The Significance of Short Latency in Mesothelioma for Attribution of Causation: Report of a Case with Predisposing Germline Mutations and Review of the Literature

Malignant mesothelioma is a tumour of the serosal membranes, related to asbestos exposure. Median latency is in the order of 40 years in various registries, but small numbers of cases with shorter latencies have long been reported and often dismissed as unrelated to asbestos exposure. However, emerging data regarding the significance of inherited mutations leading to a predisposition to mesothelioma suggest that the causative effect of asbestos may be associated with shorter latencies in a subset of patients. Here, we describe a male patient with germline mutations in RAD51 and p53 who developed peritoneal mesothelioma 8.5 years after well-documented asbestos exposure and discuss the current literature on the subject. Mesothelioma in situ is now a WHO-accepted diagnosis, but preliminary data reveal a potential lead time of 5 or more years to invasive disease, and this is also a factor which may affect the recording of latency (and potentially survival) in the future.

Comparison of Threshold and Tolerance Nociceptive Withdrawal Reflexes in Horses

The nociceptive withdrawal reflex (NWR) is used to investigate nociception in horses. The NWR threshold is a classical model endpoint. The aims of this study were to determine NWR tolerance and to compare threshold and tolerance reflexes in horses. In 12 horses, the NWR was evoked through electrical stimulation of the digital nerve and recorded via electromyography from the deltoid. Behavioral reactions were scored from 0 to 5 (tolerance). First, the individual NWR threshold was defined, then stimulation intensity was increased to tolerance. The median NWR threshold was 7.0 mA, whereas NWR tolerance was 10.7 mA. Upon visual inspection of the records, two main reflex components R1 (median latency 44 ms) and R2 (median latency 81 ms) were identified at threshold. Increasing stimulation intensity to tolerance led to a significant increase in the amplitude and duration of R1 and R2, whereas their latency decreased. At tolerance, a single burst of early, high-amplitude reflex activity, with a median latency of 39 ms, was detected in 15 out of 23 stimulations (65%). The results of this study suggest that (1) it is feasible to determine NWR tolerance in horses and (2) high-intensity stimuli initiate ultrafast bursts of reflex activity, which is well known in practice and has now been quantified using the NWR model.

Modeling the Cellular Origin of EVI1 + MLL-AF9-Driven Acute Myeloid Leukemia (AML)

