Patients with mantle cell lymphoma (MCL) and follicular lymphoma treated with bortezomib have consistent response rates of 30–50% across several clinical trials, suggesting a common tumour biology that may predict response. It remains unknown which processes affected by proteasome inhibitors (PI) are most important in their activity in non-Hodgkin Lymphoma (NHL). Leading theories include inhibition of the cell cycle, nuclear factor κB (NFKB1; NF-κB) signalling, angiogenesis and decreased degradation of anti-apoptotic proteins. Between June 2001 and December 2006, 103 patients enrolled in a multicentre Cancer Therapy Evaluation Program-sponsored Phase II trial and were treated with single-agent bortezomib. Eligibility criteria included: (i) confirmed indolent NHL or MCL, (ii) <3 prior cytotoxic treatment regimens, and (iii) adequate organ reserve (O'Connor et al, 2005; Gerecitano et al, 2009). Tissue microarrays (TMA) were stained for a panel of targets selected for their possible prognostic associations with NHL or mechanisms of action (MOA) of PI (Table S1). We correlated outcome with pre-treatment tumour protein expression patterns in this unique patient population. Tissue microarrays were constructed from 55 pre-treatment tissue blocks as previously published (Koreishi, 2010). Stains for CDKN1A (p21), CDKN1B (p27), BIRC5 (Survivin), TP53 (p53), BCL2, MCL1, CFLAR (c-FLIP), Caspase, VCAM1, REL/RELA (p65), PSMB1 (proteasome subunit β1), PSMA5 (proteasome subunit α5), TOP2A(TOPOα), MIB1/MKI67 (Ki67), CCND1 (cyclin D1), MUM1, BCL6 and CTAG1B (NYEso) were graded by two independent pathologists, and a consensus grade was determined for each marker. Cases were considered positive if >20% of cells showed staining. In cases of discrepancy, the higher value was reported. Stains were also graded on a scale from 0 to 4, representing the proportion of cells per high power field. Nuclear RELA was estimated using continuous percentages, and then separated into quartiles for analysis. In those cases where the diagnostic samples did not run through the entire TMA block, shavings from the initial block were graded separately. Fisher's exact test was used to assess the association between response rates [progressive disease (PD) versus complete response (CR)/partial response (PR)/stable disease (SD), CR/PR versus SD/PD] and the expression of each marker. Progression-free survival (PFS) was defined from the start of treatment to the date of death or progression, whichever occurred first. Patients were censored at their last date of follow-up if they were alive and progression-free. For patients who responded to therapy (CR/PR), duration of response (DOR) was calculated from the date of the best response to the date of progression, and patients who remained progression-free at the last follow-up were censored. None of the patients included in this analysis died prior to disease progression. The Log-rank test or permutation log-rank test was used to compare PFS and DOR between levels of stain expression. Multiple comparison adjustment was not applied considering the exploratory nature of the study. All tests were completed in sas 9.2 (SAS Institute, Inc., Cary, NC, USA) and r version 2.9.2 (http://www.r-project.org/). Demographic and response/survival information for patients included in this analysis (n = 55) reflect the total population (n = 103, Table 1) (Gerecitano et al, 2009; O'Connor et al, 2010). Two proteins showed significant association with response: High expression (50–75%) of MCL1 conferred a decreased chance of achieving SD or better compared with 25–50% or 0–25% expression of MCL (54%, 100% and 73%, respectively P = 0·044). Any expression of BCL6 decreased the chance of achieving SD or better (42% vs. 77%, P = 0·034). Two markers correlated with PFS: Decreased CDKN1B correlated with lower PFS (log-rank test P = 0·047). Patients with zero expression of CDKN1B (n = 2) progressed within 1.4 months (1-year PFS = 0), whereas 1-year PFS of other patients with expression level of 0–25%, 25–50% and 50–75% were 43% [95% confidence interval (CI): 18–66%], 20% (95%CI: 5–42%), and 39% (95%CI: 16–61%), respectively. Patients with zero expression of CFLAR (n = 31) had better PFS compared to patients with 0–25% and 25–50% expression of CFLAR: 1-year PFS was 37% (95%CI: 18–50%), 29% (95%CI: 4–61%), and 0% (95%CI: NA-NA) respectively, log-rank test P = 0·004 (Fig 1). The median time to progression for the entire sample was 5.2 (95%CI: 3.2–10.1) months. Two of these proteins are involved with distinct apoptotic pathways. MCL1 is an antiapoptotic BCL2 family member that correlates with resistance to PI in preclinical studies. This mechanism of resistance may be overcome when bortezomib is combined with small molecule inhibitors of the BCL2 family of proteins (Paoluzzi et al, 2008). In contrast to MCL1, CFLAR decreases death