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Introduction Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of B- cell malignancies leading to durable responses in patients with relapsed/refractory disease. 1,2 One of the most severe toxicities associated with this treatment is immune effector cell-associated neurotoxicity syndrome (ICANS), which was seen in 65-75% of patients treated with axicabtagene ciloleucel (axi-cel) in initial clinical trials. ICANS can range from mild headache to coma, and can occur with or without cytokine release syndrome (CRS). Due to the recent development of CAR T-cell therapy, the long-term effects of ICANS are unknown. This study sought to determine the long-term outcomes in patients with neurotoxicity from axi-cel. Methods We conducted a retrospective chart review of patients who received CAR T-cell therapy with axi-cel between June 2018 and June 2021. Neurotoxicity was graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) ICANS grading system. 3 The primary outcome was percentage of patients who had neurotoxicity defined as ICANS grade ≥ 1 as well as the percentage of patients with neurotoxicity lasting ≥ 1 month. We captured descriptive data such as age, sex, ethnicity, comorbidities, IPI score, stage, baseline neurologic dysfunction, performance status, and number of prior treatments. Secondary outcomes included progression free survival (PFS) and overall survival (OS). Results Thirty-four patients received axi-cel between June 2018 and June 2021 at our institution. Median age of patients was 65. Twenty patients (59%) were male and 14 (41%) were female. The majority of patients received axi-cel for diffuse large B-cell lymphoma (97%). Study population was predominantly hispanic (35%), white (32%), African american (29%) and asian (3%). (Sixteen patients (47%) developed neurotoxicity of any grade, with 7 patients (21%) ≥ grade 3. Of note, 4 patients (12%) died during admission for CAR T-cell therapy and 3/4 deaths were in patients with ICANS ≥ grade 3. Median follow up time was 8 months. Of the 12 patients with neurotoxicity who survived initial admission for CAR-T, 9 (75%) patients recovered from neurotoxicity and mental status was at baseline at discharge without recurrence during follow up. Three (25%) of patients had prolonged neurotoxicity lasting > 1 month. Long-term neurotoxicity included confusion, disorientation, and mild cognitive impairment in the three patients. One patient recovered 15 months after CAR T-cell infusion. 2 patients had prolonged neurotoxicity resulting in deterioration of functional status and death in 1 patient, and 1 patient transitioning to hospice and being lost to follow up. Conclusions Neurotoxicity from axicabtagene ciloleucel is a common adverse event, with half of patients in our cohort having neurotoxicity of some degree, and 20% ≥ grade 3. Twenty-five percent of patients that developed neurotoxicity had long-term effects lasting > 1 month, which resulted in deterioration of functional status in 2 patients. Long-term neurotoxicity included disorientation, confusion, and memory impairment. Our study is limited by a small sample size. Larger studies with longer follow-up times are needed to further characterize the long-term outcomes of neurotoxicity associated with CAR T-cell therapy. Neurotoxicity can be confounded by other causes of neurological dysfunction in these patients such as hospital delirium, chemotherapy toxicity, encephalopathy from infection, and subtle baseline neurologic dysfunction that may not be apparent at presentation. Next steps include prospective evaluation of patients with formal neurology evaluation prior to CAR T-cell therapy and periodically after treatment, in order to objectively monitor late neurologic effects of CAR T-cell therapy. 1. Fl, L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, (2019). 2. Jacobson, C. Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL). in (ASH, 2020). 3. Dw, L. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 25, (2019). Disclosures Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; Guidepoint: Consultancy; GLC: Consultancy; Kymera Therapeutics: Research Funding. Verma: Celgene: Consultancy; BMS: Research Funding; Stelexis: Current equity holder in publicly-traded company; Curis: Research Funding; Eli Lilly: Research Funding; Medpacto: Research Funding; Novartis: Consultancy; Acceleron: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; Throws Exception: Current equity holder in publicly-traded company.

