Citations

SummaryPatients with early stage diffuse large B‐cell lymphoma (DLBCL) receive RCHOP (rituximab cyclophosphamide, doxorubicin, vincristine, prednisone) alone or with involved field radiotherapy (IFRT). Anti‐CD20 radioimmunotherapy (RIT) delivers radiation to microscopic sites outside of known disease. This phase II study aimed to achieve a functional complete response (CR) rate of ≥75% to RCHOP and 90Yttrium‐ibritumomab tiuxetan RIT. Patients with stages I/II DLBCL received 4–6 cycles of RCHOP followed by RIT [14·8 MBq/kg (0·4 mCi/kg)]; patients with positron emission tomographypositive sites of disease after RCHOP/RIT received 30 Gy IFRT. Of the 62 patients enrolled; 53 were eligible. 42% (22/53) had stage I/IE; 58% (31/53) stage II/IIE. After RCHOP, 79% (42/53) were in CR/unconfirmed CR. Forty‐eight patients proceeded to RIT. One partial responder after RIT received IFRT and achieved a CR. The best response after RCHOP + RIT in all 53 patients was a functional CR rate of 89% (47/53; 95% confidence interval: 77–96%). With a median follow‐up of 5·9 years, 7 (13%) patients have progressed and 4 (8%) have died (2 with DLBCL). At 5 years, 78% of patients remain in remission and 94% are alive. Chemoimmunotherapy and RIT is an active regimen for early stage DLBCL patients. Eighty‐nine percent of patients achieved functional CR without the requirement of IFRT. This regimen is worthy of further study for early stage DLBCL in a phase III trial.

Abstract IL-9 is a Th2 cytokine associated with T regulatory cell function, parasite expulsion and allergic airway inflammation. In many tumors IL-9 contributes to the establishment of a tolerogenic / immunosuppressive environment or acts directly to drive tumor growth, whereas in melanomas it inhibits tumor growth. Little is known about the effect of IL-9 in breast cancer biology. Here we show that IL-9 is a key factor in establishing a permissive growth environment for two murine breast cancer cells lines: TUBO cells that express Her2/neu and 4T1 cells that resemble aggressive, triple-negative breast cancers. We observed that TUBO cells were rejected by 78%, and 4T1 cells by 68% of IL-9 -/- (IL-9ko) mice, and that in the remaining mice the tumors developed later and grew slower than in WT mice. Tumor rejection is CD8+ T cell dependent and is capable of producing a memory response against tumor rechallenge. Delayed depletion of CD8+ T cells in mice that had rejected 4T1 cells showed no tumor growth in 63 % of the mice, suggesting that in these mice the tumor had been completely eradicated and was not held in stasis by immune surveillance. Furthermore we found a 3.7 fold increase (p=0.007) in the number of activated CD8+ T cells derived from IL-9ko mice rejecting tumors as compared to CD8+ T cells from tumor bearing WT mice. More importantly, the transfer of activated splenocytes from IL-9ko mice led to tumor rejection in WT mice (p<0.001). Moreover, WT mice treated with neutralizing anti-IL-9 evidenced slower 4T1 tumor growth compared to untreated and isotype control antibody treated mice. These data suggest that IL-9 neutralization should be examined as an adjuvant to immunotherapeutic or chemotherapeutic approaches. Supported by the NCI : CA155295 Citation Format: Dominique B. Hoelzinger, Ana Lucia Dominguez, Peter A. Cohen, Sandra J. Gendker. IL-9 is involved in the establishment of a tolerogenic milieu that prevents anti-tumor immunity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3640. doi:10.1158/1538-7445.AM2014-3640

Abstract ASCL1 is an important regulatory transcription factor in pulmonary neuroendocrine cell development, but its value as a biomarker of neuroendocrine differentiation in lung adenocarcinoma (AD) and as a potential prognostic biomarker remains unclear. We examined ASCL1expression in lung cancer samples of varied histologic subtype, clinical outcome, and smoking status and compared to expression of traditional neuroendocrine markers. ASCL1 mRNA expression was found almost exclusively in smokers with AD, in contrast to non-smokers. ASCL1 protein expression by immunohistochemistry (IHC) correlated best with synaptophysin compared to chromogranin and CD56/NCAM. Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the RET oncogene in ASCL1 positive tumors (ASCL1+) compared to ASCL1- tumors (q-value < 10 - 9). High levels of RET expression in ASCL1+ but not in ASCL1- tumors was associated with significantly shorter overall survival in stage 1 (p = 0.007) and in all AD (p = 0.037). RET protein expression by IHC had an association with overall survival in the context of ASCL1 expression. In silico gene set analysis and in vitro experiments by ASCL1 shRNA in AD cells with high endogenous expression of ASCL1 and RET implicated ASCL1 as a potential upstream regulator of the RET oncogene. Also, silencing ASCL1 in AD cells markedly reduced cell growth and motility. These results suggest that ASCL1 and RET expression define a clinically relevant subgroup of approximately 10% of AD characterized by neuroendocrine differentiation. Citation Format: Farhad Kosari, Cristiane M. Ida, Marie Christine Aubry, Lin Yang, Irina V. Kovtun, Janet L. Schaefer Klein, Sandra C. Tomaszek, Stephen J. Murphy, Ping Yang, Dennis Wigle, George Vasmatzis. ASCL1 and RET expression define a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5251. doi:10.1158/1538-7445.AM2014-5251

