The immune system encompasses a broad array of defense mechanisms against foreign threats, including invading pathogens and transformed neoplastic cells. Toll-like receptors (TLRs) are critically ...involved in innate immunity, serving as pattern recognition receptors whose stimulation leads to additional innate and adaptive immune responses. Malignant cells exploit the natural immunomodulatory functions of TLRs, expressed mainly by infiltrating immune cells but also aberrantly by tumor cells, to foster their survival, invasion, and evasion of anti-tumor immune responses. An extensive body of research has demonstrated context-specific roles for TLR activation in different malignancies, promoting disease progression in certain instances while limiting cancer growth in others. Despite these conflicting roles, TLR agonists have established therapeutic benefits as anti-cancer agents that activate immune cells in the tumor microenvironment and facilitate the expression of cytokines that allow for infiltration of anti-tumor lymphocytes and the suppression of oncogenic signaling pathways. This review focuses on the clinical application of TLR agonists for cancer treatment. We also highlight agents that are undergoing development in clinical trials, including investigations of TLR agonists in combination with other immunotherapies.
Background Climate factors and pollen counts may play a role in hay fever. Objective We sought to determine the impact of specific climate factors and pollen counts on the US prevalence of hay fever ...and statewide variation in prevalence. Methods We used a merged analysis of the 2007 National Survey of Children's Health from a representative sample of 91,642 children aged 0 to 17 years and the 2006-2007 National Climate Data Center and Weather Service measurements of relative humidity (%), indoor heating degree days, precipitation, Palmer Hydrological Drought Index, clear sky and issued ultraviolet indices, stratospheric ozone levels, and outdoor air temperature and National Allergy Bureau total pollen counts. Multivariate survey logistic regression models controlled for sex, race/ethnicity, age, household income, and birthplace. Results The US prevalence of hay fever in childhood was 18.0% (95% CI, 17.7% to 18.2%), with the highest prevalence in southeastern and southern states. Hay fever prevalence was significantly lower with second and third quartile mean annual relative humidity (logistic regression, P ≤ .01 for both), fourth quartile mean annual Palmer Hydrological Drought Index ( P = .02), third and fourth quartile mean annual heating degree days ( P < .0001 for both), and third and fourth quartile mean annual stratospheric ozone levels but increased with second, third, and fourth quartile mean annual temperature ( P ≤ .02 for both), fourth quartile mean annual precipitation ( P = .0007), mean total pollen counts ( P = .01), and second, third, and fourth quartile issued ultraviolet index ( P ≤ .0001 for all). Principal-component analysis was also used to determine the combined effects of correlated climate variables and pollen counts. Conclusions This study provides evidence of the influence of climate on the US prevalence of childhood hay fever.
Following a short course of external radiation to the T7−T8 spine, systemic treatment included a combination of the anti-CD38 monoclonal antibody daratumumab along with cyclophosphamide, doxorubicin, ...vincristine, and prednisone every 3 weeks, which resulted in partial response after three cycles, indicated by a reduction M-spike to 0.7 g/dL. Treatment typically includes a combination of modern anti-myeloma agents, such as the proteasome inhibitor bortezomib, along with chemotherapy.3 In the Myeloma E9486 trial, the largest interventional study on plasmablastic myeloma, treatment with vincristine, carmustine, melphalan, cyclophosphamide and prednisone showed a response rate of 47%.1 To the best of our knowledge this is the first report of plasmablastic myeloma treated with a regimen that included daratumumab, which resulted in a partial response. Learning points Plasmablastic myeloma is a rare and aggressive neoplasm presenting with overlapping features of multiple myeloma and non-Hodgkin's lymphoma.
Worldwide incidence and mortality due to the coronavirus disease 2019 (COVID-19) pandemic is greatest in the United States, with the initial epicenter in New York. In Nassau County, New York, where ...we practice, our institution has had more than 2500 cases and has discharged from the hospital more than 1000 patients. As many academic and private institutions have swiftly shifted their clinical and research priorities to address the pandemic, data are emerging regarding both the impact of malignancy on COVID-19 outcomes as well as the challenges faced in assuring that cancer care remains unimpeded. Of concern, recent studies of cancer patients primarily in China and Italy have suggested that advanced malignancy is associated with increased susceptibility to severe COVID-19 infection. At present, more than 500 clinical trials are underway investigating the pathogenesis and treatment of COVID-19, including expanded use of oncology drugs, such as small molecular inhibitors of cytokine pathways. Here, we begin by reviewing the latest understanding of COVID-19 pathophysiology and then focus our attention on the impact of this virus on hematologic and oncologic practice. Finally, we highlight ongoing investigational treatment approaches that are so relevant to the care of oncology patients during this extraordinary pandemic.
Abstract
Objectives
Crystal-storing histiocytosis (CSH) is rare in plasma cell dyscrasias, with only 3 cases reported in the setting of amyloid. No cases of crystal-negative histiocytosis coincident ...with multiple myeloma and amyloidosis have been reported previously.
Methods
A 58-year-old woman presented with pain due to destructive bone lesions and was found to have plasma cell myeloma (PCM) and marrow amyloid deposition associated with crystal-negative histiocytosis. Differential diagnoses included Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai Dorfman disease. BRAF mutations were negative, and there was no evidence of paraprotein crystals, arguing against typical CSH.
