A total of 36 consecutive patients with AML in CR underwent reduced-intensity allogeneic hematopoietic SCT (RISCT) with fludarabine and melphalan conditioning. All patients were ineligible for myeloablative transplantation because of age or comorbidity. In total, 30 patients were in first CR and six patients were in second CR. Donors were siblings in 21 (58%) patients and were unrelated in 15 (42%) patients. Hematopoietic cell transplant specific comorbidity scores ≥3 were present in 26 (72%) patients. With a median follow-up of 52 months (range, 34–103 months), OS and PFS rates at 4 years were 71% (s.e., 8%) and 68% (s.e., 8%), respectively. At 4 years, the cumulative incidence of non-relapse mortality was 20% (s.e., 7%) and of relapse mortality was 8% (s.e., 5%). Neither OS nor PFS was affected by older age (>60 years), unrelated donor, melphalan dose, or comorbidity score. At last follow up, of the 24 surviving patients, 21 (88%) had performance status (ECOG) of 0 without any active chronic GVHD requiring steroids. Hence, RISCT with fludarabine and melphalan conditioning produces durable long-term remission in older patients with AML.
reduced intensity allogeneic transplantation; AML; hematopoietic SCT
Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II–IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.
Haploidentical stem cell transplantation; T cell depletion; T cell replete haploidentical graft; GVHD prevention; High-dose posttransplantation cyclophosphamide
Bacteria often face fluctuating environments, and in response many species have evolved complex decision-making mechanisms to match their behaviour to the prevailing conditions. Some environmental cues provide direct and reliable information (such as nutrient concentrations) and can be responded to individually. Other environmental parameters are harder to infer and require a collective mechanism of sensing. In addition, some environmental challenges are best faced by a group of cells rather than an individual. In this review, we discuss how bacteria sense and overcome environmental challenges as a group using collective mechanisms of sensing, known as ‘quorum sensing’ (QS). QS is characterized by the release and detection of small molecules, potentially allowing individuals to infer environmental parameters such as density and mass transfer. While a great deal of the molecular mechanisms of QS have been described, there is still controversy over its functional role. We discuss what QS senses and how, what it controls and why, and how social dilemmas shape its evolution. Finally, there is a growing focus on the use of QS inhibitors as antibacterial chemotherapy. We discuss the claim that such a strategy could overcome the evolution of resistance. By linking existing theoretical approaches to data, we hope this review will spur greater collaboration between experimental and theoretical researchers.
quorum sensing; collective behaviour; systems biology; social evolution
We investigated the safety and early disease-control data obtained with intravenous busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (SCT). Fifty-one patients with median age 36 years (range 20–64) received a matched sibling (n=24), syngeneic (n=2) or matched unrelated donor transplant (n=25) for ALL in first complete remission (n=30), second complete remission (n=13), or with active disease (n=8). More than half of the patients had high-risk cytogenetic profiles as defined by the presence of t(9;22) (n=17), t(4;11) (n=3), or complex cytogenetics (n=7). Clo 40 mg/m2 was given once daily, each dose followed by pharmacokinetically-dosed Bu infused over three hours daily for 4 days followed by hematopoietic cell infusion 2 days later. The Bu dose was based upon the drug clearance determined by a test Bu dose, 32 mg/m2, given 48 hours prior to the high dose regimen. The target daily area under the curve (AUC) was 5,500 microMol-min for patients less than 60 years of age and 4000 microMol-min for patients ≥60 years of age. The regimen was well tolerated with 100 day non-relapse mortality (NRM) rate of 6%. With a median follow-up of 14 months among surviving patients (range, 6–28 months), the one-year overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) rates were 67% (95%CI: 55%–83%), 54% (95%CI: 41%–71%), and 32% (95%CI: 16%–45%), respectively. For patients transplanted in first remission, the one-year OS, DFS, and NRM rates were 74%, 64%, and 25%, respectively. The combination of Clo-Bu provides effective disease control while maintaining a favorable safety profile.
We conducted a retrospective review of patients with extrapulmonary small cell carcinomas (EPSCCs) to explore the distribution, treatments, patterns of relapse and outcomes by primary site.
