Abstract: Hyperostosis (lipping) due to costovertebral arthritis was found frequently (84.3%) impinging on the sympathetic trunks (ganglia and cord), rami communicantes and roots of the splanchnic nerves on both sides of the spine in more than 1,000 dissecting room cadavers examined and 34 cadavers of adult and elderly people specially dissected. As a result of the compression, the affected sympathetic structures were angulated, deflected from their course, enlarged and often infiltrated with connective tissue. The possible symptoms which may result from this kind of compression are discussed.

Abstract: Weekly medium change or midweek feeding of long-term bone marrow cultures (LTMBCs) results in a significant increase in total myeloid cell production. Proliferative myeloid cells peak 48 hours after feeding, and nonproliferative myeloid cells reach maximum levels at 72 hours. This increase in myelopoiesis is invariably preceded by a significant elevation in biologically and immunologically measurable colony-stimulating factor (CSF) in the supernatants of LTBMC. The level peaks 24 hours after medium change, then gradually returns to basal values. The decrease in CSF relates to its consumption by generating myeloid precursors because no fluctuation in the levels occur in cultures without active myelopoiesis. No significant inhibitors or promoters of CSF were detected. When highly purified L cell CSF, CSF in lung-conditioned medium, or CSF concentrated from LTBMC supernatant is added to cultures, an identical increase in myelopoiesis occurs. Anti- CSF antiserum, added to culture at the time of medium change, totally neutralizes supernatant CSF levels but does not affect myelopoiesis. These findings suggest a potential regulatory role for CSF in myelopoiesis in LTBMC. CSF appears to function within the microenvironment through a mechanism involving cell:cell interactions or by causing the production of other substances that stimulate myelopoiesis. Because exogenous CSF stimulates myelopoiesis, it is likely that it too can react either directly or through microenvironmental cells to stimulate primitive myeloid cells to divide.

Abstract: We have shown previously that the cause of anemia in healthy elderly subjects can usually not be identified. In this study, hematopoiesis was examined in 18 healthy elderly subjects with unexplained anemia and in 15 young and 15 healthy elderly individuals without anemia. No reduction in circulating testosterone was noted, making decreased androgen levels as a cause for the anemia unlikely. The 2,3 diphospho- glycerate (2,3DPG) levels in the anemic subjects were significantly higher than their corresponding controls, suggesting that the anemia was pathologic, as no increase would be expected if the low hemoglobin was a physiologic adjustment to age. The anemia was associated with a reduction in marrow normoblast and CFU-E number, but no decrease in BFU- E levels was seen. This suggests that the mechanism of the anemia is a decrease in stem cell proliferation. This could be caused by a reduction in circulating erythropoietin or a defect in end organ response. A second possibility is that a basic cellular abnormality exists. The presence of an overall reduction in hematopoiesis in anemic elderly (decreased peripheral blood counts, reduced marrow myeloid precursors, and CFU-C levels) makes this especially likely. The abnormality may be caused by a mechanism unrelated to the aging process. The fact that nonanemic elderly also have reductions in hematopoiesis suggests that age contributes to the defect.

Abstract: Urinary ferritin levels were measured by a “2-site” immunoradiometric assay in normal volunteers and in patients with various hematologic disorders. The mean urinary ferritin concentration in normal subjects averaged 2.2 microgram/liter, only 3% of the serum ferritin level. Elevated urinary ferritin levels averaging 45 microgram/liter were observed in patients with hematologic malignancies, but there was a proportional increase in serum ferritin so that the urinary level still averaged only 7% of the serum value. The highest urinary ferritin values (mean 170 microgram/liter) were associated with chronic hemolytic anemia, and in these patients, urinary ferritin rose disproportionately in relation to the serum, averaging 82% of it. This higher urinary level apparently reflects increased ferritin in renal tubular cells due to glomerular filtration of unbound hemoglobin, a mechanism that is supported by a highly significant correlation between urinary ferritin and serum haptoglobin levels. In normal subjects and in patients with malignancy, the source of urinary ferritin appears different, since a highly significant correlation was observed between urinary ferritin and reticuloendothelial iron stores as measured by serum ferritin or total iron-binding capacity. In this setting, the most likely source of urinary ferritin is the iron contained in renal tubular cells, which is apparently in equilibrium with body iron stores.

