Defective T-cell response to COVID-19 vaccination in acute myeloid leukaemia and myelodysplastic syndromes.

Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.

Combination romidepsin and azacitidine therapy is well tolerated and clinically active in adults with high-risk acute myeloid leukaemia ineligible for intensive chemotherapy.

Azacitidine (AZA) is important in the management of patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor which synergises with AZA in vitro. The ROMAZA trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m2 on Days 8 and 15, with AZA 75 mg/m2 administered for 7/28 day cycle. Nine of the 38 (23·7%) patients treated at the MTD were classified as responders by Cycle 6 (best response: complete remission [CR]/incomplete CR n = 7, partial response n = 2). Correlative next-generation sequencing studies demonstrated important insights into therapy resistance.

A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial.

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.

A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are unfit for or relapsed postautologous stem-cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitor vistusertib in an intermittent dosing schedule of 125 mg b.d. for 2 days per week. Thirty patients received vistusertib and six received vistusertib-rituximab for up to six cycles (28-day cycles). Two partial responses were achieved on monotherapy. Durations of response were 57 and 62 days, respectively, for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression-free survival was1.69 (95% confidence interval [CI] 1.61-2.14) months and median overall survival was 6.58 (95% CI 3.81-not reached) months, respectively. The median duration of response or stable disease across the trial duration was 153 days (95% CI 112-not reached). Tumour responses according to positron emission tomography/computed tomography versus computed tomography were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib ± rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1-2. Common vistusertib-related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1-2), diarrhoea (27% G1-2, 6% G3), fatigue (30% G1-2, 3% G3), mucositis (25% G1-2, 6% G3), vomiting (17% G1-2), and dyspepsia (14% G1-2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.

Too many pills to swallow: A case of a mixed overdose.

Propranolol is a highly lipid-soluble beta-receptor antagonist. We describe a case of mixed overdose, including propranolol, amlodipine and olanzapine, resulting in severe resistant hypotension which was successfully treated. A 21-year-old student ingested 6.4 g of propranolol, 280 mg of amlodipine and 560 mg of olanzapine. The patient was brought to the emergency department and exhibited signs of severe systemic toxicity - profound hypotension and circulatory collapse, respiratory depression and coma. The patient had conventional therapy but failed to respond to this and was therefore commenced on IntraLipid infusion, high-dose insulin infusion and inotrope infusion. An endoscopy was performed in intensive care which revealed a large drug beozar - this was removed. We believe that this combination of infusions with early endoscopy could be beneficial in treating similar patients in the future and present the first case of a propranolol drug bezoar.

Tattoos and piercings: bodily expressions of uniqueness?

The study aimed to investigate the motivations underlying the body modification practices of tattooing and piercing. There were 80 participants recruited from an Australian music store, who provided descriptions of their tattoos and piercings and completed measures of need for uniqueness, appearance investment and distinctive appearance investment. It was found that tattooed individuals scored significantly higher on need for uniqueness than non-tattooed individuals. Further, individuals with conventional ear piercings scored significantly lower on need for uniqueness than individuals with no piercings or with facial and body piercings. Neither appearance investment nor distinctive appearance investment differed significantly among tattoo or piercing status groups. Strength of identification with music was significantly correlated with number of tattoos, but not number of piercings. It was concluded that tattooing, but not body piercing, represents a bodily expression of uniqueness.

Suicidal ideation in patients with irritable bowel syndrome.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) traditionally is considered as more of a nuisance than having especially serious consequences. However, this is not the picture witnessed in tertiary care where we have encountered some tragic cases, prompting an assessment of suicidal ideation in such patients. METHODS: One hundred follow-up, tertiary care IBS (tIBS) patients were compared with 100 secondary IBS (sIBS), 100 primary IBS (pIBS) care patients, and 100 patients with active inflammatory bowel disease (IBD). Patients were asked if they had either seriously contemplated or attempted suicide specifically because of their bowel problem as opposed to other issues. The hospital anxiety depression score was recorded, as were other clinical details on all patients. RESULTS: A total of 38% of tIBS patients had contemplated suicide because of their symptoms compared with 16% and 4% in the sIBS and pIBS groups (tIBS vs. sIBS vs. pIBS, P = .002, P < .001). The figure for IBD was 15% (tIBS v. IBD, P < .001). Five tIBS and 1 IBD patient had attempted suicide for gastrointestinal reasons. Mean depression scores did not exceed threshold (10) in the sIBS group contemplating suicide (9.7), but were increased in the equivalent tIBS group (11.7). Hopelessness because of symptom severity, interference with life, and inadequacy of treatment were highlighted as crucial issues for all IBS patients. CONCLUSIONS: IBS has the potential for a fatal outcome from suicide with depression not accounting for all the variance in suicidal ideation. Our observations emphasize the level of hopelessness felt by these patients and the need for improvement in the services provided to them.

Structure of the sterile alpha motif (SAM) domain of the Saccharomyces cerevisiae mitogen-activated protein kinase pathway-modulating protein STE50 and analysis of its interaction with the STE11 SAM.

The sterile alpha motif (SAM) is a 65-70-amino acid domain found in over 300 proteins that are involved in either signal transduction or transcriptional activation and repression. SAM domains have been shown to mediate both homodimerization and heterodimerization and in some cases oligomerization. Here, we present the solution structure of the SAM domain of the Saccharomyces cerevisiae protein, Ste50p. Ste50p functions as a modulator of the mitogen-activated protein kinase (MAPK) cascades in S. cerevisiae, which control mating, pseudohyphal growth, and osmo-tolerance. This is the first example of the structure of a SAM domain from a MAPK module protein. We have studied the associative behavior of Ste50p SAM in solution and shown that it is monomeric. We have examined the SAM domain from Ste11p, the MAPK kinase kinase that associates with Ste50p in vivo, and shown that it forms dimers with a self-association K(d) of approximately 0.5 mm. We have also analyzed the interaction of Ste50p SAM with Ste11p SAM and the effects of mutations at Val-37, Asp-38, Pro-71, Leu-73, Leu-75, and Met-99 of STE50 on the heterodimerization properties of Ste50p SAM. We have found that L73A and L75A abrogate the Ste50p interaction with Ste11p, and we compare these data with the known interaction sites defined for other SAM domain interactions.

Structure of the GTPase-binding domain of Sec5 and elucidation of its Ral binding site.

The exocyst complex is involved in the final stages of exocytosis, when vesicles are targeted to the plasma membrane and dock. The regulation of exocytosis is vital for a number of processes, for example, cell polarity, embryogenesis, and neuronal growth formation. Regulation of the exocyst complex in mammals was recently shown to be dependent upon binding of the small G protein, Ral, to Sec5, a central component of the exocyst. This interaction is thought to be necessary for anchoring the exocyst to secretory vesicles. We have determined the structure of the Ral-binding domain of Sec5 and shown that it adopts a fold that has not been observed in a G protein effector before. This fold belongs to the immunoglobulin superfamily in a subclass known as IPT domains. We have mapped the Ral binding site on this domain and found that it overlaps with protein-protein interaction sites on other IPT domains but that it is completely different from the G protein-geranyl-geranyl interaction face of the Ig-like domain of the Rho guanine nucleotide dissociation inhibitor. This mapping, along with available site-directed mutagenesis data, allows us to predict how Ral and Sec5 may interact.