Occlusive renovascular disease caused by atherosclerotic renal artery stenosis (ARAS) elicits complex biological responses that eventually lead to loss of kidney function. Recent studies indicate a complex interplay of oxidative stress, endothelial dysfunction, and activation of fibrogenic and inflammatory cytokines as a result of atherosclerosis, hypoxia, and renal hypoperfusion in this disorder. Human studies emphasize the limits of the kidney adaptation to reduced blood flow, eventually leading to renal hypoxia with activation of inflammatory and fibrogenic pathways. Several randomized prospective clinical trials show that stent revascularization alone in patients with atherosclerotic renal artery stenosis provides little additional benefit to medical therapy once these processes have developed and solidified. Experimental data now support developing adjunctive cell-based measures to support angiogenesis and anti-inflammatory renal repair mechanisms. These data encourage the study of endothelial progenitor cells and/or mesenchymal stem/stromal cells for the repair of damaged kidney tissue.

Ischemia-reperfusion injury (IRI) due to hypotension is a common cause of human acute kidney injury (AKI). Hypoxia-inducible transcription factors (HIFs) orchestrate a protective response in renal endothelial and epithelial cells in AKI models. As human mucin 1 (MUC1) is induced by hypoxia and enhances HIF-1 activity in cultured epithelial cells, we asked whether mouse mucin 1 (Muc1) regulates HIF-1 activity in kidney tissue during IRI. Whereas Muc1 was localized on the apical surface of the thick ascending limb, distal convoluted tubule, and collecting duct in the kidneys of sham-treated mice, Muc1 appeared in the cytoplasm and nucleus of all tubular epithelia during IRI. Muc1 was induced during IRI, and Muc1 transcripts and protein were also present in recovering proximal tubule cells. Kidney damage was worse and recovery was blocked during IRI in Muc1 knockout mice compared with congenic control mice. Muc1 knockout mice had reduced levels of HIF-1α, reduced or aberrant induction of HIF-1 target genes involved in the shift of glucose metabolism to glycolysis, and prolonged activation of AMP-activated protein kinase, indicating metabolic stress. Muc1 clearly plays a significant role in enhancing the HIF protective pathway during ischemic insult and recovery in kidney epithelia, providing a new target for developing therapies to treat AKI. Moreover, our data support a role specifically for HIF-1 in epithelial protection of the kidney during IRI as Muc1 is present only in tubule epithelial cells.

Summary A persistently positive positron emission tomography ( PET ) scan during therapy for diffuse large B‐cell lymphoma ( DLBCL ) is predictive of treatment failure. A response‐adapted strategy consisting of an early treatment change to four cycles of R‐ ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R‐ CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET ‐positive patients received four cycles of R‐ ICE , PET ‐negative patients received two more cycles of R‐ CHOP . A ≥45% 2‐year progression‐free survival ( PFS ) for mid‐treatment PET ‐positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two‐year PFS was 70%; 42% [90% confidence interval (CI), 19–63%] for PET ‐positives and 76% (90% CI 65–84%) for PET ‐negatives. Three‐year overall survival ( OS ) was 69% (90% CI 43–85%) and 93% (90% CI 86–97%) for PET ‐positive and ‐negative cases, respectively. The 2‐year PFS for mid‐treatment PET ‐positive patients intensified to R‐ ICE was 42%, with a wide confidence interval due to the low proportion of positive mid‐treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.

A cystic fibrosis (CF) mouse expressing the human mucin MUC1 transgene (CFM) reverted the CF/Muc1−/−phenotype (little mucus accumulated in the intestine) to that of CF mice expressing mouse Muc1, which exhibited increased mucus accumulation. Western blots and immunohistochemical analysis showed that the MUC1 protein was markedly increased in CFM mice in which it was both membrane bound and secreted into the intestinal lumen. Studies to determine the reason for increased levels of the extracellular domain of MUC1 mucin identified mRNA and protein of two novel splice variants and the previously described secreted MUC1 lacking the cytoplasmic tail (MUC1/SEC). Novel MUC1 splice variants, CT80 and CT58, were both transmembrane proteins with cytoplasmic tails different from the normal MUC1. The MUC1-CT80 and MUC1/SEC forms are found expressed mainly in the CFM mice intestines. Thus MUC1 expression is increased, and it appears that alternate cytoplasmic tails may change its role in signaling. MUC1 could be an important contributor to the CF intestinal phenotype.