A Very Rare Case of Sarcoid-Lymphoma Syndrome Imposing an Intriguing Diagnostic Challenge.

An enigmatic association between sarcoidosis and lymphoma has been proposed in the past. This poses a significant diagnostic challenge, especially when the time interval is less than one year between the two diagnoses. A 54-year-old male patient presented to his primary care physician with worsening acute kidney injury and hypercalcemia. His chest x-ray showed bilateral interstitial nodular thickening and mild bilateral hilar fullness. After a diagnostic workup, the patient was diagnosed with sarcoidosis and started on prednisone. He initially improved, but returned with acute kidney injury, hypercalcemia, and generalized lymphadenopathy. An excisional lymph node biopsy was positive for diffuse large B-cell lymphoma. Our case illustrates the sarcoidosis-lymphoma syndrome. Although there is no recommendation to screen patients with sarcoidosis for malignancy, it is crucial to be aware of this association and to evaluate any new or enlarging lymphadenopathy with a biopsy. It is essential to assess response to prednisone in patients with sarcoidosis.

Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab-deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2-Immune-DNA repair deficiency- subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 .

Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 .

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial.

IMPORTANCE: Administration of pembrolizumab plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non-small cell lung cancer (NSCLC). OBJECTIVE: To evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled. INTERVENTIONS: Patients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m2), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m2) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab. MAIN OUTCOMES AND MEASURES: Coprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis. RESULTS: A total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score ≥1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score ≥1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B. Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively. CONCLUSIONS AND RELEVANCE: The findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.

GCF2/LRRFIP1 represses tumor necrosis factor alpha expression.

Tumor necrosis factor alpha (TNF-alpha) is an important mediator of inflammation, apoptosis, and the development of secondary lymphoid structures. Multiple polymorphic microsatellites have been identified in and around the gene, and there are also multiple single-base pair biallelic polymorphisms in the introns and promoter. The TNF-alpha -308 promoter polymorphism is a G-to-A transition which has been statistically associated with various autoimmune disorders. Some studies have found that it may directly mediate the increased transcription of TNF-alpha in some circumstances. This study characterizes proteins interacting at the polymorphic promoter site. Affinity purification of binding proteins and confirmatory chromatin immunoprecipitation assays were used to identify the proteins. Electrophoretic mobility shift analyses and surface plasmon resonance were used to define binding characteristics. Proteins interacting at this site include GCF2/LRRFIP1 and Ets-1. GCF2/LRRFIP1 appears to act as a repressor and occupies the -308 site in cells that do not make TNF-alpha. Cells competent to produce TNF-alpha have Ets-1 bound to the -308 promoter site. Active transcription is accompanied by NF-kappaB and c-Jun binding to the proximal promoter. Thus, dynamic changes on the TNF-alpha promoter, particularly at the -308 site, accompany the transition from repressed to active transcription. GCF2/LRRFIP1 is the first TNF-alpha repressor identified.

Patients' reasons for refraining from discussing internet health information with their healthcare providers.

This exploratory study examined factors that constrain patients from discussing Internet health information with their healthcare providers. Participants (N = 714) were asked to list reasons why they have not talked with their providers about Internet health information they had found. Factors (N = 767) included patient attributions about the information, systems or circumstances, fear of treading on the provider's turf, face-saving concerns, and patient perceptions of provider attributions about the information. Comparisons between those who had and those who had not talked to their healthcare providers about their Internet research revealed significant differences in types of constraining factors indicated. Issues concerning an increasingly Internet-savvy public and provider-patient relationships are considered in the discussion within the framework of the goals, planning, action theory. Continued efforts in provider and patient education can help to overcome barriers that restrict communication concerning Internet health research.

Provider-patient dialogue about Internet health information: an exploration of strategies to improve the provider-patient relationship.

OBJECTIVE: This study examined patients' experiences talking to their providers about internet health information. METHODS: Participants (n=770) recruited from internet health message boards completed an online survey, including questions focusing on a recent interaction with a provider about internet health information. RESULTS: Face-saving patient introduction strategies were associated with providers validating patients' efforts. Providers' validation of patients' efforts was associated with higher patient ratings of satisfaction, validation, and reduced concern, while providers' disagreement with the information was associated with lower ratings. The provider taking the information seriously was associated with higher patient satisfaction. CONCLUSION: An understanding of the occurrence of provider-patient talk about internet health information and its relationship to patient satisfaction, validation, and reduced concern is important for providers and medical educators who seek to better understand, and thus improve, provider-patient communication. PRACTICE IMPLICATIONS: Showing the patient that the information is being seriously considered and validating the patients' efforts in researching the information may ameliorate some of the negative effects of disagreement.

Histone acetylation and chromatin conformation are regulated separately at the TNF-alpha promoter in monocytes and macrophages.

