Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer.

Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8+ T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4+ T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4+ T cell states that are clonally expanded. These CD4+ T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4+ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.

Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox.

Cytotoxic T cells are important effectors of anti-tumor immunity. While tumor killing is ascribed to CD8+ T cell function, pre-clinical and clinical studies have identified intra-tumoral CD4+ T cells that possess cytotoxic programs and can directly kill cancer cells. Cytotoxic CD4+ T cells are found in other disease settings including infection and autoimmunity. Here, we review the phenotypic and functional characteristics of cytotoxic CD4+ T cells in non-cancer and cancer contexts. We conduct a comparative examination of cytolytic mechanisms of cytotoxic CD4+ T cells across disease states and synthesize features that define these cells independent of context. We discuss regulatory mechanisms driving ontogeny and effector function and evidence for the clinical relevance of cytotoxic CD4+ T cells in cancer. In this context, we highlight important gaps in understanding in the biology of cytotoxic CD4+ T cells as well as the potential use of these cells in immunotherapies for specific cancers.

Non-viral precision T cell receptor replacement for personalized cell therapy.

T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1-3. Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRß). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.

Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.

Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.

Immunity in the Time of Metastases.

Multiplexed interrogation of tumor genomic and immune features in serial patient metastases reported in a recent issue of Cell (Angelova et al., 2018) reveals a pivotal role for immune editing in shaping clonal evolution of metastases.

Utility of a fusion protein T-cell co-stimulation blocker Belatacept in heart transplant recipients: Real world experience from a high volume center.

BACKGROUND: Belatacept (BTC), a fusion protein, selectively inhibits T-cell co-stimulation by binding to the CD80 and CD86 receptors on antigen-presenting cells (APCs) and has been used as immunosuppression in adult renal transplant recipients. However, data regarding its use in heart transplant (HT) recipients are limited. This retrospective cohort study aimed to delineate BTC's application in HT, focusing on efficacy, safety, and associated complications at a high-volume HT center. METHODS: A retrospective cohort study was conducted of patients who underwent HT between January 2017 and December 2021 and subsequently received BTC as part of their immunosuppressive regimen. Twenty-one HT recipients were identified. Baseline characteristics, history of rejection, and indication for BTC use were collected. Outcomes included renal function, graft function, allograft rejection and mortality. Follow-up data were collected through December 2023. RESULTS: Among 776 patients monitored from January 2017 to December 2021 21 (2.7%) received BTC treatment. Average age at transplantation was 53 years (± 12 years), and 38% were women. BTC administration began, on average, 689 [483, 1830] days post-HT. The primary indications for BTC were elevated pre-formed donor-specific antibodies in highly sensitized patients (66.6%) and renal sparing (23.8%), in conjunction with reduced calcineurin inhibitor dosage. Only one (4.8%) patient encountered rejection within a year of starting BTC. Graft function by echocardiography remained stable at 6 and 12 months posttreatment. An improvement was observed in serum creatinine levels (76.2% of patients), decreasing from a median of 1.58 to 1.45 (IQR [1.0-2.1] to [1.1-1.9]) over 12 months (p = .054). eGFR improved at 3 and 6 months compared with 3 months pre- BTC levels; however, this was not statistically significant (p = .24). Treatment discontinuation occurred in seven patients (33.3%) of whom four (19%) were switched back to full dose CNI. Infections occurred in 11 patients (52.4%), leading to BTC discontinuation in 4 patients (19%). CONCLUSION: In this cohort, BTC therapy was used as alternative immunosuppression for management of highly sensitized patients or for renal sparing. BTC therapy when combined with CNI dose reduction resulted in stabilization in renal function as measured through renal surrogate markers, which did not, however, reach statistical significance. Patients on BTC maintained a low rejection rate and preserved graft function. Infections were common during BTC therapy and were associated with medication pause/discontinuation in 19% of patients. Further randomized studies are needed to assess the efficacy and safety of BTC in HT recipients.

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

The Association of Chinese Ethnicity and Language Preference with Advance Directive Completion Among Older Patients in an Integrated Health System.