We previously reported that transplantation of hematopoietic stem cells (HSC) expressing a doxycycline (DOX)-regulated AML-associated MLL-AF9 fusion transgene can induce an invasive and chemoresistant disease in mice formed by tumour cells that express the transcription factor EVI1, a known marker of poor prognosis in AML and some solid cancers. To better understand the association of EVI1 and the cellular origin of the disease we analyzed Evi1-IRES-GFP reporter mice (female, n=8, 8-10 weeks old) and found that not only the, quiescent long-term hematopoietic stem cell (LT-HSC : lineage marker-negative (lin -) cKit +Sca1 +(= LSK), CD34 -CD135 -CD150 +CD48 -, 24±3.7%, n=8) compartment, but also more proliferating multipotent progenitors such as MPP1 (LSK, CD34 +CD135 -CD150 +CD48 -, 23±4.6%, n=8), MPP2 (LSK, CD34 +CD135 -CD150 +CD48 +, 6±2.3%, n=8) and MPP3 (LSK, CD34 +CD135 -CD150 -CD48 +, 2±1%, n=8) contain a significant number of cells that express abundant Evi1 ("Evi1 high") at steady state. Notably, we did not observe any significant changes in numbers of Evi1 + cells nor levels of Evi1 mRNA expression in the LT-HSC and MPP1 compartments 5 days after DOX-mediated induction of the iMLL-AF9 fusion. To address the impact of Evi1 on clonogenic growth of iMLL-AF9-expressing LT-HSC, we plated Evi1 high and Evi1 low naïve cells in methylcellulose (MC) and found that upon addition of DOX, Evi1 high cells formed more colonies with an invasive morphology ("type IV") compared to Evi1 low cells (n=11, p<0.05). Immunophenotypically, cells from Evi1 high cell-derived colonies retained a more immature phenotype, reflected by higher cKit +Sca1 + expression (n=11, p<0.05). Plated Evi1 high cells formed Evi1 + colonies whereas Evi1 low lost Evi1 expression (n=11, p<0.05). To address the differential transformation susceptibility in vivo, we transplanted identical numbers of naïve steady-state Evi1 + iMLL-AF9 LT-HSC and MPP1 into irradiated syngeneic recipients. While recipients of Evi1 + MPP1 cells developed an invasive AML earlier than Evi1 + LT-HSC-transplanted mice (n=27, median latency: 96.5 vs. 146.5d, n.s.), very similar disease phenotypes were observed. In contrast, transplants of Evi1 - MPP1 or LT-HSC resulted in a significantly delayed disease induction (n=31, median latency: >200d; LT-HSC: n.s.; MPP1: p<0.05). Although Evi1 + cell-induced disease did present with more extensive organ infiltration by leukemic blasts than Evi1 - AML the phenotypes were similar. We also wondered whether modulation of the HSC compartment by exogenous factors may change Evi1 expression and affect AML induction. We found that 2 days after a single injection (200mg/kg) of recombinant mouse thrombopoietin (mTPO) the number of LT-HSC (n=23; 647 vs. 1165/10 6 lin - cells, p<0.05), but not of MPP1, significantly increased. Similarly, a single application of the synthetic mTPO receptor agonist Romiplostim (RP, 200mg/kg) resulted after 48h in an increase of LT-HSC (n=14; 647 vs. 1459/10 6 lin - cells, p<0.0005). Likewise, a single dose (10mg/kg) of polyinosinic:polycytidylic acid (pI:pC) also significantly increased the number of LT-HSC (n=9; 460 vs. 2300/10 6 lin - cells, p<0.005) but not of MPP1 after 24h. In contrast, 5-Fluorouracil (5-FU; 150mg/kg) did not significantly change the number of LT-HSC and MPP1, 3- and 6-days post-injection. However, only mTPO and RP but not pI:pC or 5-FU significantly increased the fraction of Evi1 high expressing LT-HSC (23 vs. 50%, 23 vs. 49%; n=29, p<0.0001) and MPP1 (22 vs. 47%, 22 vs- 48%; n=29, p<0.0001). Transplantation of identical numbers of iMLL-AF9 LT-HSC and MPP1 isolated 2 days after mTPO application to the donors into irradiated syngeneic recipients resulted in a significantly faster induction of Evi1 + AML than controls (n=19, MPP1: 35 vs. 96.5d, p<0.0001; LT-HSC: 41 vs 146.5d, p<0.0001). Currently ongoing single-cell RNA sequencing experiments of LT-HSC and MPP1 with and without in vivo mTPO stimulation conditionally expressing the iMLL-AF9 fusion should provide some mechanistic insights into increased susceptibility for EVI1 + AML. Our results so far demonstrate that the dynamics of the HSC compartment critically affects the cellular origin and biology of MLL-AF9 driven AML. Disclosures Kurokawa: MSD K.K.: Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Company: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Teijin Limited: Research Funding, Speakers Bureau; Daiichi Sankyo Company.: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding, Speakers Bureau.

Myocarditis and pericarditis in association with COVID-19 mRNA-vaccination: cases from a regional pharmacovigilance centre