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine, which participates in a wide range of immunoregulatory activities. It is generally produced at highest levels by cells of the myeloid lineage in response to activation of pathogen recognition receptors such as Toll-like receptors. Impaired production predisposes to infection with intracellular organisms, and overproduction results in systemic or organ-specific inflammation. Control of expression is essential to maintain homeostasis, and this control is mediated via multiple strategies. We examined two separate aspects of chromatin accessibility in this study of the human TNF-alpha promoter. We examined the role of histone acetylation and chromatin remodeling in cell lines and primary cells and identified two individual steps associated with activation of TNF-alpha production. Histone H3 and H4 acetylation was found to be strongly dependent on the developmental stage of human monocytes. It did not appear to be regulated by acute stimuli, and instead, chromatin remodeling was found to occur after acute stimuli in a cell line competent to produce TNF-alpha. These data suggest that there is a hierarchy of controls regulating expression of TNF-alpha. Acetylation of histones is a prerequisite but is insufficient on its own for TNF-alpha production.

Influence of bedding type on mucosal immune responses.

The mucosal immune system interacts with the external environment. In the study reported here, we found that bedding materials can influence the intestinal immune responses of mice. We observed that mice housed on wood, compared with cotton bedding, had increased numbers of Peyer's patches (PP) visible under a dissecting microscope. In addition, culture of lymphoid organs revealed increased production of total and virus-specific IgA by PP and mesenteric lymph node (MLN) lymphocytes from mice housed on wood, compared with cotton bedding. However, bedding type did not influence serum virus-specific antibody responses. These observations indicate that bedding type influences the intestinal immune system and suggest that this issue should be considered by mucosal immunologists and personnel at animal care facilities.

Exploration of the construct of reliance among patients who talk with their providers about internet information.

Three hundred fifty participants, recruited from Internet health message boards, completed online surveys about their experiences talking with health care providers about Internet health information. Two distinct dimensions of reliance emerged from the data, one regarding the patient's reliance on the health care provider for decision making and the other regarding the patient's reliance on the health care provider to stay healthy. Self-reliant patients tended to be female, have lower incomes, and report less frequent visits to the health care provider than did health-care-provider-reliant patients. Age, comfort level, and frequency of talking about Internet health information were not related to reliance level.

Apoptotic cells, autoantibodies, and the role of HMGB1 in the subcellular localization of an autoantigen.

A current model for the evolution of systemic lupus erythematosus hypothesizes that there is a genetic predisposition coupled with an environmental or infectious trigger. This study investigated whether apoptotic cells given with a proinflammatory signal could induce features of lupus. Balb/c mice were injected with an apoptotic Balb/c-derived myeloid cell line, J774.1, either with or without the DNA-binding protein HMGB1 for five injections over 16 days in an IACUC approved study. Mice were sacrificed at 6 weeks and 12 weeks after treatment. Renal disease was assessed by immunofluorescence and autoantibodies were defined by ELISA. Western blotting was performed to characterize autoantigens. Mice injected with apoptotic cells developed antibodies to histones, SSA, ssDNA, and phospholipids. Antibodies to SSA and ssDNA persisted; however, antibodies to histones, and phospholipid declined at 12 weeks. IgG deposits in the kidney were detected at 6 weeks and persisted through 12 weeks primarily in animals that received both apoptotic cells and HMGB1. Autoantibodies in mice were diverse but the mice that received apoptotic cells developed particularly high titer antibodies to an unknown 78kDa protein. This protein became externalized on the surface of J774.1 cells in the presence of HMGB1. Mice that received apoptotic J774.1 cells with HMGB1 developed more extensive renal IgG deposition. While the mechanism is uncertain, an important effect of HMGB1 was to alter the subcellular distribution of a major autoantigen, making the autoantigen accessible for immune responses. This is the first description of an inflammatory stimulus altering the immunologic availability of a potential autoantigen.

T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome.

Patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) typically exhibit thymic hypoplasia, conotruncal cardiac defects, and hypoparathyroidism. The immunodeficiency that results from the thymic hypoplasia has been extensively described and consists primarily of T-cell lymphopenia. A curious feature of the T-cell lymphopenia is that the age-related rate of decline of T-cell numbers is slower in patients than controls. This leads to T-cell numbers in adulthood that are minimally decreased compared with controls. This suggests that homeostatic mechanisms might be acting to preserve the peripheral blood T-cell numbers in patients. We characterized changes in CD4/CD45RA and CD4/CD45RO T-cell populations in patients and controls of various ages and determined T-cell recombination excision circles and telomere length within the CD4/CD45RA population. Patients had evidence of accelerated conversion of naive to memory cells and had evidence of more extensive replicative history within the CD4/CD45RA compartment compared with controls. Oligoclonal T-cell receptor (TCR) Vbeta families and missing Vbeta families were seen more often in patients than controls. These data are consistent with homeostatic proliferation of T cells in patients with limited T-cell production due to thymic hypoplasia.