BACKGROUND: Little is known about possible differences in advance directive completion (ADC) based on ethnicity and language preference among Chinese Americans on a regional level. OBJECTIVE: To understand the association of ethnicity and language preference with ADC among Chinese Americans. DESIGN: Retrospective cohort analysis with direct standardization. PARTICIPANTS: A total of 31,498 Chinese and 502,991 non-Hispanic White members enrolled in Kaiser Permanente Northern California during the entire study period between 2013 and 2017 who were 55 or older as of January 1, 2018. MAIN MEASURES: We compared the proportion of ADC among non-Hispanic White and Chinese patients, and also analyzed the rates according to language preference within the Chinese population. We calculated ADC rates with direct standardization using covariates previously found in literature to be significant predictors of ADC such as age and utilization. KEY RESULTS: Among Chinese members, 60% preferred English, 16% preferred another language without needing an interpreter, and 23% needed an interpreter. After standardizing for age and utilization, non-Hispanic Whites were more than twice as likely to have ADC as Chinese members (20.6% (95% confidence interval (CI): 20.5-20.7%) vs. 10.0% (95% CI: 9.6-10.3%), respectively). Among Chinese members, there was an inverse association between preference for a language other than English and ADC (13.3% (95% CI: 12.8-13.8%) if preferring English, 6.1% (95% CI: 5.4-6.7%) if preferring non-English language but not needing an interpreter, and 5.1% (95% CI: 4.6-5.6%) if preferring non-English language and needing an interpreter). CONCLUSIONS: Chinese members are less likely to have ADC relative to non-Hispanic White members, and those preferring a language other than English are most affected. Further studies can assess reasons for lower ADC among Chinese members, differences in other Asian American populations, and interventions to reduce differences among Chinese members especially among those preferring a language other than English.

Utilization of Regional Anesthesia in the Electrophysiology Lab: A Narrative Review.

PURPOSE OF REVIEW: The electrophysiology lab is an important source of growth of anesthetic volume as the indications and evidence for catheter ablations and various cardiac implantable electronic devices improve. Paired with this increase in volume is an increasing number of patients with substantial comorbid conditions presenting for their EP procedures. For these patients, the interaction between their comorbidities and traditional anesthesia practices may create the risk of hemodynamic instability, cardiovascular or respiratory complications, and potential need for prolonged post-operative monitoring negatively impacting length of hospital stay. RECENT FINDINGS: Regional anesthetic techniques, including pectoralis, serratus, and erector spinae plane blocks, offer options for both regional analgesia and surgical anesthesia for a variety of EP procedures. Existing case reports and extrapolations from other areas support these techniques as viable, safe, and effective components of an anesthetic plan. In this article, we will review the development and challenges of various EP procedures and how different regional anesthetic techniques can function as a component of the anesthesia plan.

West Nile Virus Transmission by Solid Organ Transplantation and Considerations for Organ Donor Screening Practices, United States.

West Nile virus (WNV) is the most common domestic arbovirus in the United States. During 2018, WNV was transmitted through solid organ transplantation to 2 recipients who had neuroinvasive disease develop. Because of increased illness and death in transplant recipients, organ procurement organizations should consider screening during region-specific WNV transmission months.

Do-not-resuscitate (DNR) status and major depressive disorder (MDD): Clinical association and hospitalization outcomes.

