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Background The clinical impact of addressing potential germline alterations from tumor-only next-generation sequencing (NGS) is not well characterized. Current guidelines for cancer genetic testing may miss clinically actionable germline changes, which may have important implications for cancer screening, treatment, and prevention. We examined whether increasing involvement of the clinical genetics service during somatic tumor-only NGS review at Molecular Tumor Board (MTB) increases the detection of germline findings. Methods In a retrospective evaluation of patients who underwent tumor-only NGS and were reviewed at MTB, we quantified genetic counseling (GC) referrals as well as germline testing uptake and results across three cohorts: before (C1) and after (C2) the addition of tumor-only NGS review and after (C3) instituting a formal process to coordinate NGS-based genetics referrals to preexisting oncology appointments. All statistical tests were two-sided. Results From 2013 to 2017, 907 tumor-only NGS reports were reviewed at MTB (nC1 = 281, nC2 = 493, nC3 = 133); gastrointestinal (22.5%), lung (19.7%), genitourinary (14.8%), and breast (14.1%) were the most common index cancers. GC visits due to MTB increased with each successive cohort (C1 = 1.1%, C2 = 6.9%, C3 = 13.5%; P for trend [ P trend] <.001), as did germline testing (C1 = 0.7%, C2 = 3.2%, C3 = 11.3%; P trend <.001). Diagnosis of germline pathogenic variants increased with each successive cohort (C1 = 1.4%, C2 = 2.0%, C3 = 7.5%; P trend =.003) and with germline pathogenic variants found by MTB review (C1 = 0.4%, C2 = 0.4%, C3 = 2.3%; P trend =.12). Conclusions Both review of tumor-only NGS by genetics and the institution of a process coordinating GC with oncology appointments increased the discovery of germline pathogenic variants from tumor-only NGS testing. Furthermore, this process identified germline pathogenic variant carriers who would not have otherwise met standard criteria for germline testing. [ABSTRACT FROM AUTHOR]

Background: Delays in time to treatment initiation (TTI) for new cancer diagnoses cause patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of increased TTI and association with overall survival. Methods and findings: We utilized prospective data from the National Cancer Database for newly diagnosed United States patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004–13. TTI was defined as days from diagnosis to first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (N = 363,863), renal (N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 to 29 days (P<0.001). Aside from year of diagnosis, determinants of increased TTI included care at academic center, race, education, prior history of cancer, transfer of facility, comorbidities and age. Increased TTI was associated with worsened survival for stages I and II breast, lung, renal and pancreas cancers, and stage I colorectal cancers, with hazard ratios ranging from 1.005 (95% confidence intervals [CI] 1.002–1.008) to 1.030 (95% CI 1.025–1.035) per week of increased TTI. Conclusions: TTI has lengthened significantly and is associated with absolute increased risk of mortality ranging from 1.2–3.2% per week in curative settings such as early-stage breast, lung, renal and pancreas cancers. Studies of interventions to ease navigation and reduce barriers are warranted to diminish potential harm to patients. [ABSTRACT FROM AUTHOR]

Purpose: Precision oncology is widely discussed, but cohort studies are limited. We previously reported our prospective experience of precision oncology in solid tumors, and here we report our longitudinal experience, focusing on therapeutic impact. Patients and Methods: We conducted a retrospective review of 600 consecutive patients seen at Cleveland Clinic from 2013 to 2016 for treatment of incurable solid tumor malignancies for whom tumor genomic profiling was ordered using FoundationOne (Cambridge, MA). Results were discussed at our multidisciplinary genomics tumor board. Data analyzed included subsequent therapy and overall survival (OS). Results: Median age was 59 years (range, 18 to 94 years), 308 (51.3%) were female, and 533 (88.8%) were white. Targeted therapy was recommended in 310 patients (51.7%). After results, 313 patients (52.2%) started any subsequent therapy; of these, 95 (30%; 15.8% overall) received genomics-driven therapy (G), and 218 (70%) received non–genomics-driven treatment (NG). For the G versus NG group, the on-label, off-label, and clinical trial therapy breakdowns were 23% versus 88%, 47% versus 3%, and 30% versus 9%, respectively. Median OS for patients receiving no therapy after tumor genomic profiling was 5.5 months; for the G and NG groups, it was 18 (P <.001) and 14.4 (P <.001) months, respectively (P = NS for G v NG). The use of G increased from 10% in the first 250-patient cohort (reported earlier) to 20% in the subsequent 350-patient cohort. Conclusion: Tumor genomic profiling influenced treatment in 15.8% of patients. More patients received treatment via clinical trials in the G cohort, and although not statistically significant, there was a trend toward increased OS in the G (v NG) group. These data can further guide real-world applications of precision oncology. [ABSTRACT FROM AUTHOR]

