The emotional component of inner speech: A pilot exploratory fMRI study.

Inner speech is one of the most important human cognitive processes. Nevertheless, until now, many aspects of inner speech, particularly the emotional characteristics of inner speech, remain poorly understood. The main objectives of our study are to identify the neural substrate for the emotional (prosodic) dimension of inner speech and brain structures that control the suppression of expression in inner speech. To achieve these goals, a pilot exploratory fMRI study was carried out on 33 people. The subjects listened to pre-recorded phrases or individual words pronounced with different emotional connotations, after which they were internally spoken with the same emotion or with suppression of expression (neutral). The results show that there is an emotional component in inner speech, which is encoded by similar structures as in spoken speech. The unique role of the caudate nuclei in the suppression of expression in the inner speech was also shown.

Concurrent Lymphoma and COVID-19: Diagnostic and Therapeutic Challenges of High-Grade Lymphoma and COVID-19.

The coronavirus disease 2019 (COVID-19) global pandemic has put an unprecedented strain on cancer care. The initial months were marred by fears of immunocompromised patients becoming opportunistic hosts to this deadly virus. We present a case of newly diagnosed high-grade B-cell lymphoma in a patient with COVID-19 and discuss the diagnostic and therapeutic challenges posed. A 76-year-old female presented with one month of progressive malaise, poor appetite, weight loss, and night sweats. A surveillance COVID-19 polymerase chain reaction (PCR) resulted positive. With strict isolation precautions, the daily focused physical examination masked several key findings including multifocal adenopathy. She developed hypoxic respiratory failure and progressive transaminitis and cytopenias. Image-guided, rather than excisional, biopsy revealed high-grade B-cell lymphoma. Superimposed COVID-19 infection presented multiple challenges, but she completed treatment and achieved remission. Suspicion for underlying malignancy was high. Institutional concerns included obtaining imaging studies and the gold standard excisional tissue biopsy while maintaining acceptable staff exposure. Fortunately, a lymph node core biopsy confirmed the histopathological diagnosis of high-grade B-cell lymphoma. The administration of chemoimmunotherapy (rituximab, cyclophosphamide, doxorubicin, dose-reduced vincristine, and prednisone (R-CHOP)) posed inherent risks, notably, worsening cytopenias and hepatotoxicity. The approach to treatment was further complicated as the interaction of high-grade lymphoma and COVID-19 remained unclear. Medical teams have faced delays executing formerly routine diagnostic studies and formulating timely and appropriate treatment strategies. Careful consideration of risks and benefits must be weighed. A multidisciplinary approach is crucial to successfully treat patients. The relationship between COVID-19 and cancer treatment is yet to be established, and large sample-size studies are required.

A T cell inflammatory phenotype is associated with autoimmune toxicity of the PI3K inhibitor duvelisib in chronic lymphocytic leukemia.

Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results in treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naive and central memory CD4 T cells and naive CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs, and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity.

Immunotherapy-associated complete heart block in a patient with NSCLC: A case report and literature review.

The role for PD-1/PD-L1 and CTLA-4 targeted immunotherapy is well outlined in the treatment of metastatic NSCLC. Increased survival benefit supports the use of these medications and the development of next-generation agents with improved efficacy and favorable side-effect profiles. The prevalence of immunotherapy-associated cardiotoxicity (IAC) has grown significantly over the past two years as awareness of this toxicity class has emerged. High-grade conduction disorders comprise a subset of cardiotoxicities with a high case fatality rate. We presented a case of suspected combination ipilimumab-nivolumab associated 3rd degree heart block. The onset of this event was 16 days after immunotherapy initiation. A literature review has suggested that over 75% of cases of cardiotoxicity are observed within the first 6 weeks. We present findings from an interrogation of the FDA Adverse Event Reporting System (FAERS) and provide clinical guidance for the early identification of high-risk patients.

An Unusual Case of Prolymphocytic Leukemia Transformation in a Patient With Chronic Lymphocytic Leukemia.