OBJECTIVES: To understand (1) the association of Major Depressive Disorder (MDD) and do-not-resuscitate (DNR) status among hospitalized patients and (2) the association of MDD and hospitalization outcomes among DNR patients. METHODS: This was a cross-sectional analysis of United States Healthcare Cost and Utilization Project, Nationwide Inpatient Sample data from 2009 to 2013 for patients >18 years. To address the first objective, we used multivariable logistic regression among all hospitalized patients to compute the adjusted odds ratio (aOR) of having DNR status if patients have active MDD of varying severities after controlling for age, sex, race, suicidal ideation, and Elixhauser Comorbidity Index. To address the second objective, we used multivariable regression among patients with DNR status to compute aOR of having hospitalization outcomes such as increased length of stay, higher total charges, leaving against medical advice, and mortality if patients have MDD. RESULTS: Among all hospitalizations, 2.3% had DNR status. There was an inverse association between severity of MDD and having DNR status. Relative to those without MDD, patients with moderate recurrent MDD episode (aOR 0.74 (95% confidence interval (CI): 0.65-0.85) and severe recurrent MDD episode (aOR of 0.42 (95% CI: 0.37-0.48)) were significantly less likely to have DNR status. Among DNR patients, those with all severities of MDD except mild single episode MDD were >40% less likely to die during hospitalization. Among DNR patients, patients with MDD had 0.7 day longer length of stay, and >$4,500 higher total charges. SIGNIFICANCE OF RESULTS: Patients are less likely to have DNR status if they have active MDD. Among patients with DNR status, those with MDD are less likely to die during hospitalization than those without MDD. With current practice, depression is not associated with increased likelihood of death due to foregoing resuscitation prematurely, though the exact mechanisms of these findings need further investigation.

Donor-derived Cryptococcus gattii sensu stricto infection in two kidney transplant recipients, southeastern United States.

Cryptococcus gattii infection is a rare cause of severe pulmonary disease and meningoencephalitis that has only recently been detected in the southeastern United States. We describe an organ transplant-associated outbreak of C. gattii infection involving an HIV-negative immunosuppressed donor in this region who died following new-onset headache and seizure of unknown cause. Retrospective cryptococcal antigen (CrAg) testing of donor serum was positive. Two of the three transplant recipients developed severe C. gattii infection 11 and 12 weeks following transplantation. One recipient died from severe pulmonary infection, identified on autopsy, and the other ill recipient survived following treatment for cryptococcal meningitis. This outbreak underscores the importance of considering cryptococcosis in patients with clinical findings suggestive of subacute meningitis or other central nervous system (CNS) pathology, and the potential benefit of routine pre-transplant donor CrAg screening using lateral flow assay to guide recipient antifungal prophylaxis. The case also adds to emerging evidence that C. gattii is a potential threat in the southeastern United States.

Early changes in the circulating T cells are associated with clinical outcomes after PD-L1 blockade by durvalumab in advanced NSCLC patients.

Immune checkpoint inhibitors (ICI) are designed to activate exhausted tumor-reactive T cells thereby leading to tumor regression. Durvalumab, an ICI that binds to the programmed death ligand-1 (PD-L1) molecule, is approved as a consolidation therapy for treatment of patients with stage III, unresectable, non-small cell lung cancer (NSCLC). Immunophenotypic analysis of circulating immune cells revealed increases in circulating proliferating CD4 + and CD8 + T cells earlier after durvalumab treatment. To examine durvalumab's mechanism of action and identify potential predictive biomarkers, we assessed the circulating T cells phenotypes and TCR genes of 71 NSCLC patients receiving durvalumab enrolled in a Phase I trial (NCT01693562, September 14, 2012). Next-generation sequencing of TCR repertoire was performed on these NSCLC patients' peripheral blood samples at baseline and day 15. Though patients' TCR repertoire diversity showed mixed responses to the treatment, patients exhibiting increased diversity on day 15 attained significantly longer overall survival (OS) (median OS was not reached vs 17.2 months for those with decreased diversity, p = 0.015). We applied network analysis to assess convergent T cell clonotypes indicative of an antigen-driven immune response. Patients with larger TCR clusters had improved OS (median OS was not reached vs 13.1 months for patients with smaller TCR clusters, p = 0.013). Early TCR repertoire diversification after durvalumab therapy for NSCLC may be predictive of increased survival and provides a mechanistic basis for durvalumab pharmacodynamic activity.

Mechanisms and clinical manifestations of cardiovascular toxicities associated with immune checkpoint inhibitors.