Pre-transplant PET/CT may be prognostic in diffuse large B-cell lymphoma (DLBCL) patients undergoing autologous stem cell transplantation (ASCT). We reviewed relapsed and pre-transplant PET/CT scans of 32 patients with DLBCL treated with ASCT to determine the Deauville score and the maximum standardized uptake value (SUVmax). Patients with a Deauville score of 4 had a significantly inferior prognosis. The 3-year progression-free survival (PFS) for patients with Deauville 1-3 score was 64%, compared to 0% for Deauville 4, while the 3-year overall survival (OS) was 84% and 25%, respectively (p < .001, p = .002). The change in the SUVmax (>66 versus ≤66%) was not predictive of PFS or OS, but a high pre-transplant SUVmax (>6) demonstrated a trend towards an inferior PFS. Pre-transplant PET/CT is a tool for identifying DLBCL patients at high risk for treatment failure with ASCT and could be used to risk-stratify patients in prospective clinical trials of novel transplant strategies. [ABSTRACT FROM AUTHOR]

B-cell non-Hodgkin lymphomas (NHL) display dysregulation of pathways controlling cell proliferation and apoptosis. Combined proteasome and mTOR inhibition, demonstrated with bortezomib and everolimus in a preclinical model, thus warrants evaluation in humans. We conducted a phase I study to identify the maximum tolerated dose (MTD) and safety of this combination in relapsed/refractory (r/r) NHL. Twenty-nine patients were enrolled from July 2008 to March, 2015. Toxicities were primarily hematologic, and dose-limiting thrombocytopenia defined the MTD as 5mg everolimus daily with 1.3 mg/m² bortezomib d1, 4, 8, and 11 every 21 days. Of 25 response-evaluable patients there was one complete response in a patient with MCL and three partial responses (two MCL, one FL) for an overall response rate of 16%. In conclusion, the combination of everolimus and bortezomib results in dose limiting thrombocytopenia, but is tolerable. This combination has limited clinical activity in heavily pretreated NHL. [ABSTRACT FROM AUTHOR]

Background Exposure to ionizing radiation has been linked to myelodysplastic syndromes (MDS); it is not clear whether therapeutic radiation doses used for prostate cancer pose an increased MDS risk. Methods We performed a retrospective cohort study of prostate cancer patients diagnosed between 1986 and 2011 at Cleveland Clinic, comparing those who underwent definitive treatment with radical prostatectomy (RP) to radio-therapy either external beam radiotherapy (EBRT) or prostate interstitial brachytherapy (PI) and to population- based registries. Competing risk regression analyses were used to determine the cumulative risk of developing MDS. All statistical tests were two-sided. Results Of 10924 patients, 5119 (47%) received radiation (n = 2183 [43%] in EBRT group and n = 2936 [57%] in PI group) and 5805 (53%) were treated with RR Overall, 31 cases of MDS were observed, with age-adjusted incidence rates no higher than in population-based registries. In univariate analyses, advancing age (hazard ratio [HR] = 1.14; 95% confidence interval [CI] -- 1.09 to 1.20; P< .001) and radiotherapy exposure (HR = 3.44; 95% CI = 1.41 to 8.37; P= .007) were statistically significantly associated with development of MDS. In multivariable analyses, although advanced age (HR = 1.13; 95% CI= 1.06 to 1.19; P< .001) remained statistically associated with MDS, radiation did not, although a small non-statistically significant trend existed for PI-treated patients. MDS rates were no higher than in population-based registries. Conclusions With relatively short follow-up, prostate cancer patients definitively treated with radiation did not appear to have a statistically increased risk of subsequent MDS. [ABSTRACT FROM AUTHOR]

Pre-existing central nervous system ( CNS) involvement may influence referral for autologous haematopoietic cell transplantation ( AHCT) for patients with non-Hodgkin lymphoma ( NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement ( CNS+) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma ( CNS−). There were significant baseline differences between the cohorts. CNS+ patients were more likely to be younger, have lower performance scores, higher age-adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression-free survival ( PFS) and overall survival ( OS) at 5 years. A matched pair comparison of the CNS+ group with a subset of CNS− patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT ( n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission ( n = 96) at the time of AHCT. CNS+ patients can achieve excellent long-term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis. [ABSTRACT FROM AUTHOR]