We have reviewed the outcomes of one of the largest data sets of consecutive patients with EPSCC identified from two major cancer centres.
Consecutive patients with a histopathological diagnosis of EPSCC from the two institutions were retrospectively identified.
Primary and secondary outcome measures
Outcomes were evaluated including stage at presentation, treatments given, sites of relapse, time to distant relapse, progression-free survival and overall survival (OS).
From a total 159 patients, 114 received first-line chemotherapy, 80.5% being platinum-based. Response rate was 48%. Commonest primary sites were genitourinary and gynaecological. 44% of patients presented with metastatic disease. 55.9% relapsed with liver the commonest site, whereas only 2.5% developed brain metastases. Median OS was 13.4 months for all patients, 7.6 months and 19.5 months for those with metastatic and non-metastatic disease, respectively. Gynaecological and head and neck patients had significantly better OS compared to gastrointestinal patients.
EPSCCs demonstrate high response rates to chemotherapy and high rates of distant metastases. Primary sites may influence prognosis, and survival is optimal with a radical strategy. Brain metastases are rare and we therefore do not recommend prophylactic cranial irradiation.
carcinoma; extrapulmonary; neuroendocrine; relapse; small cell carcinoma; survival
We evaluated the outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced intensity conditioning (RIC). Median age at HCT was 55 years. Donors were: matched sibling donor (MSD), 34%; HLA-well-matched unrelated donors (URD), 45%; and partially/mismatched URD, 21%. Risk stratification according to Dynamic International Prognostic Scoring System (DIPSS): low, 12%; intermediate-1, 49%; intermediate-2, 37%; and high, 1%. The probability of survival at 5-years was 47% (95% CI 40–53). In a multivariate analysis, donor type was the only independent factor associated with survival. Adjusted probabilities of survival at 5-years for MSD, well matched URD and partially matched/mismatched URD were 56% (95% CI 44–67), 48% (95% CI 37–58), and 34% (95% CI 21–47), respectively (p=0.002). Relative risks (RR) for NRM for well-matched URD and partially matched/mismatched URD were 3.92 (p=0.006) and 9.37 (p<0.0001), respectively. A trend towards increased NRM (RR 1.7, p=0.07) and inferior survival (RR 1.37, p=0.10) was observed in DIPSS-intermediate-2/high-risk patients compared to DIPSS-low/intermediate-1 risk patients.
RIC HCT is a potentially curative option for patients with MF, and donor type is the most important factor influencing survival in these patients.
Myelofibrosis; allogeneic transplantation; reduced intensity; prognosis
Controlling platelet activation and clotting initiated by cardiovascular interventions remains a major challenge in clinical practice. In this work, the anti-thrombotic properties of a polysaccharide-based nitric oxide (NO)-releasing dextran derivative are presented. Total platelet adhesion, platelet morphology and whole blood clotting kinetics were used as indicators to evaluate the anti-clotting properties of this material. With a total NO delivery of 0.203±0.003 μmol, the NO-releasing dextran derivative (Dex-SNO) mixed with blood plasma demonstrated a significantly lower amount of platelet adhesion and activation onto a surface and reduced whole blood clotting kinetics. Nearly 75% reduction in platelet adhesion and a significant retention of platelet morphology were observed with blood plasma treated with Dex-SNO, suggesting this to be a potential anti-platelet therapeutic agent for preventing thrombosis that does not have an adverse effect on circulating platelets.
Nitric oxide; S-nitrosothiol; anti-thrombogenic; platelet adhesion; platelet activation; platelet morphology; whole blood clotting kinetics
Vitamin B12 and folic acid (referred to as vitamin supplementation) improves the toxicity profile of pemetrexed containing regimens. Low baseline vitamin B12 and folate levels are reflected in a raised total homocysteine level (HC). Studies have suggested that pretreatment HC levels predict neutropenia toxicity. We have tested supplementation with vitamin B12 and folate in non-pemetrexed platinum-based regimens to decrease treatment-related toxicity and looked for a correlation between toxicity and change in homocysteine levels.