B-cell prolymphocytic leukemia (B-PLL) is a rare leukemia characterized by rapidly increasing leukocytosis with splenomegaly and lymphadenopathy. Treatment strategies are largely based on studies of chronic lymphocytic leukemia (CLL). Antibodies against the cell surface protein CD20 are considered to be first-line therapy. A 76-year-old male with known CLL presented 2 weeks after starting chemoimmunotherapy for newly refractory CLL after failing ibrutinib therapy. White blood cell count was elevated at 226.7 × 103/µL. Fluorescent in situ hybridization analysis of a bone marrow specimen showed new development of complex cytogenetics. Flow cytometry revealed B cells appearing slightly dimmer on CD45 and brighter on CD20 compared with typical B-CLL suggestive of less mature lymphocyte forms. The patient was diagnosed with B-PLL and started on obinutuzumab and venetoclax with rapid normalization of white blood cells. This case recapitulates the challenges in diagnosing and treating B-PLL. Ibrutinib resistance is a growing area of study with several proposed mechanisms of acquired resistance. The pathogenesis of B-PLL is not completely understood, although mutations in MYC are presumed to play a role.

Ofatumumab plus high dose methylprednisolone followed by ofatumumab plus alemtuzumab to achieve maximal cytoreduction prior to allogeneic transplantation for 17p deleted or TP53 mutated chronic lymphocytic leukemia.

We hypothesized that ofatumumab with sequential methylprednisolone - alemtuzumab would be an effective and tolerable regimen for patients with high-risk chronic lymphocytic leukemia (CLL) with TP53 dysfunction. Thirty CLL patients with TP53 dysfunction (15 treatment naive (TN), 15 relapsed/refractory (R/R)) were enrolled in this phase II study. Therapy included ofatumumab with methylprednisolone for 2-4 monthly cycles, then ofatumumab with alemtuzumab for 4-24 weeks, then allogeneic transplantation or maintenance. The rate of overall response, complete response, marrow minimal residual disease (MRD) negativity, 3-year progression-free survival and overall survival were 80, 13, 80, 53, and 66%, respectively, in TN patients and 68, 0, 54, 25, and 53%, respectively, in R/R patients. Notable grade 3/4 toxicities included neutropenia and infection in 43 and 40% of patients, respectively. At median follow-up of 45 months, 13 patients died, and 10 patients are alive posttransplant. Overall, we observed high rates of MRD-negativity and acceptable tolerability in high-risk CLL.

Controversial fluorescence in situ hybridization cytogenetic abnormalities in chronic lymphocytic leukaemia: new insights from a large cohort.

The significance of rarer cytogenetic abnormalities in chronic lymphocytic leukaemia (CLL) remains controversial. We performed fluorescence in situ hybridization (FISH) prior to initial therapy on 618 CLL patients seen at our centre between 2005 and 2012. With a median follow-up of 5·6 years, we found that 55 patients harbouring 14q32 rearrangements without t(14;18) had a shorter time to first treatment (TTFT) (median 26 months, P = 0·03) than patients with t(14;18) (median not reached). Patients with mono- or bi-allelic del(13q) as a sole abnormality had a similarly long TTFT (median not reached). Those patients who harboured 3 or more FISH abnormalities without del(17p) had a short TTFT (4·6 months), comparable to patients with del(17p) (8 months); however, the overall survival for patients with 3 or more FISH abnormalities was longer than for patients with del(17p) with 0 or 1 additional abnormalities (median not reached vs. 54 months). FISH cytogenetics remains a useful genetic tool in the clinic, even in the era of next generation sequencing and, as such, our data provide valuable new insights for counselling patients.

Somatic mutation as a mechanism of Wnt/ß-catenin pathway activation in CLL.