In this article we summarize suspected adverse events following immunization (AEFI) of pericarditis, myocarditis and perimyocarditis that were reported by our regional pharmacovigilance centre after COVID-19 mRNA-vaccination and discuss their association with these vaccines. Seventeen cases were reported between March and July 2021. Of these, nine had perimyocarditis, five myocarditis and three pericarditis. Twelve patients were male (71 %). The median age was 38 years (range 17 - 88). The most commonly observed presenting symptom was acute chest pain (65%). While 47% of the patients were previously healthy, 53% had at least one pre-existing comorbidity, with hypertension being the most prevalent (24%). The European Society of Cardiology diagnostic criteria for the reported AEFIs were fulfilled in twelve cases (71%). The AEFIs occurred after the first vaccine dose in six cases (35%), after the second vaccine dose in ten cases (59%) and after both doses in one case (6%). The median latency of all AEFIs taken together was 14 days (range 1 - 28) after the first vaccination and 3 days (range 1 - 17) after the second one. All patients except one were hospitalized (94%) with a median length of stay of 7.5 days (range 3 - 13). The majority of patients (n = 11, 65%) did not experience any complications, and 13 (77%) of the patients were recovered or recovering at the time of discharge. In 16 of the 17 cases (94%), the association between the AEFI and mRNA-vaccination was considered possible by the pharmacovigilance centre.

The outcome of TSHoma from a tertiary care institute in India

Background: Thyroid-stimulating hormone (TSH)-secreting pituitary adenoma (TSHoma) is the rarest functioning pituitary adenoma. Methods: A retrospective analysis of eight patients of TSHomas to highlight the presentations, diagnostic challenges, and treatment outcomes. Results: Median age at diagnosis was 42 years, median latency to diagnosis was 2.5 years, and thyrotoxic and compressive symptoms were the most common presenting symptoms. At presentation, three cases were plurihormonal, six cases were on medical treatment including thyroxine, and two cases were incidentally discovered. Imaging revealed macroadenoma in all cases. Seven cases underwent pituitary surgery, after which three achieved remission. Another case entered remission after adjunctive radiotherapy. Thyrotropin (TSH) immunostaining was demonstrated in six out of seven adenomas. Conclusion: TSHoma is a rare functioning pituitary tumor with both silent and symptomatic presentations. Diagnosis can be established with biochemical and imaging features, even without dynamic tests.

HGG-39. CLINICAL CHARACTERISTICS AND OUTCOME OF PATIENTS WITH RADIATION-INDUCED GLIOMA

The development of gliomas subsequent to therapeutic cranial irradiation is a rare but serious complication. The purpose of this study is to understand the clinical characteristics and outcome of patients with radiation-induced glioma (RIG). Between 2001 and 2018, we identified 10 patients with RIG, which satisfied the Cahan’s criteria in our data base. There was no sex predominance (M: 5, F: 5), and the median age of the primary diseased was 13.5 years (range: 1–39). The primary diseases included 2 germinoma, 2 acute lymphoblastic lymphoma, 2 medulloblastoma, 1 diffuse astrocytoma, 1 pilocytic astrocytoma, 1 pituitary adenoma and 1 metastatic tumor from lung cancer. All the patients received cranial radiation (range: 12–60 Gy). The median latency time between primary disease and RIG was 16 years (range: 9–30 years), which was not correlated with age at the time of primary disease (r2= 0.014, p=0.74). Radiation-induced gliomas included 8 glioblastoma and 2 grade III glioma based on histological diagnosis. After surgical removal or biopsy of the RIG, 4 patients underwent chemotherapy alone (nimustine, temozolomide (TMZ), carboplatin and etoposide), and 6 received chemotherapy (nimustine, TMZ, bevacizumab) combined with radiotherapy (range: 40-66Gy). The median progression free survival and survival time from RIG were 10.1 and 27.5 months, respectively. In summary, RIG may occur many years after successful initial treatment using radiotherapy, and the outcome of our patients with RIG supports the use of radiotherapy and/or chemotherapy after surgical resection.

Incidence of second primary malignancy (SPM) in patients with mucosa-associated lymphoid tissue lymphoma (MALToma).