Introduction In the United States, autologous hematopoietic cell transplantation (autoHCT) has fallen out of favor over chemotherapy consolidation for non–high-risk acute myeloid leukemia (AML) when allogeneic hematopoietic cell transplantation (alloHCT) is unfeasible, which is common in racial minorities because of donor registry under-representation and socioeconomic challenges. We compared autoHCT consolidation outcomes with chemotherapy alone in a minority-rich cohort in the Bronx. Patients and Methods We identified adults with favorable or intermediate cytogenetic risk AML in first complete remission after induction at Montefiore Medical Center from 1999 to 2015, and analyzed 81 patients who received consolidation with ≥2 cycles of chemotherapy, of whom 28 received autoHCT. Results The cohort predominantly consisted of ethnic/racial minorities (69%). Age, sex, race, presenting white cell count, and cytogenetic risk were similar between groups. The autoHCT group had longer relapse-free (RFS; 43 vs. 11 months; P = .003) and overall (OS) survival (not reached vs. 36 months; P = .043). Adjusted multivariable analysis showed significant benefit of autoHCT over chemotherapy alone for RFS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.37-0.75; P Conclusion In this inner-city non–high-risk AML cohort, autoHCT provided OS and RFS benefit compared with chemotherapy alone. AutoHCT might constitute a valuable option for ethnic/racial minorities affected by significant barriers to alloHCT, whereas integration of measurable residual disease can help select patients more likely to benefit.

In the United States adult T cell lymphoma–leukemia (ATLL) carries a dismal prognosis and mainly affects immigrants from human T cell lymphotropic virus 1 endemic areas. Allogeneic hematopoietic stem cell transplant (alloHSCT) can be effective and is recommended as an upfront treatment in the National Comprehensive Cancer Network guidelines. We studied the barriers to alloHSCT in one of the largest ATLL populations in the United States. Comprehensive chart and donor registry reviews were conducted for 88 ATLL patients treated at Montefiore Medical Center from 2003 to 2018. Among 49 patients with acute and 32 with lymphomatous subtypes, 48 (59.5%) were ineligible for alloHSCT because of early mortality (52%), loss to follow-up (21%), uninsured status (15%), patient declination (10%), and frailty (2%). Among 28 HLA-typed eligible patients (34.6%), matched related donors were identified for 7 (25%). A matched unrelated donor (MUD) search yielded HLA-matched in 2 patients (9.5%), HLA mismatched in 6 (28.5%), and no options in 13 (62%). Haploidentical donors were identified for 6 patients (46%) with no unrelated options. There were no suitable donors for 7 (25%) alloHSCT-eligible patients. The main limitation for alloHSCT after donor identification was death from progressive disease (82%). AlloHSCT was performed in 10 patients (12.3%) and was associated with better relapse-free survival (26 versus 11 months, P = .04) and overall survival (47 versus 10 months, P = .03). Early mortality and progressive disease are the main barriers to alloHSCT, but poor follow-up, uninsured status, and lack of suitable donor, including haploidentical, are also substantial limitations that might disproportionally affect this vulnerable population. AlloHSCT can achieve long-term remissions, and strategies aiming to overcome these barriers are urgently needed to improve outcomes in ATLL.

Adult T-cell leukemia/lymphoma (ATLL) is a rare, human T-cell lymphotropic virus 1 (HTLV-1)-driven malignancy with treatment challenges and a dismal prognosis. Allogeneic stem cell transplant (alloSCT) has shown encouraging outcomes, especially long-term survival, for ATLL patients, but data are sparse and mostly limited to Japanese patients. This is the largest experience studying the feasibility of stem cell haploidentical donors, which will greatly improve donor transplantation in ATLL outside Japan/Europe.Comparing the outcomes of ATLL patients who underwent either autologous SCT (ASCT) or alloSCT and studying factors affecting transplant outcomes.Retrospective study including patients transplanted between 2005 and 2020; median follow-up of 41 months.Tertiary oncologic center.With 116 patients, this was one of the largest ATLL cohorts in the USA; 21 patients were transplanted with 16 alloSCTs and 5 ASCTs (43% female; median age 56 years [range 39-74]; 67% Black and 29% Hispanic).Chart review.The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 54% and 39%, respectively, and 3-year progression-free survival (PFS) and overall survival (OS) were 27% and 35%, respectively.Four out of 5 patients relapsed after ASCT, with 3 dying from disease progression and 1 lost to follow-up; 1-year RI was 80% versus 32% in alloSCT (P=0.045). In exploratory multivariate analysis, patients achieving first complete response and with good baseline performance scores had significantly better outcomes compared to their counterparts regardless of transplant type. Hispanic patients had worse outcomes, including NRM, PFS, and OS, with OS HR of 7; P=0.04. Thirteen patients died within 2 years, 3 of whom were ASCT recipients: 8 from relapse/progression, including the 3 ASCT patients, and 4 from transplant-related toxicities.AlloSCT led to better long-term outcomes and lower relapse rates than ASCT. Haploidentical and HTLV-1-positive donors are feasible in the absence of suitable donors. Interestingly, Hispanic patients had worse outcomes compared to Black patients in the multivariate analysis. To our knowledge, this has not been previously described and could possibly be attributed to epidemiologic genetic variations in HTLV-1 subtypes between the 2 groups. Further investigation is required, including genomic profiling of these patients.

