine prognostic factors that contributed to prognosis. Results Patient demographics were: median age 36 years (range 17-78 years), female 42.9%, B symptoms 44.4%, stage “3S” 19.4%, nodular sclerosis subtype 66.4%, and mixed cellularity subtype 18.5%. Initial sites of involvement were: axilla 44.5%, head and neck (H&N) 88.2%, mediastinum 81.5%, abdomen 89.9%, pelvis 42.9%, groin 20.2%. The median follow-up for all patients was 67 months. Of the 118 patients treated at M.D. Anderson, 88% achieved a complete response (CR). Of those achieving CR, 71% received ABVD 6 cycles or more, and 37.5% received consolidative RT. After achieving CR, 14/88 (13.5%) had failures above the diaphragm, 1/88 (1.1%) failed below the diaphragm, and 1/18 (1.1%) failed on both sides of diaphragm. Further evaluation of those that failed above the diaphragm demonstrated that the most common sites of failure were H&N 9/18 (50%), mediastinum 5/18 (27.8%), and axilla 3/18 (16.7%). Patients with initial axilla involvement were more likely to exhibit failure above the diaphragm after CR when compared to those without initial axilla involvement (5-Yr LRF: 23.6% involved vs. 3.6% uninvolved, p < 0.02). The same was also true when comparing those with and without initial mediastinal involvement (5-Yr LRF: 9.5% involved vs. 0% uninvolved, p = 0.05). For those with initial H&N involvement, no significant differences in LRF were observed. We did observe higher failure rates for those with bulky H&N disease when compared to non-bulky H&N (5-Yr LRF: 35.7% bulky vs. 5.7% non-bulky, p < 0.05). The addition of mediastinal RT improved the 5-years LRF from 18% to 3.8% (p < 0.05), the 5-years FFF from 72.4% to 88.9% (p < 0.05), and 5-years DFS from 82.4% to 93% (p = 0.002). The addition of H&N RT showed a trend toward both improved LRF (5-Yr: Yes RT 0% vs. No RT 16.3%, p 0.091) and DFS (5-Yr: Yes RT 94.4% vs. No RT 86%, p = 0.068). In multivariate analysis, prognostic factors significant for increased local failure events were initial axilla and/or mediastinal involvement and bulky H&N disease. The lack of B symptoms and more than 6 cycles of ABVD were associated with improved DFS (p Conclusions For patients with stage III Hodgkin's, disease below the diaphragm appears to be well managed by chemotherapy alone (at least when 6 cycles of ABVD is given). For disease above the diaphragm, our limited study suggests that consolidative RT after CR appears to confer a benefit to those with initial axilla or mediastinal involvement, or bulky H&N disease. A randomized trial further exploring these findings would be beneficial. Disclosures: No relevant conflicts of interest to declare.

The identification of gene mutations that cause lipodystrophies, conditions characterized by a lack of normal adipose tissue, has revealed new proteins that play a role in adipocyte biology. Lipin is one such protein identified in a lipodystrophic mouse strain and found to be critical for normal adipocyte differentiation. Interestingly, lipin displays a biphasic expression pattern in adipocytes, with peaks of expression at two points during adipogenesis--a transient induction in preadipocytes prior to expression of peroxisome proliferator-activated receptor gamma, and a second wave of expression in mature adipocytes. Thus, lipin appears to have critical roles in both adipocyte differentiation and in the function of mature adipocytes.