Abstract: Background: Classical Hodgkin lymphoma (cHL) displays near-universal genetic deregulation of PD-1 ligand expression, and relapsed/refractory (R/R) cHL is uniquely sensitive to PD-1 blockade. However, such treatment for patients (pts) who relapse after or are ineligible for autologous stem cell transplantation (ASCT) appears to be rarely, if ever, curative. Deploying PD-1 blockade early after ASCT could leverage the remodeling immune landscape and minimal residual disease state to increase the cure rate of ASCT. We therefore conducted a phase 2 multi-center single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab (pembro) in pts with chemosensitive R/R cHL after ASCT. Another arm of this study enrolled pts with R/R DLBCL and will be presented separately. Methods: Adult pts with R/R cHL who had received 2-3 lines of prior therapy and ASCT and who were chemosensitive prior to ASCT were enrolled on this study. In addition to meeting standard eligibility criteria for pembro treatment, pts had to have recovered from ASCT toxicities and begin study treatment within 60 days of stem cell infusion (goal within 21 days). They received pembro 200mg IV every 3 weeks for 8 cycles. PET-CT scans were obtained at post-ASCT baseline, after 3 and 7 cycles, then at 12 and 18 months post-ASCT. The primary endpoint was the progression-free survival rate (PFS) at 18 months after ASCT, assessed using International Harmonization Project 2007 criteria. Results: 31 pts were enrolled and 1 withdrew consent before starting treatment. Among the 30 eligible patients, median age was 33 (20-69). 26 pts (87%) were high-risk by virtue of primary refractory disease (57%), relapse within 12 months (17%), extranodal disease at relapse (27%) or absence of metabolic CR at ASCT (10%). At study baseline post-ASCT, 97% were in CR. 24 pts (80%) completed 8 cycles of pembro per protocol. 6 pts (20%) stopped pembro early for pt choice (n=2, including 1 pt with gr2 pneumonitis) or toxicity (n=4, including 2 pts with gr3 hepatitis, 1 with g3 pneumonitis, 1 with g2 diplopia). 9 pts (30%) experienced a total of 28 gr3 or higher adverse events (AEs). The most common gr4 AE was neutropenia (10%). 3 patients (10%) experienced 7 gr3-4 AEs at least probably related to pembro (gr3 diarrhea and gr3 eosinophilic colitis in 1 pt, gr3 leukopenia and gr4 neutropenia in 1 pt, gr3 leukopenia and gr3 ALT and AST elevation in 1 pt). 11 pts (37%) experienced at least one immune-related AE of gr2 or higher severity: pneumonitis (n=2 gr2, n=1 gr3), thyroid dysfunction (n=1 gr2), transaminitis (n=2 gr3), colitis/diarrhea (n=1 gr2, n=2 gr3), rash (n=2 gr2), pulmonary hemorrhage (n=1 gr3), arthritis (n=1 gr2), and increased creatinine (n=1 gr2). There was no treatment-related death. Among the 30 eligible pts, 2 were lost to follow-up after their 12m assessments (both in CR). 27 pts (90%) were evaluable for the primary endpoint (the last pt is still in follow-up and results will be updated for the meeting). 6 patients (20%) relapsed at a median of 8 months (3-18) from ASCT, and all other evaluable patients were in CR at the 18m timepoint. The KM estimate of 18m PFS for high-risk patients was 78% (95%CI 54-91). The 18m overall survival was 100%. Tumor biopsies from a pt who progressed on study demonstrated an increase in the %age of PD1+ T cells at progression, as well as an increase in the %age of PD-L1+ macrophages and PD-L1+ Reed-Sternberg cells (Figure). Other correlative studies including immune reconstitution and MRD analyses are ongoing. Conclusions: Pembrolizumab administered after ASCT in patients with R/R cHL has a safety profile that appears similar to its use in the R/R setting, although possibly with a higher rate of neutropenia. The 18-month progression-free rate in this high-risk cohort compares favorably with previous published studies, and supports the hypothesis that PD-1 blockade in this setting may increase the efficacy of ASCT. This should be tested in a randomized trial. Figure. Figure. Disclosures Armand: Pfizer: Consultancy; Affimed: Consultancy, Research Funding; Otsuka: Research Funding; Merck: Consultancy, Research Funding; Infinity: Consultancy; Adaptive: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Chen:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy. LaCasce:Humanigen: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Bristol-Myers Squibb: Other: Data safety and monitoring board; Seattle Genetics: Consultancy, Honoraria. Jacobson:Pfizer: Consultancy; Humanigen: Consultancy; Precision Bioscience: Consultancy; Novartis: Consultancy; Kite: Consultancy; Bayer: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Rodig:Bristol-Meyers-Squibb: Research Funding; KITE Pharma: Research Funding; Affimed Inc.: Research Funding; Merck & Co., Inc.: Research Funding. Shipp:AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Merck: Research Funding. Herrera:BMS: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Seattle Genetics: Research Funding; Immune Design: Research Funding; Astra Zeneca: Research Funding.