Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

Adaptive functional reorganization in amyotrophic lateral sclerosis: coexisting degenerative and compensatory changes.

BACKGROUND AND PURPOSE: Considerable functional reorganization takes place in amyotrophic lateral sclerosis (ALS) in face of relentless structural degeneration. This study evaluates functional adaptation in ALS patients with lower motor neuron predominant (LMNp) and upper motor neuron predominant (UMNp) dysfunction. METHODS: Seventeen LMNp ALS patients, 14 UMNp ALS patients and 14 controls participated in a functional magnetic resonance imaging study. Study-group-specific activation patterns were evaluated during preparation for a motor task. Connectivity analyses were carried out using the supplementary motor area (SMA), cerebellum and striatum as seed regions and correlations were explored with clinical measures. RESULTS: Increased cerebellar, decreased dorsolateral prefrontal cortex and decreased SMA activation were detected in UMNp patients compared to controls. Increased cerebellar activation was also detected in UMNp patients compared to LMNp patients. UMNp patients exhibit increased effective connectivity between the cerebellum and caudate, and decreased connectivity between the SMA and caudate and between the SMA and cerebellum when performing self-initiated movement. In UMNp patients, a positive correlation was detected between clinical variables and striato-cerebellar connectivity. CONCLUSIONS: Our findings indicate that, despite the dysfunction of SMA-striatal and SMA-cerebellar networks, cerebello-striatal connectivity increases in ALS indicative of compensatory processes. The coexistence of circuits with decreased and increased connectivity suggests concomitant neurodegenerative and adaptive changes in ALS.

Low incidence of severe cGvHD and late NRM in a phase II trial of thymoglobulin, tacrolimus and sirolimus for GvHD prevention.

Chronic GvHD (cGvHD) is the leading cause of late non-relapse mortality (NRM) and morbidity after allogeneic hematopoietic stem cell transplant (AHSCT). We analyzed the late effects of a phase II trial testing the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymoglobulin Thymo) in combination with tacrolimus and sirolimus (TTS) in 47 patients (pts) for the prevention of acute and chronic GvHD after unrelated AHSCT. The median follow-up was 45.2 months. The cumulative incidence of NIH severe cGvHD at 48 months was 6.4% with no new occurrences past 6 months for the entire follow-up period. The overall cumulative incidence of cGvHD was 44.7%. Out of 20 pts who are alive and disease-free at the last follow-up, only 4 pts continue to need systemic immune suppression. We observed low late NRM with only 3 transplant-related deaths after 6 months post transplant. At 4 years of follow-up, the overall cumulative incidence of NRM and disease relapse was 27.7% and 30.0%, respectively. PFS and overall survival (OS) at 4 years were 42 and 47%. At long term follow-up, TTS was associated with low incidence of severe cGvHD and late NRM.

Mycobacterium mucogenicum bacteremia in immune-compromised patients, 2008-2013.

Mycobacterium mucogenicum (MM) is a rapidly growing nontuberculous mycobacterium that may rarely cause bacteremia in immune-compromised hosts. All MM cases from 2008 to 2013 were analyzed across 4 risk groups: stem cell transplantation (SCT), hematologic malignancy, solid tumors, and others. Descriptive analysis was performed, as well as comparative analysis of neutropenic patients (absolute neutrophil count ≤1000/µL) with nonneutropenic patients. Of 39 MM cases, 27 patients had undergone SCT. Neutropenia was present in 12 patients. There was a significant difference in the presence of fever at the time of MM bacteremia between neutropenic and nonneutropenic groups (92% versus 42%; P=0.005). Central venous catheter (CVC) was present in 33 cases. All patients were treated with >1 antibiotic. Most frequently used combination antibiotic regimen involved clarithromycin and amikacin. Median duration of antibiotic treatment was 42days. Bacteremia resolved in all cases with CVC removal and combination antibiotic treatment.

DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation.

Parainfluenza virus (PIV) may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure.

Morbidity and mortality attributable to Rothia bacteremia in neutropenic and nonneutropenic patients.