e20043 Background: MALTomas are extranodal marginal zone lymphomas that arise from B cells in various mucosal lymphoid tissue and are typically indolent. Patients with MALTomas may be at risk for additional cancers due to their long-term survival following treatment, however the incidence of SPM in MALTomas in the U.S. has not been previously described. Methods: Adults with MALT lymphoma were identified using the 2000-2016 SEER-18 database. SPM was defined as tumors diagnosed ≥6 months and up to x months from lymphoma diagnosis. SEER*stat was used to calculate SPM by multiple primary standardized incidence ratio based on observed (O) and expected (E) cases. The expected cases of new cancers of specific types were estimated by assuming that incidence rates for new primary tumors corresponded to sex, age, and calendar time–specific SEER rates for similar invasive primary cancers and applying those rates to the accumulated person-years (PYR) of observation. Excess absolute risk (EAR) of malignancy per 10,000 PYR at risk was calculated as ([O − E]/PYR) × 10,000. Results: As summarized in the table, 12,500 patients were diagnosed with MALT lymphoma of which 1466 (11.8%) developed 1626 SPMs (O/E rate 1.5, 95%CI 1.4-1.5, P < 0.001, EAR 70.4). Median latency period was 54 months (range 6 - 201). Non-Hodgkin lymphomas at separate tissue sites were the most common SPM, with 299 documented cases (O/E rate 6.2, 95%CI -5.4-6.8, P < 0.001, EAR 33.4). Between 6-24 months from MALToma diagnosis, head and neck, renal cell, liver, and anal cancers were increased, while after 24 months, gastric and small bowel cancers, CLL, ALL, and myeloma were increased compared to the general population of the same age group. Conclusions: There is distinct pattern of SPM among patients with MALT lymphoma in within and after 2 years from diagnosis, with an increased incidence compared to the general population. Consider the median latency, SPM may be due in part to the long-term survival and relatively older age of this population. [Table: see text]

Adjuvant Chemotherapy Administration and Survival Outcomes in Lymphoma Survivors with Common Solid Tumors: A Population-Based Study

Background: Adjuvant therapy is an essential component of treatment for many early-stage (stage I-III) breast, colon, or lung cancers after curative surgery. Patients newly diagnosed with these cancers who also have a history of diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) have typically undergone anthracycline-based chemotherapy to treat their lymphoma, and may be less likely to receive adjuvant chemotherapy for subsequent solid cancers because of prior toxicities or limits on cumulative doses. Some studies suggested lower use of adjuvant chemotherapy in HL survivors with breast cancer (Elkin et al., JCO 2011), and worse overall survival (OS) outcomes in lymphoma survivors with solid tumors (Sanna et al., Ann Oncol 2007). Our objective was to examine the use of adjuvant chemotherapy and OS among DLBCL/HL survivors compared with the general population of patients with three common cancers: breast, colon, and lung. Methods: From the Surveillance, Epidemiology, and End Results (SEER) database, we identified patients aged 20-79 diagnosed with breast (stage I-III), colon (stage II-III), or lung (stage II-IIIA) cancers in 2004-2015, who underwent surgery and were thus candidates for adjuvant chemotherapy by virtue of age and stage. Among them we distinguished "cases" of DLBCL or HL survivors (diagnosed with lymphoma >1 year before the index cancer), treating other patients as "controls". We compared administration of chemotherapy (versus no or unknown administration status, as recorded by SEER) and OS in each cancer, in multivariable robust Poisson regression or Cox models, respectively, reporting relative risk (RR) or hazard ratio (HR) with 95% confidence intervals (CI). All models were adjusted for age, sex, race, year of diagnosis, stage of the index cancer, lymph node involvement, type of surgery (e.g. breast conservation or mastectomy, partial or total colectomy, lobectomy or pneumonectomy), and endocrine receptor status for breast cancer. Results: Among patients with breast cancer (n=532,686), we identified 360 DLBCL and 349 HL survivors (with median latency between lymphoma and cancer diagnoses of 79 and 222 months, respectively). Among patients with colon cancer (n=149,993), there were 165 DLBCL and 88 HL survivors (median latency 71 and 156 months, respectively). Among patients with lung cancer (n=23,396) there were 37 DLBCL and 25 HL survivors (medial latency 60 and 147 months, respectively). In breast and colon cancers, DLBCL survivors were significantly older, and HL survivors younger than controls, but this difference was absent in lung cancer (Table). HL survivors were diagnosed with breast cancer at an earlier stage than controls (P=.006), but in all other studied scenarios we observed no significant difference in stage or extent of nodal spread between DLBCL/HL survivors and controls. After adjustment for baseline characteristics, we observed no significant difference between patients with and without a history of lymphoma in the rates of chemotherapy administration (adjusted RR, 0.87 to 1.04), except HL survivors with colon cancer, who had a 20% lower rate than controls (RR, 0.80, 95% CI, 0.64-1.00). OS was significantly worse for patients with prior HL lymphoma in all 3 cancers, but for DLBCL survivors only in breast cancer. Consistent results were observed in the subpopulation of patients who actually received adjuvant chemotherapy. Conclusions: In most studied scenarios, despite prior exposure to intensive chemotherapy, survivors of DLBCL or HL received adjuvant chemotherapy for common cancers at similar rates relative to patients with no history of lymphoma. Therefore, contrary to prior suggestions, differences in application of chemotherapy cannot explain survival disparities between lymphoma survivors and other patients with the same cancers. HL survivors had consistently worse OS even in the subpopulation receiving chemotherapy, suggesting that other (e.g. cardiovascular) sources of mortality related to late toxicities of HL treatment may be contributing, rather than differences in treatment. Unique survival patterns among DLBCL survivors suggest that limits on anthracycline-based chemotherapy due to cumulative lifetime dosing may impair outcomes in breast cancer, but not in cancers like colon or lung, which are treated with non-overlapping taxane- or fluorouracil-based adjuvant regimens. Disclosures Olszewski: Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding.