Results
The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, and she subsequently underwent autologous stem cell transplant and ixazomib maintenance. She achieved complete remission with improvement of her symptoms and preserved remission after following up at 60 months.
Conclusions
We describe a case of crystal-negative histiocytosis associated with PCM. CSH is a rare disorder associated with paraprotein-producing conditions in which immunoglobulins aggregate as intracellular crystals in the lysosomes of organ-specific phagocytic macrophages. Light chain tropism in PCM can also lead to the development of amyloid deposition in organs and, in rare cases, is associated with light chain aggregation as intracellular crystals in macrophages.
Palliative care (PC) plays an established role in improving outcomes in patients with solid tumors, yet these services are underutilized in hematologic malignancies (HMs). We reviewed records of ...hospitalized patients with active HM to determine associations between PC consultation and length of stay, intensive care unit stay, 30-day readmission, and 6-month mortality compared with those who were not seen by PC.
We reviewed all oncology admissions at our institution between 2013 and 2019 and included patients with HM actively on treatment, stratified by those seen by PC to controls not seen by PC. Groups were compared using Wilcoxon rank-sum, chi-square, and Fisher's exact tests on the basis of the type and distribution of data. Multiple logistic regression models with stepwise variable selection methods were used to find predictors of outcomes.
Three thousand six hundred fifty-four admissions were reviewed, among which 370 unique patients with HM were included. Among these, 102 (28%) patients saw PC, whereas the remaining 268 were controls with similar comorbidities. When compared with controls, PC consultation was associated with a statistically significant reduction in 30-day readmissions (16%
27%;
= .024), increased length of stay (11.5
6 days;
< .001), increased intensive care unit admission (28%
9%;
< .001), and increased 6-month mortality (67%
15%;
< .001). These data were confirmed in multivariable models.
In this retrospective study, more than two thirds of patients with HM did not receive PC consultation despite having similar comorbidities, suggesting that inpatient PC consultation is underutilized in patients with HM, despite the potential for decreased readmission rates.
Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes ...and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos (
= 21), OR = 4.7 (95% confidence interval, 1.3-16.7), and African American Blacks (
= 33), OR = 3.5 (1.1-11.5), as compared with White patients (
= 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated (
> 0.05) with adverse outcome: hypertension (
= 56), OR = 2.2 (0.9-5.4); diabetes (
= 18), OR = 0.9 (0.3-2.9); age >65 years (
= 63), OR = 1.8 (0.7-4.6); high-dose melphalan with autologous stem cell transplant <12 months (
= 7), OR = 0.9 (0.2-5.4); and immunoglobulin G <650 mg/dL (
= 42), OR = 0.9 (0.3-2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome.
Patients with multiple myeloma are immunocompromised, raising the question whether they are at higher risk of severe COVID-19 disease. In this large case series on COVID-19 in patients with multiple myeloma, we report 29% mortality rates among hospitalized patients and identify race/ethnicity as the most significant risk factor for severe outcome.
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For investigations of human B-cell receptor (BCR) repertoires, we have developed a protocol for large-scale surveys of human antibody heavy chain (VH) rearrangements. Here we study IgA repertoires, ...as more IgA antibodies are synthesized in the human body on a daily level than all other isotypes combined. In fact, IgA is secreted at all mucosal surfaces, and it is also secreted in the perspiration that coats our cutaneous surfaces. In these studies we can characterize the IgA clonal diversity of B-cell populations obtained from any donor. To recover representative repertoire libraries, we make our libraries from antibody gene transcript templates (i.e., cDNA), as these are closer reflections of the immune repertoire expressed at the antibody protein level. To avoid biases potentially introduced by upstream oligonucleotide primers that hybridize to variable region framework regions, our approach also uses rapid amplification of cDNA ends (RACE) of antibody transcripts. For exploration of human IgA responses, we have designed a duplexing antisense constant region primer that efficiently amplifies, side-by-side, heavy chain transcripts of both the IgA1 and IgA2 subclasses. By these methods we have begun to define the molecular differences in the IgA1 and IgA2 responses occurring simultaneously in different donors. These methods will be used to investigate the effects of microbial virulence factors on host defenses, during autoimmune responses, and in B-cell malignancies.
Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, ...we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis.
Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable, primarily due to the treatment-refractory/resistant nature of the disease. A rational approach to this ...compelling challenge is to develop new drugs that act synergistically with existing effective agents. This approach will reduce drug concentrations, avoid treatment resistance, and also improve treatment effectiveness by targeting new and nonredundant pathways in MM. Toward this goal, we examined the antimyeloma effects of MAL3-101, a member of a new class of non-ATP-site inhibitors of the heat shock protein (Hsp) 70 molecular chaperone. We discovered that MAL3-101 exhibited antimyeloma effects on MM cell lines in vitro and in vivo in a xenograft plasmacytoma model, as well as on primary tumor cells and bone marrow endothelial cells from myeloma patients. In combination with a proteasome inhibitor, MAL3-101 significantly potentiated the in vitro and in vivo antimyeloma effects. These data support a preclinical rationale for small molecule inhibition of Hsp70 function, either alone or in combination with other agents, as an effective therapeutic strategy for MM.
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