Early and reliable prediction of the likelihood of achieving adequate stem cell collection for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) would improve collection efficiency, prevent unnecessary aphereses, and permit appropriate treatment alterations. No previous study has reported a threshold CD34+ cell collection quantity on Day 1 or 2 of leukapheresis that could predict successful stem cell collection. We performed a retrospective analysis of all MM patients undergoing first attempt of stem cell collection at our institution from 2001 through 2008. Recursive partitioning analysis was used to identify Day 1 or Day 1+2 CD34+ collection quantity that predicted failure to reach target ≥2 × 106 CD34+ cells/kg within five days of collection. Totally, 172 patients were included in the analysis. Patients underwent mobilization with G-CSF or G-CSF+ chemotherapy. 23 of 172 patients (13.4%) failed to collect sufficient (≥2 × 106 CD34+ cells/kg) CD34+ cells after five days of apheresis: 22 of 29 who collected ≤0.70 × 106 CD34+ cells/kg and 1 of 143 who collected >0.70 × 106 CD34+ cells/kg (75.9% vs. 0.7%, P < 0.001) on Day 1. Collection failure occurred in 23 of 30 patients who collected ≤1.54 × 106 CD34+ cells/kg and 0 of 142 who collected >1.54 × 106 CD34+ cells/kg (76.7% vs. 0%, P < 0.001) on Days 1 + 2. Day 1 CD34+ cell collection quantity identifies patients unlikely to achieve adequate collection for ASCT. Patients who collect ≤0.70 × 106 CD34+ cells/kg on day 1 could be considered for treatment modifications to improve CD34+ collection, such as early administration of plerixafor or large volume apheresis. J. Clin. Apheresis, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with cytarabine and methotrexate) is an intense chemotherapy regimen frequently used for hematologic malignancies including mantle cell lymphoma. To address whether treatment with hyper-CVAD impairs mobilization of peripheral blood stem cells, we retrospectively analyzed mobilization data from 77 consecutive adult patients with mantle cell lymphoma who underwent peripheral blood stem cell (PBSC) mobilization for planned autologous stem cell transplant (ASCT). Compared to patients treated with alternative regimens, patients treated with hyper-CVAD collected fewer CD34++ cells, required more total days of pheresis, and more frequently required a second mobilization attempt, despite being more likely to have undergone mobilization with a VP16-containing regimen. In multivariable linear regression analysis, treatment with hyper-CVAD was associated with a significant reduction in total CD34++ cells mobilized ( p < 0.001). These findings suggest that alternative mobilizing strategies prior to ASCT are needed for patients with mantle cell lymphoma who have received hyper-CVAD. [ABSTRACT FROM AUTHOR]

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the preferred treatment modality for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). To assess long-term outcomes of these patients, we retrospectively analysed data from 309 consecutive patients who underwent ASCT for DLBCL between 1994 and 2006. We found that non-relapse mortality (NRM) became the major cause of death beginning approximately 8 years after ASCT. The most common causes of NRM during the study period were respiratory failure (31%), infection (13%), cardiac toxicity (15%) and secondary malignancy (15%). The strongest predictor of relapse mortality (RM) was disease status at transplant: patients who were in second or greater complete or partial remission had a higher risk of RM than those in first complete or partial remission [hazard ratio (HR) 3·7, P < 0·001], as did those who were relapsed or refractory (HR 4·9, P < 0·001). We describe the longest reported follow-up of a large cohort of DLBCL patients uniformly-treated with ASCT. Although relapse was initially the more likely cause of death, NRM exceeded RM after 8 years. After ASCT, surviving patients have significantly increased risk mortality rates relative to the general population and this excess risk persists over time. [ABSTRACT FROM AUTHOR]

The article presents a study regarding the medical case of 16 haemotological malignancy patients. The study uses total body irradiation (TBI), etoposide and antithymocyte globulin (ATG) to conduct multiple unit umbilical cord blood transplantation (MU-UCBT). The result shows that three patients experienced early deaths and one had graft failure but was infused with cryopreserved remission autologous bone marrow and remains alive in complete remission for 1056 days.