One major goal of cancer genome sequencing is to identify key genes and pathways that drive tumor pathogenesis. Although many studies have identified candidate driver genes based on recurrence of mutations in individual genes, subsets of genes with nonrecurrent mutations may also be defined as putative drivers if they affect a single biological pathway. In this fashion, we previously identified Wnt signaling as significantly mutated through large-scale massively parallel DNA sequencing of chronic lymphocytic leukemia (CLL). Here, we use a novel method of biomolecule delivery, vertical silicon nanowires, to efficiently introduce small interfering RNAs into CLL cells, and interrogate the effects of 8 of 15 mutated Wnt pathway members identified across 91 CLLs. In HEK293T cells, mutations in 2 genes did not generate functional changes, 3 led to dysregulated pathway activation, and 3 led to further activation or loss of repression of pathway activation. Silencing 4 of 8 mutated genes in CLL samples harboring the mutated alleles resulted in reduced viability compared with leukemia samples with wild-type alleles. We demonstrate that somatic mutations in CLL can generate dependence on this pathway for survival. These findings support the notion that nonrecurrent mutations at different nodes of the Wnt pathway can contribute to leukemogenesis.

Association of advanced leukemic stage and skin cancer tumor stage with poor skin cancer outcomes in patients with chronic lymphocytic leukemia.

IMPORTANCE: Although it has been well established that patients with chronic lymphocytic leukemia (CLL) have an increased risk of developing skin cancer, few studies have investigated the effect of CLL stage on the risk of poor skin cancer outcomes. The present study of CLL staging assesses outcomes of melanoma, squamous cell carcinoma, and Merkel cell carcinoma in this high-risk population. OBJECTIVE: To determine if progression of CLL measured by advanced Rai stage (III or IV) is associated with worse skin cancer outcomes. DESIGN, SETTING, AND PARTICIPANTS: Twenty-year retrospective study at 2 academic centers in Boston, Massachusetts, of adults with CLL and either melanoma, squamous cell carcinoma, or Merkel cell carcinoma. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for the development of poor skin cancer outcomes (local recurrence, nodal metastasis, distant metastasis, or death from skin cancer). RESULTS: In total, 133 patients with 377 primary skin cancers and a median follow-up of 41 months were included. Squamous cell carcinoma predominated (92.0%). The risk of death from skin cancer was equivalent to the risk of death from CLL (13.5%). On multivariate analysis, advanced Rai stage (III or IV) at the time of the first skin cancer diagnosis (HR, 4.5; 95% CI, 2.3-8.9) and a high skin cancer tumor (T) stage (HR, 4.9; 95% CI, 2.2-10.8) were associated with poor skin cancer outcomes. Those with both a low skin cancer T stage and a low Rai stage (n = 265) had a low risk (5.3%; 95% CI, 3.2%-8.7%) of poor skin cancer outcomes. Those with a low T stage and a high Rai stage (n = 89) had a significantly higher risk of poor skin cancer outcomes (16.9%; 95% CI, 10.9%-26.0%). The 23 patients with a high T stage had high risks of poor outcomes regardless of CLL status (27.3% if a low Rai stage and 50.0% if a high Rai stage, with wide 95% CIs). CONCLUSIONS AND RELEVANCE: In patients with CLL and non-basal cell carcinoma skin cancer, mortality is as high from skin cancer as from CLL. The Rai stage and skin cancer T stage should be considered when risk-stratifying patients with skin cancer. Regular communication between dermatologists and oncologists will help facilitate the identification of patients with CLL who are at high risk of having poor skin cancer outcomes.

Evolution and impact of subclonal mutations in chronic lymphocytic leukemia.

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.

SF3B1 and other novel cancer genes in chronic lymphocytic leukemia.

BACKGROUND: The somatic genetic basis of chronic lymphocytic leukemia, a common and clinically heterogeneous leukemia occurring in adults, remains poorly understood. METHODS: We obtained DNA samples from leukemia cells in 91 patients with chronic lymphocytic leukemia and performed massively parallel sequencing of 88 whole exomes and whole genomes, together with sequencing of matched germline DNA, to characterize the spectrum of somatic mutations in this disease. RESULTS: Nine genes that are mutated at significant frequencies were identified, including four with established roles in chronic lymphocytic leukemia (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five with unestablished roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene (with mutations occurring in 15% of patients). SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with chronic lymphocytic leukemia. We further discovered that tumor samples with mutations in SF3B1 had alterations in pre-messenger RNA (mRNA) splicing. CONCLUSIONS: Our study defines the landscape of somatic mutations in chronic lymphocytic leukemia and highlights pre-mRNA splicing as a critical cellular process contributing to chronic lymphocytic leukemia.