Patient and method
Eighty-three patients with advanced lung cancer and malignant mesothelioma were randomly assigned to receive platinum-based chemotherapy with (arm A) or without (arm B) vitamin B12 and folic acid supplementation. The primary end point was grade 3/4 neutropenia and death within 30 days of treatment. Secondary end points included quality of life, overall survival (OS) and the relationship between baseline and post supplementation HC levels and toxicity.
In the intention-to-treat population, no significant difference was seen between the two groups with respect to chemotherapy-induced grade 3/4 neutropenia and death within 30 days of chemotherapy (36% vs 37%; p=0.966, emesis (2% vs 6%; p=0.9) or OS (12.3 months vs 7 months; p=0.41). There was no significant difference in survival rates by baseline HC level (p=0.9). Decrease in HC with vitamin supplementation was less frequent than expected. High baseline HC levels decreased with vitamin supplementation in only 9/36 (25%) patients (successful supplementation). Post hoc analysis showed that patients in arm A who were successfully supplemented (9/36=25%) had less neutropenic toxicity (0% vs 69%; p=0.02) compared to unsupplemented patients.
The addition of vitamin B12 and folic acid to platinum-containing regimens did not overall improve the toxicity, quality of life or OS. Rates of grade 3/4 neutropenia at 36/37% was as predicted. Further studies to increase the rate of successful supplementation and to further test the biomarker potential of post supplementation HC levels in predicting chemotherapy-induced neutropenia in platinum-based chemotherapy are warranted.
Trial registration number:
EudracCT 2005-002736-10 ISRCTN8734355.
Lung Cancer; Lung Cancer Chemotherapy
Strains of Escherichia coli cause a wide variety of intestinal and extra-intestinal diseases in both humans and animals, and are also often found in healthy individuals or the environment. Broadly, a strong phylogenetic relationship exists that distinguishes most E. coli causing intestinal disease from those that cause extra-intestinal disease, however, isolates within a recently described subclass of Extra-Intestinal Pathogenic E. coli (ExPEC), termed endometrial pathogenic E. coli, tend to be phylogenetically distant from the vast majority of characterised ExPECs, and more closely related to human intestinal pathogens. In this work, we investigate the genetic basis for ExPEC infection in the prototypic endometrial pathogenic E. coli strain MS499.
By investigating the genome of MS499 in comparison with a range of other E. coli sequences, we have discovered that this bacterium has acquired substantial lengths of DNA which encode factors more usually associated with ExPECs and less frequently found in the phylogroup relatives of MS499. Many of these acquired factors, including several iron acquisition systems and a virulence plasmid similar to that found in several ExPECs such as APEC O1 and the neonatal meningitis E. coli S88, play characterised roles in a variety of typical ExPEC infections and appear to have been acquired recently by the evolutionary lineage leading to MS499.
Taking advantage of the phylogenetic relationship we describe between MS499 and several other closely related E. coli isolates from across the globe, we propose a step-wise evolution of a novel clade of sequence type 453 ExPECs within phylogroup B1, involving the recruitment of ExPEC virulence factors into the genome of an ancestrally non-extraintestinal E. coli, which has repurposed this lineage with the capacity to cause extraintestinal disease. These data reveal the genetic components which may be involved in this phenotype switching, and argue that horizontal gene exchange may be a key factor in the emergence of novel lineages of ExPECs.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1075) contains supplementary material, which is available to authorized users.
Comparative genomics; Evolution; Niche expansion
Study of mass in ear was undertaken with the aim that clinical diagnosis was in most but not all cases consistent with the histo-pathological diagnosis. Therefore incisional or excisional biopsy with histo-pathological study is a must in all types of small masses in ear. A study of 50 patients, attending Ear, Nose and Throat department, was done and specimen collected from them and subjected to histopathological examination. These masses were further classified as inflammatory, benign and malignant lesions and the frequency of their occurrence in saurashtra region (Jamnagar, GUJARAT), their age and sex distribution were observed. Most common lesion was found to be inflammatory Polyps (20), followed by Cholesteatomas (12) and chronic non-specific inflammations (7), Abscess (1). In malignant lesions Squamous cell carcinoma (7) was the commonest followed by Embryonal rhabdomyosarcoma (1) and in benign lesion, Carcinoid tumor (1) and Nevus (1) were diagnosed on histo-pathological examination. Right side masses were more common than left side; males were more affected than females. Adolescents/children more affected than adults for benign lesions while reverse was true for malignant lesions.
