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Long-term COVID-19 pneumonia during anti-CD20 therapy Journal Pre-proof Resolution of one-year persisting COVID-19 pneumonia and development of immune thrombocytopenia in a follicular lymphoma patient with preceding rituximab maintenance therapy: a follow-up report and literature review of cases with prolonged infections

Discrimination of Philadelphia‐negative myeloproliferative neoplasms (Ph‐MPNs) from reactive hypercytosis and myelofibrosis requires a constellation of testing including driver mutation analysis and bone marrow biopsies. We searched for a biomarker that can more easily distinguish Ph‐MPNs from reactive hypercytosis and myelofibrosis by using RNA‐seq analysis utilizing platelet‐rich plasma (PRP)‐derived RNAs from patients with essential thrombocythemia (ET) and reactive thrombocytosis, and CREB3L1 was found to have an extremely high impact in discriminating the two disorders. To validate and further explore the result, expression levels of CREB3L1 in PRP were quantified by reverse‐transcription quantitative PCR and compared among patients with ET, other Ph‐MPNs, chronic myeloid leukemia (CML), and reactive hypercytosis and myelofibrosis. A CREB3L1 expression cutoff value determined based on PRP of 18 healthy volunteers accurately discriminated 150 driver mutation–positive Ph‐MPNs from other entities (71 reactive hypercytosis and myelofibrosis, 6 CML, and 18 healthy volunteers) and showed both sensitivity and specificity of 1.0000. Importantly, CREB3L1 expression levels were significantly higher in ET compared with reactive thrombocytosis (P < .0001), and polycythemia vera compared with reactive erythrocytosis (P < .0001). Pathology‐affirmed triple‐negative ET (TN‐ET) patients were divided into a high– and low–CREB3L1‐expression group, and some patients in the low‐expression group achieved a spontaneous remission during the clinical course. In conclusion, CREB3L1 analysis has the potential to single‐handedly discriminate driver mutation–positive Ph‐MPNs from reactive hypercytosis and myelofibrosis, and also may identify a subgroup within TN‐ET showing distinct clinical features including spontaneous remission.

Nasal natural killer (NK)-cell lymphoma was resistant to various antitumor agents. Although high expression of p-glycoprotein has been reported, other molecular mechanism of the chemo-resistance is largely unknown. Activation of STAT3 and expression of major apoptosis-related proteins Bcl-2, Bcl-x, and Mcl-1 were analyzed by immunohistochemistry. Effects of STAT3 inhibitor AG490 on NK-YS cell line were analyzed by Western blotting and flow cytometric apoptosis assay. STAT3 was activated in six of the nine nasal NK-cell lymphomas (67%). In contrast, STAT3 activation was detected in 35% of diffuse large B-cell lymphoma (DLBCL) and in 10% of follicular lymphoma (FL). Frequent activation of STAT3 was significantly correlated with Mcl-1 expression in nasal NK-cell lymphoma, i.e., Mcl-1 was positive in five of six STAT3-active cases and negative in all three STAT3-inactive ones. In DLBCL, not only six out of seven STAT3-active cases (86%) but also eight out of thirteen STAT3-inactive cases (62%) were positive for Mcl-1 expression. Latent membrane protein-1 was positive in four nasal NK-cell lymphomas, among which three cases showed intermediate STAT3 activation. Inhibition of STAT3 activation by JAK inhibitor AG490 decreased Mcl-1 expression and induced apoptosis in STAT3-active NK-YS cells. Serum starvation rather increased the Mcl-1 level in NK-YS cells, and this effect was also canceled by AG490. These results suggest that activation of STAT3-Mcl-1 axis may play a role in the chemotherapy resistance of nasal NK-cell lymphoma. The pathway may be one of the future therapeutic targets of this intractable disease.

The majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) harbor JAK2, CALR, or MPL mutations. We compared clinical manifestations of different subtypes of JAK2 and CALR mutations in Japanese patients with MPNs. Within our cohort, we diagnosed 166 patients as polycythemia vera (PV), 212 patients as essential thrombocythemia (ET), 23 patients as pre-primary myelofibrosis (PMF), 65 patients as overt PMF, and 27 patients as secondary myelofibrosis following the 2016 WHO criteria. Compared to patients with JAK2V617F-mutated PV, JAK2 exon 12-mutated PV patients were younger, showed lower white blood cell (WBC) counts, lower platelet counts, higher red blood cell counts, and higher frequency of thrombotic events. Compared to JAK2-mutated ET patients, CALR-mutated ET patients were younger, showed lower WBC counts, lower hemoglobin levels, higher platelet counts, and fewer thrombotic events. CALR type 1-like mutation was the dominant subtype in CALR-mutated overt PMF patients. Compared with JAK2V617F-mutated ET patients, JAK2V617F-mutated pre-PMF patients showed higher LDH levels, lower hemoglobin levels, higher JAK2V617F allele burden, and higher frequency of splenomegaly. In conclusion, Japanese patients with MPNs grouped by different mutation subtypes exhibit characteristics similar to those of their Western counterparts. In addition, ET and pre-PMF patients show different characteristics, even when restricted to JAK2V617F-mutated patients.

Etidronate therapy inhibits bone resorption and improves calcium balance, and such therapy may prevent bone loss and reduce the risk of subsequent hip fracture.

Objectives:  Nasal natural killer (NK)/T‐cell lymphoma is characterized by chemo‐resistance, angiodestruction, and aggressive tumor progression. Few studies exist on molecular characteristics of this disease entity. Methods:  Expression levels of major apoptosis‐related proteins Bcl‐2, Bcl‐x, Mcl‐1, Bax, and a proliferative marker Ki‐67 were analyzed in 11 nasal NK/T‐cell lymphoma cases by immunohistochemical methods. Nine cases were of NK‐cell lineage and two cases were of T‐cell lineage. For comparison, 12 follicular lymphoma (FL) cases and 16 diffuse large B‐cell lymphoma (DLBCL) cases were also studied. Results and conclusions:  Bax expression was low in all nasal NK‐cell lymphoma cases, which constitute the major population of nasal NK/T‐cell lymphoma. Bax expression in nasal NK‐cell lymphoma was similar to FL and significantly lower compared with DLBCL. Bcl‐2 expression was significantly lower in nasal NK/T‐cell lymphoma compared with that of FL and DLBCL. Bcl‐x expression was high in all three lymphomas. Two distinct Mcl‐1 expression groups existed for nasal NK/T‐cell lymphoma (6.2 ± 5.2% and 59.1 ± 12.3%, 95% CI). Ki‐67 expression was high in nasal NK/T‐cell lymphoma, and worse prognostic groups tended to express higher levels of Ki‐67. The results suggest a combination of impaired apoptosis and aggressive proliferation in nasal NK/T‐cell lymphoma, and may provide explanations for its poor prognosis.

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