receptor-initiated apoptotic drive. High levels of CFLAR are associated with chemotherapy resistance and poor clinical outcome in other NHLs (Valnet-Rabier et al, 2005). Bortezomib down-regulates the expression of CFLAR in in vitro models (Ri et al, 2008). CDKN1B is a known tumor suppressor gene whose regulation is highly dependent on proteasomal degradation, and increased degradation correlates with poor prognosis in MCL (Chiarle et al, 2000). It is therefore interesting that in both the present study and the PINNACLE trial (Goy et al, 2010) low pretreatment levels of CDKN1B still hold poor prognostic value despite proteasome inhibition. Perhaps some threshold amount of CDKN1B expression is necessary for inhibition of its degradation to impact on prognosis. BCL6 is involved in the pathogenesis of a variety of germinal centre NHL. Bortezomib increases intracellular levels of BCL6 (Cerchietti et al, 2009), and may therefore be ineffective in patients whose tumors express increased levels at baseline. This finding supports ongoing trials evaluating bortezomib in combination with inhibitors of BCL6 (e.g. inhibitors of heat shock protein 90 or histone deacetylase). The use of TMA technology allowed for the staining of many more markers across patients under uniform conditions. Each of the proteins found to correlate with response or survival plays a significant role in the pathogenesis of lymphoma. Limitations of this study include: (i) Different subtypes of NHL are included, (ii) numbers are relatively small due to difficulties in obtaining pathology blocks and (iii) we are not able to conclude whether these markers are specific to patients treated with bortezomib, or are prognostic markers for the diseases studied. The exploratory observations reported will be used in ongoing and future prospective studies to help us identify potential biomarkers of response, which may inform rational combinations of bortezomib with other agents based on insights into molecular pathogenesis. This research was funded by Millennium Pharmaceuticals, The Takeda Oncology Company. J.G. was supported by a Cancer and Leukemia Group B Foundation Clinical Research Award and a Lymphoma Foundation Mortimer J. Lacher, MD Hematology/Oncology Fellowship. The authors would like to acknowledge the advice and consultation of Dr. Carol Portlock during the design of this study. J.G. designed research, analysed and interpreted the data, and wrote the manuscript; S.G. performed research and collected data, J.T-F. performed research and wrote the manuscript, M.A. performed research, S.O., D.L. and C.G. collected and organized data; J.Z and Z.Z. performed statistical analysis and wrote the manuscript, A.M. performed research. G.M. designed research, O.A.O. designed research and wrote the manuscript. J.G. has received research support and served as an uncompensated advisor to Millennium Pharmaceuticals, The Takeda Oncology Company within the past 2 years. OAO has received research support and served as a consultant to Millenium Pharmaceuticals, the Takeda Oncology Company. Alice McDonald and George Mulligan are employees of Millenium Pharmaceuticals, the Takeda Oncology Company. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
20646 Background: The objective of the study is to find quality indicators that predict outcomes of EOL care. Methods: Items from performance measures proposed by Earle et al (Int J Qual Health Care 2005;17:505) were used to develop multivariate logistic regression models for the outcomes 1) whether a patient enters into Hospice, 2) dies in an acute care institution, and 3) is admitted into the ICU within one month of death. We analyzed data from a cohort of veteran patients. Process variables included the type of underlying disease, whether pain or symptom medications were administered, whether psychological support was given, and whether patients were admitted to the MICU. Analyses were done with SAS. Conclusions: Supportive care measures, such as pain and symptom medications are associated with increased likelihood of entering Hospice, and support counseling increases the likelihood of dying in an acute care institution and being admitted to the ICU within the last month of life. These findings should be confirmed in other studies. Multivariate Predictors of Entering Hospice and Dying in an Acute Care Institution Pt entered hospice, OR Pt entered hospice, p Pt died in acute care institution OR Pt died in acute care, p Pt admitted to ICU, OR Pt admitted to ICU, p Age per year 0.96 0.001 0.99 0.78 0.97 0.01 Age per year 0.28 0.048 0.99 0.78 0.55 0.45 Hematologic malignancy vs others 0.28 0.048 13.7 0.007 0.55 0.45 Pain and Symptom Meds 10.5 0.042 1.72 0.73 Admit to ICU 0.17 0.004 9.72 0.001 Psychological support 0.58 0.15 4.22 0.005 4.96 0.01 DNR 1 week 0.45 0.08 3.06 0.029 No significant financial relationships to disclose.