Ear; Polyp; Cholesteatoma; Squamous cell carcinoma; Embryonal Rhabdomyosarcoma; Carcinoid tumor
Twenty severe aplastic anemia (SAA) patients underwent allogeneic stem cell transplantation (allo-SCT) with fludarabine (FLU), cyclophosphamide and antithymocyte globulin from a matched related (n=7, age ≥ 40) or unrelated donor (n=13, any age). Median age was 34 years (range 1–59). Median time from diagnosis to allo-SCT was 12 months (range 2–244). Seventeen out of 19 evaluable patients engrafted (90%). There were two secondary graft failures (10%). Median time to neutrophil recovery was 15 days (range 8–30). Chimerism studies indicated ≥90% donor-derived engraftment in 16/19 evaluable patients (75%). Four out of 20 patients (20%) developed acute (grade II–IV) GVHD, and 6/16 evaluable patients (37%) developed chronic GVHD. We observed EBV reactivation and viremia in seven patients, which was successfully treated with rituximab in all but one instance (where it was self-limiting). Thirteen patients (62%) are alive (including eight of the last nine treated) with a median follow-up of 30 months (range 3–112). Seven patients expired (graft rejection n=1, GVHD n=1, multiorgan failure n=1, infection n=2, EBV post-transplant lymphoproliferative disorder/PTLD n=2). Total body irradiation-free, FLU-based conditioning for matched related and unrelated allo-SCT is feasible with high engraftment rates. EBV PTLD remains a drawback of this approach.
Aplastic anemia; bone marrow failure; stem cell transplantation; bone marrow transplantation; conditioning regimen; fludarabine
Iron overload has been associated with increased non-relapse mortality (NRM) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing hematopoietic stem cell transplantation (HSCT). Elevated ferritin level pre-HSCT has been used as a marker for iron overload. It is unclear whether the negative effect of iron overload as measured by elevated ferritin level extends beyond the first three months post HSCT, as this would suggest a potential role for active management of iron overload post HSCT.
Sixty-three patients with AML and MDS who underwent an allogeneic HSCT from a sibling or unrelated donor between January to December 2006, had a pre-HSCT ferritin level and were alive and disease free 90 days post HSCT.
Median age was 51. Patients with the lowest pre-HSCT ferritin level (Q1) had a trend towards improved overall survival and progression free survival when compared to patients with higher level (Q2–Q4) (P=0.06, and 0.125). Cumulative incidence of NRM at 2 years was 20 and 30% respectively (P=0.4).
Pre-HSCT ferritin level may still have an impact on HSCT events beyond 3 months post transplant, suggesting a role for research into active management of iron overload with either phlebotomy or chelation.
Ferritin; Hematopoietic Stem Cell Transplant; Late Transplant Outcome; AML; MDS
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, due to high-treatment related mortality (TRM) its role is not well defined.
Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of two reduced intensity conditioning regimens, fludarabine 120 mg/m2+ melphalan 100 mg/m2(FM100) versus fludarabine 120 mg/m2+ melphalan 140 mg/m2(FM140) before allo-HCT from related or unrelated donors.
Fifty patients underwent allo-HCT using FM100 (N=23) or FM140 (N=27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (p=0.21), acute grade II-IV GVHD (p=1.0), chronic GVHD (p=0.24), response rate (p=1.0), TRM (13% versus 15%, p=1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, p=0.12, and median overall survival (OS), 35.1 versus19.7 months, p=0.38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (p=0.08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), p=0.24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with < VGPR, p=0.05). OS was similar across all variables.
We conclude that FM 100 and FM140 may result in similar patient outcomes after allo-HCT for MM.