As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. Comparing to solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematological malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post-vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post-vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies., Graphical Abstract, Evaluating the IgG levels against SARS-CoV-2 spike protein, Astha et al. demonstrate high rates of seroconversion in a diverse cohort of patients with cancer, while identifying lower immunogenicity in patients with hematological malignancies and in patients having received immunosuppressive therapies.

This paper complements the diagnosis of the recently described genus Diamantina and its only species Diamantina lombardii Novelo, Philbrick and Irgang from Minas Gerais (Brazil). Four new features not known from other Podostemaceae–Podostemoideae are documented by microtome sections and SEM graphs: (i) The digitate foliage leaves lack vascular tissue completely. (ii) Leafy shoots produce one or two flowers in terminal and subterminal position. The spathella subtending the subterminal flower is scale-like and positionally homologous to a digitate bract (leaf), whereas the spathella covering the terminal flower bud is tubular (as usual for Podostemoideae). (iii) The usually rudimentary androecium consists of two stamens which form a complete whorl together with three inconspicuous tepals around the gynophore. (iv) The bilocular ovary has an apical cleft. Each carpel tip (hollow inside) is topped by a prominent horn-like stigma. Additional peculiar features of D. lombardii (already mentioned in Philbrick et al., 2004. Syst. Bot. 29, 109–117) are shown: presence of a prominent gynophore (mainly known from African Podostemoideae), and digitate leaves (as found in Cladopus from Eastern Asia to NE Australia).

The evaluation of the thermodynamic properties and phase diagrams of the FeO–SiO 2 , NiO–SiO 2 and SiO 2 –NiO–FeO systems is presented in which a structural model is used for the liquid phase. This thermodynamic model is based on the assumption that each metallic oxide produces the depolymerization reaction of silica network with a characteristic free energy change. A least squares optimization program permits all available thermodynamic and phase diagram data to be optimized simultaneously for the binary systems. In this manner, data for these binary systems have been analyzed and represented with a small number of parameters. The binary structural model is extended to the ternary system assuming a random mixing of cations Fe 2+ and Ni 2+ , since the FeO–SiO 2 and NiO–SiO 2 binary systems exhibit similar thermodynamic behavior, that is comparable free energies of mixing.

Species of Podostemaceae grow in rapidly flowing tropical rivers, streams and water falls, strongly attached to rock substrates via expanded, adhesive-secreting holdfasts (haptera). Vanroyenella is a monotypic genus endemic to Mexico, occurring in the northern extent of the tropical distribution of Podostemaceae in the New World. Embryo sac development and nucellar plasmodium formation of Vanroyenella plumosa Novelo and Philbrick was studied. The numerous ovules are anatropous, bitegmic, exostomous, and tenuinucellate, each with a four-celled monosporic embryo sac of the Apinagia type. Disintegration of the nucellus into a plasmodium takes place prior to fertilization. Embryo sac development of Vanroyenella is similar to other members of the Podostemoideae subfamily.

