Population data evidence of interdependence of the limbs of hormonal feedback loops.

The fundamental models underlying hormonal physiological regulation and homeostasis remain poorly understood. We aimed to derive quantitative evidence regarding these models from the study of population data of balance points of different parameters and their respective controlling hormones. We studied the slopes of correlations between concentrations of circulating free thyroxine and thyrotropin, calcium and parathyroid hormone, haemoglobin and erythropoietin, and glucose and insulin in such population data, as well as the slopes of the limbs of various feedback loops estimated empirically and by reverse engineering of the population data. We used computer simulations to model the factors that influence the slopes derived from the population data, and then matched these simulations with the empirically derived slopes. Our simulations showed that changes to the population distribution of feedback loop limbs may alter the slopes of correlations within population data in specific ways. Non-random (interdependent) associations of the limbs of feedback loops may also have this effect, as well as producing discrepancies between the slopes of feedback limb loops determined experimentally and the same slopes determined by derivation from population data. Our corresponding empirical findings were consistent with the presence of such interdependence in the free thyroxine/thyrotropin, haemoglobin/erythropoietin and glucose /insulin systems. The glucose/insulin data provided evidence consistent with increasing interdependence with age in childhood. Our findings therefore provide strong evidence that the interdependence of the limbs of feedback loops is a general feature of endocrine homeostatic regulation. This interdependence potentially bestows evolutionary homeostatic and regulatory advantages.

Real-world treatment outcomes from a retrospective cohort of patients with acute myeloid leukemia from an urban safety net hospital.

INTRODUCTION: While continual advancements in acute myeloid leukemia have augmented response rates and survival, outcomes in clinical trials may not correlate with real-world practice as trials may underrepresent individuals with comorbidities, decreased performance status, and older age. Additionally, clinical trials may underrepresent certain ethnicities, and disparities based on ethnicity, socioeconomic status, and insurance have been demonstrated in acute myeloid leukemia. METHODS: We performed a retrospective chart review of adult patients with acute myeloid leukemia who were treated at Harbor-UCLA from 2014 to 2022 to examine patient characteristics, management patterns, and outcomes in a safety net hospital setting. RESULTS: The median age was 56 years old (range 18-84). In regards to risk stratification, 22%, 33%, and 41% had favorable, intermediate, and adverse risk acute myeloid leukemia, respectively. The most common induction regimens included 7 + 3 (55%), azacitidine (10%), azacitidine + venetoclax (7%), and 7 + 3 + midostaurin (7%). The complete remission rate was 51%. Among patients who received intensive induction chemotherapy, 15% underwent re-induction with a second cycle, 51% received consolidation therapy, and 5% received maintenance therapy with a targeted agent. Overall, 12% of patients received allogeneic stem cell transplant. Median overall survival was 12.2 months, and 5-year overall survival was 18%. CONCLUSIONS: Suboptimal response rates and survival in this population may be related to low rates of re-induction and allogeneic transplant in addition to high rates of adverse cytogenetics, secondary acute myeloid leukemia, and supportive care only. Efforts to increase access to clinical trials, novel therapies, and transplants for diverse and underinsured populations are essential.

Unexpected coccidioidomycosis presenting as lung nodules with presumptive diagnosis of malignancy.

Coccidioidomycosis can present as fluorodeoxyglucose (FDG) avid lung nodules which may be mistaken as relapse in patients with a history of malignancy. Detailed clinical history, relevant laboratory testing, and/or tissue biopsy with histologic evaluation are necessary for correct diagnosis.

Diffuse large B-cell lymphoma presenting as postmenopausal bleeding.

Key Clinical Message: Endometrial lymphoma is a rare etiology of abnormal uterine bleeding and endometrial thickening, and often shares similar clinical and imaging characteristics with other uterine malignancies such as endometrial carcinoma. Chemotherapy appears adequate for treating primary endometrial lymphoma. Abstract: We report a case of primary endometrial diffuse large B-cell lymphoma to increase awareness of this condition which is essential for correct diagnosis and treatment.

A case of chronic myelogenous leukemia with the T315I mutation who progressed to myeloid blast phase and was successfully treated with asciminib.

Patients with chronic myelogenous leukemia (CML) harboring the T315I mutation who progress to blast phase CML while on ponatinib may be successfully treated with asciminib monotherapy following induction therapy with cytotoxic chemotherapy.

Case of concurrent factor VII and factor XI deficiencies manifesting as spontaneous lower extremity compartment syndrome.