Rothia spp. are increasingly being recognized as emerging opportunistic pathogens associated with serious infections in immune-compromised hosts. Risk factors include neutropenia, hematologic malignancies, prosthetic devices, and intravascular catheters. We describe 29 patients at our institute from 2006 to 2014 with positive blood cultures for Rothia spp. Neutropenia was observed in 21/29 (72%) patients at the time of bacteremia, and 16/29 (61%) had leukemia. Neutropenic patients were less likely than nonneutropenic patients to have polymicrobial infection (24% versus 63%; P= 0.083) and were also more likely to have multiple positive blood cultures (76% versus 0%; P= 0.0003), indicating true infection. Sources of bacteremia included intravascular catheters, mucositis, and presumed gut translocation. A significant association was seen with steroid use (81% versus 13%; P= 0.0014) and fluoroquinolone use (86% versus 13%; P≤ 0.0001) preceding bacteremia in neutropenic patients. There was no difference between the 2 groups for admission to intensive care unit or mortality. One death was reported possibly due to Rothia infection.

Low blood lymphocyte count at 30 days post transplant predicts worse acute GVHD and survival but not relapse in a large retrospective cohort.

Multiple reports have shown that low absolute lymphocyte count at day 30 (ALC30) after allogeneic hematopoietic SCT (AHSCT) is associated with higher risk of disease relapse and worse OS. However, these reports included heterogeneous populations with different grafts and GVHD prophylaxis. Therefore, we retrospectively evaluated the association of ALC30 with transplant outcomes in a cohort of 381 consecutive patients who underwent AHSCT between 2005 and 2010 and received T-replete PBSC grafts and Tacrolimus/Mycophenolate combination as GVHD prophylaxis. Median follow-up was 57 months. Lower ALC30 (⩽400 × 10(6)/L) was associated with lower OS and increased nonrelapse mortality (NRM) for the whole cohort as well as for recipients of SD and UD grafts separately. Lower ALC30 was associated with more severe acute GVHD (aGVHD; III-IV) for the entire cohort as well as for the SD and UD groups. No association was found between lower ALC30 and relapse. Pretransplant factors associated with lower ALC30 were: unrelated donors; HLA mismatch; older donors; lower recipient age; and lower CD34+ cell dose. In this large retrospective study, ALC30⩽400 × 10(6)/L was associated with worse OS, increased NRM and severe aGVHD.

Low-dose antithymocyte globulin enhanced the efficacy of tacrolimus and mycophenolate for GVHD prophylaxis in recipients of unrelated SCT.

We performed a retrospective analysis of the outcome of 197 consecutive unrelated donor transplant recipients who received GVHD prophylaxis either TM regimen (tacrolimus and mycophenolate) (121 patients) or TM/ATG-G regimen (TM with low-dose antithymocyte globulin (ATG) of 4.5 mg/kg, ATG-G, Genzyme) (76 patients). Cumulative incidences of grade II-IV acute GVHD for the TM and TM/ATG-G cohorts were 49% and 61% (P=0.11) and grade III-IV acute GVHD for the TM and TM/ATG-G cohorts were 27% and 14% (P=0.02), respectively. There was no difference in the incidence of relapse or disease progression between TM and TM/ATG-G-16% and 23% (P=0.64). TM/ATG-G cohort had lower incidence of non-relapse mortality (NRM; 37% vs 20%, P=0.01), chronic GVHD (56% vs 43%, P<0.001) and more favorable global chronic GVHD severity (P<0.001). Univariate analyses showed improved OS and PFS of patients who received TM/ATG-G. Multivariate analysis confirmed TM/ATG-G had a favorable influence on OS (P=0.05) but not on PFS (P=0.07). We concluded that low-dose ATG of 4.5 mg/kg given in conjunction with TM improved GVHD prophylaxis without increased risk of relapse. Lower NRM, lower incidence and severity of chronic GVHD could potentially improve survival.

Long-term follow up of patients proceeding to transplant using plerixafor mobilized stem cells and incidence of secondary myelodysplastic syndrome/AML.