The spike onset zone

ObjectiveTo determine whether the maximum hemodynamic response to scalp interictal epileptic discharges (IEDs) corresponds to the region where IEDs originate and from where they propagate.MethodsWe studied 19 patients who underwent first an EEG-fMRI showing responses in the gray matter, and then intracranial EEG (iEEG). We coregistered the hemodynamic responses to the iEEG electrode contacts and analyzed IEDs in the iEEG channel adjacent to a maximum response (labeled the main channel), in relation to IEDs in other channels during a widespread intracranial IED event. IEDs in the main channel were aligned at their peak, and IEDs in each channel were averaged time-locked to these instants. The beginning and peak of IEDs in the averaged trace were identified, blinded to the identity of the main channel. The latency of IEDs was computed between the earliest and all other channels.ResultsThe median latency of IEDs in the main channel was significantly smaller than in other channels for either the peak (15.5 vs 67.5 milliseconds, p = 0.00037) or the beginning (46.5 vs 118.4 milliseconds, p = 0.000048). The latency of IED was significantly correlated to the distance from the maximum hemodynamic response (p < 0.0001 for either the peak or the beginning).ConclusionIED adjacent to a maximum hemodynamic response, which often corresponds to the seizure onset zone, is more likely to precede IEDs in remote locations during a widespread intracranial discharge. Thus, EEG-fMRI is a unique noninvasive method to reveal the origin of IEDs, which we propose to label the spike onset zone.

Torsade de pointes and systemic azole antifungal agents: Analysis of global spontaneous safety reports

Background: Literature about torsade de pointes induced by azole antifungal agents is scarce, despite the well-known association. Furthermore, little is known about the latency time between commencing an azole antifungal agent and developing torsade de pointes. The objectives of the present study were therefore to identify all cases of torsade de pointes associated with systemic azole antifungal use reported to the WHO monitoring centre (Uppsala, Sweden) and to determine the latency times between commencing the azole and developing torsade de pointes. Methods: Investigator-driven, retrospective, descriptive analysis of post-marketing pharmacovigilance data regarding systemic azole antifungal agents and the development of torsade de pointes reported to the WHO monitoring centre 1995–2015. Results: 191 cases were reported as follows: fluconazole 130, itraconazole 22, ketoconazole 5, posaconazole 1, voriconazole 33. More than half of all cases involved concomitant suspected or interacting drugs. The median latency times between starting the azole and developing torsade de pointes ranged from 1 (posaconazole) – 9.5 days (itraconazole), range <1–250). Conclusions: Clinicians should be aware of these features of azole-associated torsade de pointes, avoid interacting drugs if at all possible and monitor at-risk patients.