Immunotherapies have greatly expanded the armamentarium of cancer-directed therapies in the past decade, allowing the immune system to recognize and fight cancer. Immune checkpoint inhibitors (ICIs), in particular, have revolutionized cancer treatment and have demonstrated survival benefit in numerous types of cancer. These monoclonal antibodies increase anti-cancer immunity by blocking down-regulators of adaptive immunity, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1), resulting in anti-tumor activity. As ICIs increase immune system activation, they can cause a wide range of inflammatory side effects, termed immune-released adverse events. Though these toxicities can affect nearly any organ, the most fatal toxicity is myocarditis. Here, we discuss the diverse spectrum of cardiovascular toxicities associated with ICI use. In addition, we provide insight and future directions on mechanisms and treatments for immune-related adverse events (irAEs) involving the myocardium, pericardium, vasculature, and conduction system.

Differential contribution of chemotaxis and substrate restriction to segregation of immature and mature thymocytes.

T cell development requires sequential localization of thymocyte subsets to distinct thymic microenvironments. To address mechanisms governing this segregation, we used two-photon microscopy to visualize migration of purified thymocyte subsets in defined microenvironments within thymic slices. Double-negative (CD4(-)8(-)) and double-positive (CD4(+)8(+)) thymocytes were confined to cortex where they moved slowly without directional bias. DP cells accumulated and migrated more rapidly in a specialized inner-cortical microenvironment, but were unable to migrate on medullary substrates. In contrast, CD4 single positive (SP) thymocytes migrated directionally toward the medulla, where they accumulated and moved very rapidly. Our results revealed a requisite two-step process governing CD4 SP cell medullary localization: the chemokine receptor CCR7 mediated chemotaxis of CD4 SP cells towards medulla, whereas a distinct pertussis-toxin sensitive pathway was required for medullary entry. These findings suggest that developmentally regulated responses to both chemotactic signals and specific migratory substrates guide thymocytes to specific locations in the thymus.

Increased Mortality and Reoperation Rates After Treatment for Septic Arthritis of the Knee in People Who Inject Drugs: Nationwide Inpatient Sample, 2000-2013.

BACKGROUND: The United States has a growing opioid epidemic impacting all aspects of health care including orthopaedic surgery. Septic arthritis of the knee is a condition commonly encountered by orthopaedic surgeons related to opioid and injection drug use (IDU). Changes in the frequency of hospitalizations for IDU-related septic arthritis and differences in septic arthritis patient outcomes according to IDU status in the setting of the burgeoning opioid epidemic are unknown. QUESTIONS/PURPOSES: (1) What proportion of patients with septic arthritis of the knee use injection drugs? (2) Are there any differences in complications, reoperations, length of stay, and leaving against medical advice among patients with septic arthritis of the knee with and without IDU? (3) What are the age and racial trends in IDU-related septic arthritis of the knee from 2000 to 2013? METHODS: The Healthcare Cost and Utilization Project, Nationwide Inpatient Sample database of years 2000 to 2013 was utilized for patients between ages 15 and 64 years with a principal discharge diagnosis of native septic arthritis of the lower leg, the vast majority of which represents the knee. The Nationwide Inpatient Sample is the largest publicly available healthcare database in the United States that can show nationally representative clinical trends and outcomes. Septic arthritis was classified as related or unrelated to IDU based on previously published algorithms using billing codes. Patients with IDU-related septic arthritis were more likely to be black or Hispanic, younger, and use Medicare, Medicaid, or self-payment as their primary payment method. The yearly proportion of patients with septic arthritis who used injection drugs was determined. Hospitalization outcomes including length of stay, leaving against medical advice, number of procedures, and mortality rates were compared after adjusting for age, gender, and race in multivariable regression analyses. The yearly change in proportion of IDU-related septic arthritis in each age, race, and gender group was compared over the study period. RESULTS: The proportion of patients with IDU-related septic arthritis increased from 5% in 2000 to 11% in 2013. After adjusting for age, gender, and race, patients with IDU-related septic arthritis were more likely to die during hospitalization (adjusted odds ratio [AOR], 2.86; 95% confidence interval [CI], 1.51-5.39; p < 0.001) and undergo repeat arthroscopic (AOR, 1.24; 95% CI, 1.06-1.45; p = 0.007) or open irrigation and débridement (AOR, 1.68; 95% CI, 1.28-2.19; p < 0.001). Patients with IDU-related septic arthritis were more likely to leave against medical advice (AOR, 7.13; 95% CI, 5.56-9.15; p < 0.001) and also had an additional 5 days in length of stay (95% CI, 4.1-5.5; p < 0.001) on average compared with patients with septic arthritis unrelated to IDU. There was an increasing proportion of patients with IDU-related septic arthritis who were aged 15 to 34 years and 55 to 64 years from 2000 to 2013. CONCLUSIONS: IDU is increasingly the cause of septic knee admissions and is associated with higher rates of mortality, reoperations, resource utilization, and leaving against medical advice. Orthopaedic surgeons must adequately screen for IDU among patients with septic arthritis and monitor them closely for reoperation with a low threshold to reaspirate a knee in the postoperative period. Future studies should determine the current use and potential benefits of a multidisciplinary approach, including addiction specialists, to aid in the management of the increasing number of these patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