Factor VII and XI deficiencies are rare bleeding disorders typically associated with mild or provoked bleeding. This case report describes a patient with factor VII and XI deficiencies with an unprovoked episode of lower extremity hematoma causing compartment syndrome requiring multiple surgeries, extensive transfusion of blood products, and ultimately amputation.

Abnormal eosinophils with immature eosinophilic granules in chronic myeloid leukemia in accelerated phase.

Abnormal eosinophils with immature eosinophilic granules are typically observed in acute myeloid leukemia with inv (16) (p13.1q22) or t (16;16) (p13.1;q22) but can also be seen in chronic myeloid leukemia without inv (16) or t (16;16).

Graves' disease patients with iron deficiency anemia: serologic evidence of co-existent autoimmune gastritis.

BACKGROUND: Graves' disease (GD) has been associated with iron deficiency anemia (IDA). Atrophic gastritis leads to IDA and has been associated with autoimmune thyroid disease. This study prospectively determined the prevalence of atrophic gastritis markers and the relationship between these markers and markers of IDA in GD subjects. METHODS: Newly diagnosed GD patients (90) and controls (41) were studied. Of the newly diagnosed GD patients, 65 were consecutively enrolled and identified with GD irrespective of anemia, 25 had GD and IDA. Thyroid function, hematologic indices, and atrophic gastritis markers [parietal-cell antibodies (PCab), Helicobacter pylori antibodies (H. pylori ab), mean serum gastrin levels] were examined. RESULTS: GD patients presenting with IDA were twice as likely (64% vs. 32%, P=0.049) to harbor PCabs when compared to all other GD subjects. Unselected GD subjects (n=65) had significantly higher PCab (37% vs. 7%, P<0.001) compared to controls. Gastrin levels were significantly elevated in all GD subjects compared to controls (105 vs. 39 pg/ml, P<0.0001). This difference was magnified in PCab+ subjects (202 vs. 64 pg/ml, P=0.003). In all GD subjects, PCabs were associated with increased gastrin levels (202 vs. 75 pg/ml, P=0.0004) and lower ferritin levels (52 vs. 95, P=0.05). In GD anemic subjects, PCabs were associated with lower mean corpuscular volume (75 vs. 81, P=0.001). Gastrin levels correlated inversely with ferritin levels in all GD subjects and positively with TIBC in GD anemic subjects. CONCLUSIONS: A significant subset of patients presenting with GD may suffer from IDA due to concurrent autoimmune atrophic gastritis.

Checkpoint Blockade Treatment May Sensitize Hodgkin Lymphoma to Subsequent Therapy.

BACKGROUND: Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. MATERIALS AND METHODS: Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression-free survival (PFS), duration of response, and overall survival (OS). RESULTS: Eighty-one patients were included. Seventy-two percent had stage III-IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. CONCLUSION: In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. IMPLICATIONS FOR PRACTICE: Novel, life-prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.

Impact of Treatment Beyond Progression with Immune Checkpoint Blockade in Hodgkin Lymphoma.

Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time-to-subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.

The role of pembrolizumab in relapsed/refractory primary mediastinal large B-cell lymphoma.

Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL). PMBCL comprises approximately 10% of DLBCLs, thus making it a rare variant of DLBCL. Cure rates for PMBCL with upfront regimens like DA-REPOCH exceed 90%. However, if there is a poor response to this first-line therapy, relapsed/refractory PMBCL (rrPMBCL) has limited treatment options. The historic trend is to treat rrPMBCL with salvage regimens commonly used for DLBCL followed by high-dose therapy and autologous stem cell transplant (HDT-ASCT); however, response rates to salvage therapy remain low and few patients are able to proceed to transplant. An interesting feature of PMBCL is that even though it is classified as a subtype of DLBCL, PMBCL actually shares many clinical, pathologic, and genetic features with classical Hodgkin lymphoma (cHL). For example, both frequently express program death ligand 1 and 2 (PD-L1/2), which is not seen in other mature B-cell lymphomas. The expression of PD-L1/2 in PMBCL makes PDL1 inhibitors, such as pembrolizumab, an attractive therapeutic target. Pembrolizumab is an effective and well-tolerated therapy now approved for a number of cancer types from advanced melanoma to relapsed/refractory cHL. There are now multi-institutional trials underway assessing the role of pembrolizumab in the treatment of rrPMBCL.

Update on the role of brentuximab vedotin in classical Hodgkin lymphoma.