The long-term follow-up is presented for 317 patients with acute myeloid leukaemia who underwent human leucocyte antigen-identical sibling marrow transplants between 1984 and 1995 following preparation with busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. Among the 142 (45%) who were alive and leukaemia-free 3 years following transplantation, the leukaemia-free survival at 15 years was 72·8%. The cumulative incidence of late (>3 years beyond transplant) non-relapse mortality at 15 years was 12·9% and of late relapse was 16·5%. None of the variables considered (including age, disease stage, and graft- versus-host disease) were predictive of late failure. [ABSTRACT FROM AUTHOR]

Autologous stem cell transplantation (ASCT) with cyclophosphamide, etoposide and oral busulfan (BuCyVP) is an effective therapy for relapsed or refractory non-Hodgkin lymphoma (NHL). Substituting intravenous for oral busulfan reduces variability in drug exposure, potentially improving the safety and efficacy of the BuCyVP regimen. We retrospectively compared the outcomes of 604 consecutively treated patients who underwent ASCT for NHL with BuCyVP using oral ( n = 468) or IV ( n = 136) busulfan, without measurement of busulfan levels for pharmacokinetic (PK) analysis. Patients who received oral busulfan experienced more severe oral mucositis and a higher incidence of nonrelapse mortality. Median overall survival (OS) after ASCT was 72 months with oral busulfan but was not reached for the IV busulfan group. IV busulfan was associated with a lower rate of relapse, and superior relapse-free survival (RFS) and OS. In multivariate models, the route of busulfan administration was an independent prognostic factor for relapse ( P = 0·01), RFS ( P = 0·002) and OS ( P = 0·001). IV busulfan appears to provide better efficacy and lower toxicity than oral busulfan in ASCT with BuCyVP for NHL. Whether PK-based busulfan dosing can achieve further improvements in this setting is worthy of study. [ABSTRACT FROM AUTHOR]

Systematic studies evaluating clinical benefit of tumor genomic profiling are lacking. We conducted a prospective study in 250 patients with select solid tumors at the Cleveland Clinic. Eligibility required histopathologic diagnosis, age of 18 years or older, Eastern Cooperative Oncology Group performance status 0-2, and written informed consent. Tumors were sequenced using FoundationOne (Cambridge, MA). Results were reviewed at the Cleveland Clinic Genomics Tumor Board. Outcomes included feasibility and clinical impact. Colorectal (25%), breast (18%), lung (13%), and pancreatobiliary (13%) cancers were the most common diagnoses. Median time from consent to result was 25 days (range = 3-140). Of 223 evaluable samples, 49% (n = 109) of patients were recommended a specific therapy, but only 11% (n = 24) received such therapy: 12 on clinical trials, nine off-label, three on-label. Lack of clinical trial access (n = 49) and clinical deterioration (n = 29) were the most common reasons for nonrecommendation/nonreceipt of genomics-driven therapy. [ABSTRACT FROM AUTHOR]

Transformed lymphoma (TL) is historically associated with a poor prognosis, though autologous stem cell transplantation (ASCT) has been applied successfully. Better patient selection is needed for this intensive therapy. We analyzed the outcomes between de novo and transformed large B-cell lymphoma in patients undergoing ASCT, with regard to the immunohistochemical (IHC) features of potential prognostic utility including CD10, BCL6, MUM-1, Ki67, and BCL2. Of all patients undergoing ASCT for large B-cell lymphoma at the Cleveland Clinic Taussig Cancer Institute between 2003 and 2008, 56 patients (31 de novo and 25 TL) had undergone detailed IHC analysis. Three-year relapse-free-survival (RFS) and overall survival (OS) for TL vs. patients with de novo large B-cell lymphoma were 64%vs. 59% and 63%vs. 59%, respectively. More patients with TL were characterized as germinal-center B cell-of-origin (92%) than patients with de novo large B-cell lymphoma (71%). Immunohistochemistry did not predict relapse-free or overall survival, and ASCT afforded a high rate of PFS in patients with TL. [ABSTRACT FROM AUTHOR]

The ability to predict clinical outcomes is essential to accurate medical decision analysis. Many accepted bone marrow transplant related prognostic variables are derived from data that is over 20-years old and may or may not be applicable to current medical practice. This report reviews both older data concerning bone marrow transplantation prognostic factors as well as more current reports. In addition to pretransplant variables, this review examines easily measured post-transplant variables that may affect prognosis, as well as data concerning the cellular component of the infused graft in both allogeneic and autologous transplantation. [ABSTRACT FROM AUTHOR]