Real-Time Monitoring of Vaccination Campaign Performance Using Mobile Phones - Nepal, 2016.

In 2012, the Global Vaccine Action Plan* established a goal to achieve measles and rubella elimination in five of the six World Health Organization (WHO) regions (194 countries) by 2020 (1). Measles elimination strategies aim to achieve ≥95% coverage with 2 routine doses of measles-containing vaccine (2), and implement supplementary immunization activities (SIAs)† in settings where routine coverage is low or where there are subpopulations at high risk. To ensure SIA quality and to achieve ≥95% SIA coverage nationally, rapid convenience monitoring (RCM) is used during or immediately after SIAs (3,4). The objective of RCM is to find unvaccinated children and to identify reasons for nonvaccination in areas with persons at high risk, to enable immediate implementation of corrective actions (e.g., reassigning teams to poorly vaccinated areas, modifying the timing of vaccination, or conducting mop-up vaccination activities). This report describes pilot testing of RCM using mobile phones (RCM-MP) during the second phase of an SIA in Nepal in 2016. Use of RCM-MP resulted in 87% timeliness and 94% completeness of data reporting and found that, although 95% of children were vaccinated, 42% of areas required corrective vaccination activities. RCM-MP challenges included connecting to mobile networks, small phone screen size, and capturing Global Positioning System (GPS) coordinates. Nonetheless, use of RCM-MP led to faster data transmission, analysis, and decision-making and to increased accountability among levels of the health system.

Effect of cord blood processing on transplantation outcomes after single myeloablative umbilical cord blood transplantation.

Variations in cord blood manufacturing and administration are common, and the optimal practice is not known. We compared processing and banking practices at 16 public cord blood banks (CBB) in the United States and assessed transplantation outcomes on 530 single umbilical cord blood (UCB) myeloablative transplantations for hematologic malignancies facilitated by these banks. UCB banking practices were separated into 3 mutually exclusive groups based on whether processing was automated or manual, units were plasma and red blood cell reduced, or buffy coat production method or plasma reduced. Compared with the automated processing system for units, the day 28 neutrophil recovery was significantly lower after transplantation of units that were manually processed and plasma reduced (red cell replete) (odds ratio, .19; P = .001) or plasma and red cell reduced (odds ratio, .54; P = .05). Day 100 survival did not differ by CBB. However, day 100 survival was better with units that were thawed with the dextran-albumin wash method compared with the "no wash" or "dilution only" techniques (odds ratio, 1.82; P = .04). In conclusion, CBB processing has no significant effect on early (day 100) survival despite differences in kinetics of neutrophil recovery.

On the Verge: Immunotherapy for Colorectal Carcinoma.

Although overall survival from colorectal cancer (CRC) has steadily improved over the past decade, there is still work to be done. The gains associated with improved detection and treatment paradigms with chemotherapy and biologics appear to have reached their ceiling. Immune-based therapies have recently demonstrated clinical benefit in other cancers, including CRC with microsatellite instability (MSI), but patients with CRC without MSI have not yet derived benefit. This article reviews the history of CRC immunotherapy trials, the conceptual basis for why the activity of the immune system may be relevant to survival in CRC, and current efforts in CRC immunotherapy, and speculates about future efforts in this area based on experience with immunotherapy efforts in other classes of solid tumors.