The purpose of this study is to present and analyze empirical data on seed production and seed characteristics of Mexican and North American species of Podostemaceae. Species of Marathrum, Oserya, Podostemum, Tristicha and Vanroyenella were studied. Podostemaceae flower annually in abundance. Eight of the nine species examined produced seeds in abundance. Podostemum ricciiforme (Liebmann) Royen seldom produces seed. Significant differences occurred between annual and perennial species in mean ovule and seed number. In Podostemaceae, the outer integument of the seed plays a central role in the establishment of seeds on solid substrate. Significant differences between species were observed when comparing overall seed width and length for dry versus wetted seed (cf. percent contribution of the hydrated outer integument). In all species there was a significant positive correlation between integument size and seed size. It remains to be shown whether the observed differences in seed characteristics are ecologically significant, e.g. equate with differences in microhabitat attachment, or reflect differential selection for seed establishment. Clear patterns of relationships between seed production and geographic distribution of species studied herein are lacking. Questions that remain to be addressed concerning seed ecology are discussed.

The Podostemaceae are the largest family of strictly aquatic angiosperms; however, relatively little is known about the palynology of the family. Pollen micromorphology and ultrastructure of five representative New World taxa are described, including Marathrum rubrum Novelo & Philbrick, Oserya coulteriana Tul., Podostemum ceratophyllum Michx., Tristicha trifaria (Bory ex Willd.) Sprengel, and Vanroyenella plumosa Novelo & Philbrick. Pollen grains from all five species are relatively small, spherical, microechinate, have a tectate-granular sexine and a thick nexine in non-apertural regions, and a semitectate sexine and a thin nexine in apertural regions. Characters that vary among the taxa include dispersal unit (monads or dyads), sculptural element morphology, infratectal granule size, and aperture morphology and ultrastructure. This is the first study to describe the pollen morphology of these five taxa in detail, and it is the first to illustrate the ultrastructure of pollen wall characters for any member of the family.

A taxonomic treatment of Podostemaceae in Mexico is presented, based on herbarium study and extensive field collections. Five genera and eight species of Podostemaceae (including Tristichaceae) occur in Mexico: Marathrum Humb. & Bonpl. ( M. rubrum Novelo & Philbrick, M. schiedeanum (Cham.) Tul., M. tenue Liebm.), Oserya Tul. & Wedd. ( O. coulteriana Tul., O. longifolia Novelo & Philbrick), Podostemum Michx. ( P. ricciiforme (Liebm.) P. Royen), Tristicha Du Petit-Thouars ( T. trifaria (Bory ex Willd.) Spreng.) and Vanroyenella Novelo and Philbrick ( V. plumosa Novelo & Philbrick). More species occur on the Pacific slope (especially the states of Jalisco, Michoacan and Guerrero) than the Atlantic slope. In Mexico, Podostemaceae occur predominantly in three main climate types (A, hot and humid; B, dry; C, temperate and humid), and eight Mexican physiographic provinces. Podostemaceae are found primarily in river rapids that occur in the following vegetation types: oak-pine forest, moist mountain forest, tropical rain forest, tropical subdeciduous forest and tropical deciduous forest.

The systematic position of the river-weed family Podostemaceae remains enigmatic due to taxonomic difficulties imposed by the radically altered morphology of these alga-like angiosperms. Although previous workers have placed this group phylogenetically among a wide variety of monocotyledons and dicotyledons, most contemporary authors have proposed that river-weeds are closely related to members of the dicotyledonous order Rosales. A diversity of opinion also exists as to whether the Hydrostachyaceae are related to Podostemaceae. We have investigated the phylogeny of river-weeds by comparing DNA sequences of the chloroplast encoded rbc L gene for eight river-weed genera together with 84 other angiosperm and 11 non-flowering seed plant taxa. The high level of sequence divergence in rbc L that exists between river-weeds, Hydrostachyaceae and other angiosperms presents systematic problems that parallel those associated with the highly divergent morphology of these groups. Rooting rbc L sequences with distant non-flowering plant outgroups results in a topology where Podostemaceae comprise a basal angiosperm clade, but in which other renditions of angiosperm family relationships are depicted unreasonably. Restricting the comparison of river-weed sequences entirely with angiosperms places the group as a sister clade to the Hydrostachyaceae as some authors had anticipated, but this result is only weakly supported. The high level of both morphological and molecular divergence in the river-weed clade confounds efforts to correctly ascertain their phylogenetic relationships. A tentative hypothesis from rbc L data is that the Hydrostachyaceae and Podostemaceae are sister taxa whose closest relatives are the rosid families Crassulaceae and Haloragaceae.