We report the long-term follow up of 49 patients (pts) enrolled on plerixafor compassionate use protocol. Thirty-seven pts (76%) had failed one previous mobilization attempt, while 12 (24%) had failed two or more previous attempts. Using the combination of plerixafor and granulocyte colony-stimulating factor, we collected2.5 × 10(6) CD34+cells/kg in 33 pts (67%). Forty-three of the 49 pts proceeded to an auto-SCT (ASCT). The median days to WBC and platelet engraftment were 11 (range, 9-13 days) and 16 (range, 11-77 days) days post ASCT, respectively. The median WBC count, Hb and platelet counts 1 year after ASCT were 4.7 × 10(9)/L, 12.2 g/dL and 109 × 10(9)/L, respectively. With median follow up of 42 months (range <1-54 months), 21 pts had evidence of disease progression. Five pts developed myelodysplastic syndrome (MDS)/AML at median of 29 months post ASCT. The cumulative incidence of MDS/AML at 42 months was 17% (95% confidence interval, 6 to 32%). Development of secondary MDS/AML in pts proceeding to ASCT after plerixafor mobilization needs to be studied further in a larger cohort.

Large pericardial effusion as a complication in adults undergoing SCT.

Large pericardial effusion (LPE) leading to cardiac tamponade is a rare complication described in patients undergoing SCT. This complication is considered to be a manifestation of chronic GVHD; however its pathophysiology is poorly understood. Currently, there are no published data systematically describing the incidence, clinical characteristics and outcomes of LPEs in adult stem cell transplant recipients. We retrospectively evaluated 858 adult patients (512 autologous, 148 related and 198 unrelated donor) who underwent hematopoietic stem cell and BM transplants at our institution from 2005 to 2008 for the development of post transplant LPE. Seven patients (0.8%) were found to have LPEs and all these patients had undergone unrelated allografts. The median day of diagnosis post transplant was 229 (range 42-525). None of these patients had active manifestations of GVHD other than serositis at the time of LPE detection. Pericardial window (PW) was successfully placed in all patients who developed cardiac tamponade and most patients with LPE were effectively treated by increasing immunosuppression. We conclude that LPE is a rare late complication after allogeneic transplant in adults and in our study developed only after unrelated transplant. PW can be safely performed in these patients and LPEs can be successfully treated with intensification of systemic immunosupression.

Cardiac complications in patients undergoing a reduced-intensity conditioning hematopoietic stem cell transplantation.

Reduced-intensity conditioning (RIC) extends hematopoietic stem cell transplants (HSCT) to elderly or debilitated patients who are not candidates for HSCT. The incidence and outcomes of cardiac complications have been reported following myeloablative HSCT. We assessed the incidence and outcomes of cardiac complications in 278 recipients of RIC from July 2000 to July 2006. All patients received conditioning with BU, fludarabine and TBI. Patients were evaluated from conditioning therapy until 100 days after HSCT. Median age was 56 years. Cardiac events were defined as either one or more of the following: arrhythmias, myocardial infarction or congestive heart failure. Twenty-five patients developed arrhythmias at a median of 3 days post transplant, in 19 patients hemodynamic compromise occurred and mechanical ventilation was required in 15 patients. The arrhythmias included atrial fibrillation (n=17), atrial flutter (n=6) and supraventricular tachycardia (n=2). Troponin was elevated in 12 out of 25 patients. The mean brain natriuretic peptide was 679. All patients converted to a normal rhythm by medical therapy at a median of 2 days. Recurrence of arrhythmia occurred in 76% of patients. Day 100 mortality was 40% in this group. A history of high-dose anthracycline treatment and a low ejection fraction were risk factors for the development of cardiac complications.

Outcomes after auto-SCT in African Americans with multiple myeloma.

To study the impact of auto-SCT on the outcomes in African Americans (AA) with multiple myeloma (MM), we evaluated 101 consecutive AA patients who underwent auto-SCT. The median PFS and OS were 15.6 and 50.8 months, respectively. The median OS from diagnosis was 60 months. Traditional pre and post transplant prognostic variables earlier examined in Caucasian Americans (CA), including beta-2 microglobulin (B2M), chromosome 13 deletion, CR status after auto-SCT, gender, stage, Ig subtype, time to transplant, number of prior regimens and presence of lytic lesions, were not predictive of improved PFS or OS on univariate analysis. Age, lower CD34 cell dose infused, history of palliative radiation therapy (XRT) prior to auto-SCT and refractory disease at the time of auto-SCT were predictive of inferior PFS. History of palliative XRT was the only predictive factor of inferior PFS and OS after auto-SCT on multivariate analysis. In conclusion, MM in AA tends to relapse early after auto-SCT. It is unclear whether early relapses impact OS. Common prognostic peritransplant variables known in CA with MM may not be applicable to AA with MM.

High-dose chemotherapy and adoptive immunotherapy in the treatment of recurrent pediatric brain tumors.