Brentuximab vedotin (BV) is an effective and well-tolerated treatment for patients with classical Hodgkin lymphoma (HL). It was initially approved by the US FDA for the treatment of HL after failure of autologous hematopoietic stem cell transplant (autoHSCT) or after failure of at least two prior lines of multiagent chemotherapy in patients who are not transplant candidates, and then subsequently, as consolidation therapy after autoHSCT in patients who are at high risk for relapse. However, the role of BV in the treatment of HL is evolving. BV has shown promising efficacy as a salvage treatment in the second-line setting prior to autoHSCT. Most recently, the ECHELON-1 trial demonstrated that BV combined with AVD for the treatment of newly diagnosed advanced stage HL improved modified progression-free survival (mPFS) compared with standard ABVD. Based on these results, the US FDA has approved BV as part of the initial treatment of advanced stage HL. With the approval of BV as front-line therapy, depending on how widely the use of BV plus AVD is adopted, the role of BV in the treatment of patients with relapsed or refractory (rel/ref) HL may need to be redefined. BV retreatment can be effective, and studies of rational BV-based combination regimens may help to improve response rates and overcome BV resistance. Furthermore, BV has been demonstrated to be effective in the initial treatment of elderly or unfit patients, and ongoing studies are evaluating the addition of BV to initial chemotherapy in patients with early stage HL.

Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation.

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied. METHODS: We conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m2 subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m2 intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS). RESULTS: With a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66-97), and 2-year OS was 94.7% (95% CI 68-99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease. CONCLUSION: Combined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen. TRIAL REGISTRATION: ClinicalTrials.gov NCT01267812 , registered Dec 29, 2010.

Iron chelators induce autophagic cell death in multiple myeloma cells.

We examined the antineoplastic effects of the iron chelators, deferasirox and deferoxamine in multiple myeloma cell lines as well as primary myeloma cells. These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cytotoxic to bone marrow plasma cells from myeloma patients. We also demonstrate that autophagy induced by iron deprivation is the dominant mechanism that mediates the cytotoxicity of iron chelators in multiple myeloma. Exposure to iron chelators led to repression of mTOR signaling as evidenced by decreased phosphorylation of its target p70S6 kinase. Iron chelation, in particular with deferasirox has the potential to be readily translated to a clinical trial for multiple myeloma.

Deflecting the trajectory and changing the narrative: how self-affirmation affects academic performance and motivation under identity threat.

To the extent that stereotype and identity threat undermine academic performance, social psychological interventions that lessen threat could buffer threatened students and improve performance. Two studies, each featuring a longitudinal field experiment in a mixed-ethnicity middle school, examined whether a values affirmation writing exercise could attenuate the achievement gap between Latino American and European American students. In Study 1, students completed multiple self-affirmation (or control) activities as part of their regular class assignments. Latino American students, the identity threatened group, earned higher grades in the affirmation than control condition, whereas White students were unaffected. The effects persisted 3 years and, for many students, continued into high school by lifting their performance trajectory. Study 2 featured daily diaries to examine how the affirmation affected psychology under identity threat, with the expectation that it would shape students' narratives of their ongoing academic experience. By conferring a big-picture focus, affirmation was expected to broaden construals, prevent daily adversity from being experienced as identity threat, and insulate academic motivation from identity threat. Indeed, affirmed Latino American students not only earned higher grades than nonaffirmed Latino American students but also construed events at a more abstract than concrete level and were less likely to have their daily feelings of academic fit and motivation undermined by identity threat. Discussion centers on how social-psychological processes propagate themselves over time and how timely interventions targeting these processes can promote well-being and achievement.

Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution.

Migration of neutrophils (PMN) across epithelia is a pathological hallmark of numerous mucosal diseases. Whereas lesions at mucosal surfaces are generally self-limiting, endogenous mechanisms of resolution are incompletely understood. Previous studies revealed that resolvins directly act on PMN to attenuate transendothelial migration, less is known about the influence of resolvins on PMN-epithelial interactions and whether they act on epithelia. We studied the dynamics of resolvin E1 (RvE1) actions on leukocyte transepithelial migration. PMN exposure to RvE1 or chemerin (peptide agonist of ChemR23) reduced transepithelial migration in a concentration-dependent manner. Conversely, activation of epithelial ChemR23 promoted apical clearance of PMN. A nonbiased screen of known PMN ligands expressed on epithelial cells in response to RvE1 revealed selective induction of CD55, an apically expressed antiadhesive molecule. CD55 promoter analysis demonstrated that both RvE1 and chemerin activate the CD55 promoter. Inhibition of CD55 by neutralizing antibody prevented RvE1-dependent augmentation of apical PMN clearance. Taken together these findings implicate a "two-hit" model of inflammatory resolution, whereby activation of the PMN RvE1 receptor attenuates transepithelial migration and subsequent actions on the epithelium promote CD55-dependent clearance of PMN across the epithelial cell surface promoting active inflammatory resolution.