Laboratory studies of seed germination were conducted for five species of Podostemaceae from Mexico: Marathrum haenkeanum Engler, Marathrum rubrum Novelo & Philbrick, Oserya coulteriana Tul., Tristicha trifaria Bory ex Willd. Sprengl, Vanroyenella plumosa Novelo & Philbrick. This represents the first comparative study of seed germination for North American Podostemaceae. Germination occurred within 4 days when seeds were placed in water and under lights. Germination was ⩾95% after 9 days for all but one of the 11 collections examined. Seed placed in water but in the dark did not germinate. Marked interspecific differences in seed germination were not observed. The biology of Podostemaceae is poorly known, especially the more cryptic stages as seeds and seedlings.

Background. Cytomegalovirus (CMV) infection in the immunosuppressed transplant recipient is a cause of significant morbidity. With ganciclovir prophylaxis, the overall incidence of CMV after simultaneous kidney-whole pancreas transplantation remains as high as 40%, while CMV infection has never been reported following pancreatic islet transplantation (PIT) alone (i.e., without kidney transplantation). We designed the following study to objectively quantify the rate of transmission of CMV after clinical PIT. Methods. The 26 pancreatic islet grafts used at our institution since 1/2001 and the corresponding 11 PIT recipients were studied. The CMV serology of all organ donors was tested using a latex agglutination assay for anti-CMV antibody (CMV Scan™, Becton Dickinson®, Cockeysville, MD), a test capable of detecting one CMV-infected cell per 50,000 cells. Following PIT, recipients were closely monitored for clinical symptoms consistent with CMV infection. All patients were tested monthly for the presence of CMV antigenemia using immunofluorescent monoclonal antibodies for the CMV pp65 antigen (Light Diagnostics™, Chemicon®, Temecula, CA). All patients received valganciclovir 450 mg PO BID for 3 months following each PIT. Immunosuppression consisted of daclizumab, sirolimus, and tacrolimus. Results. Eight of the PIT recipients (72%) were CMV seronegative prior to PIT (R−). Eighteen of the 26 pancreatic islet grafts (69%) were from CMV+ donors (D+), and the remaining eight (31%) were from CMV− donors (D−). A single R− recipient received only D− pancreatic islets, while the remaining seven received at least one D+ pancreatic islets graft. In all there were 6 D+R+, 3 D−R+, 12 D+R−, and 5 D−R− PITs. No patient developed symptoms consistent with CMV infection at any time following PIT. Monthly routine blood testing of all recipients has revealed no detectable CMV antigenemia in any patient. Conclusion. In our series neither CMV transmission nor CMV infection was seen after PIT. The risk of CMV transmission is lower after PIT than the risk after simultaneous kidney--pancreas transplantation.

Rabbit skeletal muscle protein phosphatases C-I and C-II have been previously isolated as two proteins of Mr = approximately 35,000. Both enzymes display broad substrate specificities but have distinct enzymatic properties in regard to their susceptibility to heat-stable protein inhibitor-2 and their response to divalent cations. Monoclonal antibodies against both protein phosphatase C-I and C-II were produced by fusion of spleen cells of immunized BALB/c mice with SP2/0-Ag14 mouse myeloma cells. The products of the hybrid cells were screened by solid phase radioimmunoassay for the production of antibodies to protein phosphatase C-I and C-II. Positive cells were cloned and injected into mice to produce ascitic fluids. Ten monoclonal antibodies against phosphatase C-I and eight monoclonal antibodies against phosphatase C-II were obtained. These antibodies were characterized with regard to their relative binding affinities to the two protein phosphatases and their abilities to inhibit the phosphorylase phosphatase activities of the two enzymes. All ten of the phosphatase C-I monoclonal antibodies inhibited the phosphorylase phosphatase activity of phosphatase C-I, and three of these also inhibited phosphatase C-II. Only one of the eight antibodies to phosphatase C-II was inhibitory and inhibited the activities of both phosphatase C-I and C-II. Examination of the binding of these monoclonal antibodies by a solid phase radioimmunoassay showed that eight of the ten phosphatase C-I antibodies cross-reacted with phosphatase C-II, while all eight of the phosphatase C-II antibodies cross-reacted with phosphatase C-I. These findings show that phosphatases C-I and C-II possess common antigenic determinant(s) and may, therefore, be structurally related proteins.