Pediatric patients with recurrent brain tumors have a poor prognosis and limited therapeutic options. We investigated the use of high-dose chemotherapy with adoptive immunotherapy for recurrent brain tumors. Three pediatric patients with recurrent brain tumors received high-dose chemotherapy. This was followed by adoptive transfer of ex-vivo expanded T-cells. The T-cells were generated from peripheral blood after immunization with autologous cancer cells. The objectives of this study included (1) establishing the safety and feasibility of this potential treatment, (2) measuring changes in immune response after high-dose chemotherapy and adoptive immunotherapy, and (3) determining whether adoptive immunotherapy would be able to translate into a clinical response. Immune function was tested in all patients at the time of enrollment into the study. Humoral responses to recall antigens delayed-type hypersensitivity (DTH) were intact in all patients. After immunizing patients with autologous cancer cells, peripheral blood lymphocytes were harvested and activated with anti-CD3, expanded in-vitro, and infused post-autologous transplant. Patients received at least three doses of the vaccine, each consisting of an intradermal administration near a draining lymph node at biweekly intervals. Toxicity was limited and well tolerated in all patients. All three patients showed a tumor-specific immune response by serial imaging. Responses were durable at 16, 23, and 48 months, respectively.

Rhodococcus equi lung infection in an allogeneic hematopoietic stem cell transplant recipient.

In this report, we describe a case of Rhodococcus equi lung infection diagnosed in an allogeneic hematopoietic stem cell transplant with oral graft-versus-host disease 3 months after stem cell infusion. The lung lesion persisted despite an approximate 3 months of vancomycin therapy, but then responded favorably to a combination of intravenous ertapenem at 1 g daily and oral rifampin at 600 mg daily for 1 month. An overview of Rhodococcus infection in transplant recipients is presented. This case and the discussed literature suggest that combination antibiotic therapy is warranted in patients with decreased humoral and cellular immunity.

Non-bacterial infections in allogeneic non-myeloablative stem cell transplant recipients.

Data on non-bacterial infections during allogeneic non-myeloablative hematopoietic stem cell transplantation (HSCT) are widely different. We evaluated data on 48 consecutive patients who received a conditioning regimen with fludarabine and cyclophosphamide (73%) or fludarabine and total body irradiation (27%) and then underwent allogeneic non-myeloablative HSCT. Cytomegalovirus (CMV) infection was common and occurred in 48% of patients; 3 patients developed CMV disease, and all survived. CMV reactivation was found to be common with both conditioning regimens in our patient population. Invasive aspergillosis occurred in 4 patients (8%) and 3 died. Other serious non-bacterial infections were uncommon. Review of the available literature on non-myeloablative HSCT suggests that the frequency and type of opportunistic infections vary considerably.

High fatality rate of Epstein-Barr virus-associated lymphoproliferative disorder occurring after bone marrow transplantation with rabbit antithymocyte globulin conditioning regimens.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (EBV-LPD) following bone marrow transplantation can be fatal. The major risk factors for the development of EBV-LPD are ex vivo T-cell depletion or in vivo T-cell depletion with either antithymocyte globulin (ATG) or monoclonal anti-T-cell antibodies. Between March 1999 and January 2001, a total of 23 transplants with ATG of equine source (20 transplants) and ATG of rabbit source (3 transplants) used as part of the preparatory regimen were performed at the Barbara Ann Karmanos Cancer Institute in Detroit, Mich. The three patients who received rabbit ATG developed EBV-LPD between 60 and 90 days following bone marrow transplantation. However, there were no cases of EBV-LPD in the equine group. Treatment given in these cases consisted of tapering immunosuppression, antiviral therapy, unprocessed donor lymphocyte infusion, mobilized peripheral blood progenitor cell rescue infusion (one patient), and chemotherapy (one patient). All three patients died of complications from EBV-LPD. The association of rabbit ATG with the development of EBV-LPD suggests that patients receiving rabbit ATG as part of their preparatory regimens require close monitoring of the EBV viral load and possible early intervention with antiviral therapy.

Safety of low-dose low-molecular-weight-heparins in thrombocytopenic stem cell transplantation patients: a case series and review of the literature.