A 52-YEAR-OLD MAN WITH HUMAN IMMUNOdeficency virus (HIV), AIDS, chronic hepatitis B, and stage IV Burkitt lymphoma presented to the emergency department with a 2-week history of nausea, vomiting, diarrhea, and lethargy as well as a 2-day history of falls at home. He reported no vertigo, tinnitus, otalgia, or otorrhea; however, he did report a 2-month history of left-sided aural fullness and subjective hearing loss. On physical examination, the left tragus, antitragus, and conchal bowl (Figure1) exhibited nontender purple nodules and plaques extending into the cartilaginous external auditory canal. The external auditory canal was patent but narrowed. The tympanic membrane was intact and there was no otorrhea. There was no trismus or tenderness of the temporomandibular joint. A Weber test demonstrated lateralization to the right, and the results of a Rinne test were positive bilaterally. Relevant laboratory findings included a viral load of 152 000 copies/mL and a CD4 cell count of 8/μL. A skin punch biopsy specimen was obtained for histopathologic evaluation (Figure 2 and Figure 3). What is your diagnosis?
22187 Background: We investigated expression of pathways in archival prostate cancer biopsies by IHC staining. Methods: In an IRB approved protocol, primary prostate cancer specimens were obtained from archival formalin-fixed, paraffin-embedded tissue collected between 1992 and 2006 at VA New Jersey Health Care System. The most representative tumor tissue block was chosen from each of the 42 cases evaluated. ICH stains to detect tumor expression of S6 (ribosomal), p70s6, pTEN, AKT-1, BCL-1 (Cyclin D1), VEGF, c-KIT (CD117), PDGFR-alpha (C-20), and PDGFR-beta (P20) were done by US LABS (Irvine, CA). All immunostains were evaluated by two pathologists. Immunoreactivity was scored using a semiquantitative system for intensity of staining and percentage of positive cells. Staining intensity was scored as 0 (no detectable stain), 1 (weak staining detected at intermediate to high power), 2 (moderate detected at low to intermediate power) to 3 (strong detected at low power). Percentage of positive cells was scored as 0 (0%), 1 (1–33% positive cells), 2 (34–66%), or 3 (67–100%). The total score was obtained by adding the scores of intensity and percent of positive cells. Medical records were reviewed for dates of diagnosis, and demographic and laboratory information. A Cox survival model for each stain was developed with known survival variables, Gleason score, Hemoglobin (Hgb), Alkaline Phosphatase (Alk Phos), Prostate Specific Antigen (PSA), Lactate Dehydrogenase (LDH) levels at the time of D3 stage, and the ICH grade. Results: Data from 39 patients were available. The median, age was 75 yrs (range 56–94), Gleason score was 8(6–10), LDH was 186(134–899), Hgb was 12.3(6.3–15.5), PSA was 66(0.4–2675), Alk Phos was 121(45–1119).The median survival was 204 days (18–2085). None of the stains was predictive of survival on a univariate or multivariate analysis. Conclusions: The over expression of S6, p70s6, pTEN, AKT-1, BCL-1, VEGF, c-KIT, PDGFR-alpha and PDGFR-beta by ICH on archival tissue was not predictive of survival. No significant financial relationships to disclose.
Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a very rare vascular disease that involves the superior mesenteric artery or its branches. SISMAD’s incidence is as low as 0.08% with the majority of cases being found in patients of Asian descent. Due to advances in imaging modalities, in particular, abdominal computed tomography angiography (CTA), its incidence has been noted to increase. Here in, we are presenting a rare case of SISMAD with thrombosis in a young male with no past medical history. The importance of this disease as a differential for acute abdominal pain will be emphasized. Our take away point from this case report is to draw attention to the need for further studies to establish guidelines for management and follow up of SISMAD patients with thrombosis.
A 66-year-old black male was diagnosed with mantle cell lymphoma (MCL) of the gastrointestinal tract after he had presented with dyspepsia, poor oral intake and 17 kg weight loss. His bone marrow w...