Data from 131 consecutive adult patients who underwent allogeneic bone marrow transplantation (BMT) at a tertiary care center from 1997 to 1999 suggest that the presence of an in-hospital lay care-partner during the patients' hospital stay is a powerful prognostic variable of survival. One year after the transplant, 75% of the patients with a lay care-partner were alive versus 26% of those without a care-partner. A multivariable survival analysis revealed not having an in-hospital lay care-partner as a significant independent risk factor for death (p <.001). This relationship held when adjusting for other such risk factors: i.e., primary diagnosis, disease status, and source of donor marrow. The idiosyncratic nature and importance of partnered relationships for survival in allogeneic BMT and the need to intervene and improve outcomes for patients are discussed with regard to future research and clinical programs. [ABSTRACT FROM AUTHOR]

Summary. We studied the association between CD34 cell dose and transplant outcomes in 359 bone marrow (BM) and 511 peripheral blood stem cell (PBSC) transplant recipients from human leucocyte antigen (HLA)-identical siblings, reported to the International Bone Marrow Transplant Registry (IBMTR). Transplants for leukaemia were performed between 1995 and 1998. Patients were divided into those receiving below or above the median CD34+ dose, for BM (3 × 106 /kg) and PBSC (6 × 106 /kg) grafts respectively. Cox proportional hazards regression was used to adjust for baseline patient-, disease- and transplant-related characteristics. Analysis of the BM recipients showed that high CD34 cell dose was associated with lower transplant-related mortality [relative risk (RR) = 0·60, P = 0·033] and treatment failure (inverse of leukaemia-free survival, RR = 0·69, P = 0·032). Among PBSC recipients, high CD34 dose was associated with faster recovery of neutrophils to > 0·5 × 109 /l (RR = 1·38, P < 0·001) and platelets to > 20 × 109 /l (RR = 1·34, P = 0·003), lower risk of relapse (RR = 0·62, P = 0·029) and treatment failure (RR = 0·74, P = 0·03). We conclude that higher CD34 cell doses decrease treatment failure in recipients of HLA-identical sibling BM and PBSC transplants. [ABSTRACT FROM AUTHOR]

Summary. We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0·009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1·72; 95% confidence interval (CI), 1·05–2·81; P = 0·031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0·016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML. [ABSTRACT FROM AUTHOR]

A continuous flow, magnetic separation method has been proposed to isolate large numbers of cells for clinical and biotechnological applications. The separation system, based on the quadrupole magnet flow sorter, has been tested on magnetically labeled, human blood progenitor cells using monoclonal antibody against the cluster of differentiation 34 (CD34) molecule and a magnetic colloid. A small volume of the cell suspension was injected into the sorter at variable volumetric flow rates, and the resulting cell elution profiles were analyzed for cell recovery in the magnetically enriched and depleted cell fractions. Independently, the cell motion in the magnetic field has been analyzed using a novel technique of cell tracking velocimetry, which allowed the determination of cell magnetophoretic mobility. A mathematical model of the cell motion inside the quadrupole flow sorter was used to calculate the recovery of the sorted fractions based on the cell magnetophoretic mobility distribution. A comparison of experimental and theoretical data allowed the verification of assumptions underlying the magnetic cell separation process, and provided guidelines for engineering design of the magnetic flow sorter. [ABSTRACT FROM AUTHOR]

The American Association of Blood Banks requires routine culture of hematopoietic progenitor cells prior to bone marrow transplantation. We sought to evaluate the cost of that requirement and the incidence and clinical significance of positive cultures. We performed a retrospective analysis of transplant recipients at our institution. Of the 605 patients for whom 1,934 consecutive cultures of harvests were done between December 1992 and February 1996, 11 had positive cultures. Six patients received a culture-positive harvest with no adverse effects. The total cost of cultures was $35,660 (U.S. $). In North America and worldwide in 1995, routine culture of harvests would have prevented 7.9 and 18.9 cases of bacteremia, respectively, at a cost of $95,000 per bacteremia prevented. We conclude that routine culture of hematopoietic progenitor cells yields low rates of positivity and that infusion of contaminated harvests rarely results in clinically adverse outcomes. [ABSTRACT FROM PUBLISHER]