Few attempts have been made to examine the feasibility of safely administering low-molecular-weight-heparins (LMWHs) in the presence of concurrent thrombocytopenia. We retrospectively investigated the safety of low-dose LMWH in BMT patients, a population at risk of bleeding. In total, 26 patients received at least one dose of low-dose enoxaparin (ie <1 mg/kg/day) during thrombocytopenia. s.c. enoxaparin 40 mg once daily was given in 85% of the cohort. The mean number of platelet days <55 x 10(9) and <20 x 10(9)/l were 16.5 days (95% CI=8.04-24.96) and 4.14 days (95% CI=2.35-5.93), respectively. The mean number of low-dose enoxaparin administration days when platelet <55 x 10(9) and 20 x 10(9)/l were 9.89 days (95% CI=3.26-16.53) and 2.25 days (95% CI=0.57-3.93), respectively. Minor bleeding occurred in four patients (15%) whereas major episodes developed in two patients (8%). The latter two events occurred during the transition between full therapeutic (ie 1.5-2 mg/kg/day) and low-dose enoxaparin close to the onset of thrombocytopenia. The present case series, along with the discussed literature, descriptively suggests that low-dose enoxaparin may be safely administered at a platelet count in the range of 20 and 55 x 10(9)/l in BMT patients who weigh >55 kg.

Mixed hematopoietic chimerism at day 90 following allogenic myeloablative stem cell transplantation is a predictor of relapse and survival.

We retrospectively analyzed the prognostic significance of mixed chimerism and associated clinical parameters in 80 patients following unmanipulated allogenic stem cell transplantation. Chimerism studies were performed on marrow aspirates using fluorescent in situ hybridization and variable number tandem repeats techniques at day +30, day +90 and +12 months. The median overall survival (OS) was 24 months (range, 1-56 months). Mixed chimerism was found in 23, 28 and 14% of patients at day +30 (1 month), +90 (3 months), and +12 months, respectively. Day +30 chimerism studies failed to provide any prognostic information. Day +90 mixed chimeras (MC) had significantly higher relapse rates compared to day +90 complete chimeras (CC) at 6 months (P=0.03) and 18 months when compared to MC (P=0.03) following transplant. The median OS in day +90 MC and day+90 CC were, respectively (95% CI, 2-35 months), compared to 47 months (95% CI, 20-74 months) (P=0.02). In conclusion, chimerism studies on day +30 could be reserved for patients who fail to demonstrate engraftment. Day +90 MC had higher relapse rates and lower OS, and therefore may be considered for novel therapies and future studies.

Point fingerprint: a new 3-D object representation scheme.

This paper proposes a new, efficient surface representation method for surface matching. A feature carrier for a surface point, which is a set of two-dimensional (2-D) contours that are the projections of geodesic circles on the tangent plane, is generated. The carrier is named point fingerprint because its pattern is similar to human fingerprints and plays a role in discriminating surface points. Corresponding points on surfaces from different views are found by comparing their fingerprints. The point fingerprint is able to carry curvature, color, and other information which can improve matching accuracy, and the matching process is faster than 2-D image comparison. A novel candidate point selection method based on the fingerprint irregularity is introduced. Point fingerprint is successfully applied to pose estimation of real range data.

A new deformable model for analysis of X-ray CT images in preclinical studies of mice for polycystic kidney disease.

This paper describes the application of a new probabilistic shape and appearance model (PSAM) algorithm to the task of detecting polycystic kidney disease (PKD) in X-ray computed tomography images of laboratory mice. The genetically engineered PKD mouse is a valuable animal model that can be used to develop new treatments for kidney-related problems in humans. PSAM is a statistical-based deformable model that improves upon existing point distribution models for boundary-based object segmentation. This new deformable model algorithm finds the optimal boundary position using an objective function that has several unique characteristics. Most importantly, the objective function includes both global shape and local gray-level characteristics, so optimization occurs with respect to both pieces of information simultaneously. PSAM is employed to segment the mouse kidneys and then texture measurements are applied within kidney boundaries to detect PKD. The challenges associated with the segmentation non-rigid organs along with the availability of a priori information led to the choice of a trainable, deformable model for this application. In 103 kidney images that were analyzed as part of a preclinical animal study, the mouse kidneys and spine were segmented with an average error of 2.4 pixels per boundary point. In all 103 cases, the kidneys were successfully segmented at a level where PKD could be detected using mean-of-local-variance texture measurements within the located boundary.