Myeloma; Allogeneic transplantation; Reduced intensity conditioning; Fludarabine; Melphalan
The use of genomics to discover novel targets and biomarkers has placed the field of oncology at the forefront of precision medicine. First-generation epidermal growth factor receptor (EGFR) inhibitors have transformed the therapeutic landscape of EGFR mutant non-small-cell lung carcinoma through the genetic stratification of tumors from patients with this disease. Somatic EGFR mutations in lung adenocarcinoma are now well established as predictive biomarkers of response and resistance to small-molecule EGFR inhibitors. Despite early patient benefit, primary resistance and subsequent tumor progression to first-generation EGFR inhibitors are seen in 10%–30% of patients with EGFR mutant non-small-cell lung carcinoma. Acquired drug resistance is also inevitable, with patients developing disease progression after only 10–13 months of antitumor therapy. This review details strategies pursued in circumventing T790M-mediated drug resistance to EGFR inhibitors, which is the most common mechanism of acquired resistance, and focuses on the clinical development of second-generation EGFR inhibitors, exemplified by afatinib (BIBW2992). We discuss the rationale, mechanism of action, clinical efficacy, and toxicity profile of afatinib, including the LUX-Lung studies. We also discuss the emergence of third-generation irreversible mutant-selective inhibitors of EGFR and envision the future management of EGFR mutant lung adenocarcinoma.
afatinib; EGFR; erlotinib; gefitinib; LUX-Lung; NSCLC
Malignant mesothelioma (MM) carries a poor prognosis and response rates to palliative chemotherapy remain low. Identifying patients with MM that are unlikely to respond to chemotherapy could prevent futile treatments and improve patient quality of life. Studies have suggested that soluble mesothelin is a potential biomarker for early diagnosis and prognosis of MM. We set out to explore the utility of serum mesothelin in routine clinical practice.
We conducted a prospective exploratory study of serum mesothelin levels in 53 consecutive patients with MM at our institution between April 2009 and February 2011. Survival was assessed and analysed by mesothelin level as both continuous and categorical variables using Cox regression models. Differences in response rate between treatment groups were assessed by the Kruskal-Wallis Test.
All 53 patients, who had been given study information agreed to participate. The patients’ median age was 69 (range 24–90). Median mesothelin level was 2.7 nM and this value was used to dichotomize categories: ≤2.7 nM (low) and >2.7 nM (high). The progression free survival (PFS) for low vs high mesothelin was 8.0 vs 5.1 months (HR 1.8, p-0.058). When mesothelin was accessed as a continuous variable for PFS the HR was 1.03 (95% CI: 1.01 - 1.06; p = 0.013). The overall survival (OS) for low vs high mesothelin was 17.2 vs 11.3 months (HR 1.9, p = 0.088). When mesothelin was assessed as a continuous variable for OS the HR was 1.02 (95% CI: 0.99 - 1.04; p = 0.073). Thirty patients received chemotherapy of which 18 had a pre-chemotherapy serum mesothelin level. In these 18 patients, the pre-chemotherapy mesothelin level did not correlate with response.
A single random sample provides information about patient prognosis but does not predict treatment response. We suggest further prospective validation of mesothelin testing as a prognostic biomarker.
Biomarker; Mesothelin; Prognosis; Response
Tissue integration is an important property when inducing transplant tolerance, however, the hemocompatibility of the biomaterial surface also plays an important role in the ultimate success of the implant. Therefore, in order to induce transplant tolerance, it is critical to understand the interaction of blood components with the material surfaces. In this study, we have investigated the adsorption of key blood serum proteins, in vitro adhesion and activation of platelets and clotting kinetics of whole blood on flat polycaprolactone (PCL) surfaces, nanowire (NW) surfaces and nanofiber (NF) surfaces. Previous studies have shown that polymeric nanostructured surfaces improve cell adhesion, proliferation and viability; however it is unclear how these polymeric nanostructured surfaces interact with the blood and its components. Protein adsorption results indicate that while there were no significant differences in total albumin adsorption on PCL, NW and NF surfaces, NW surfaces had higher total fibrinogen and immunoglobulin-G adsorption compared to NF and PCL surfaces. In contrast, NF surfaces had higher surface FIB and IgG adsorption compared to PCL and NW surfaces. Platelet adhesion and viability studies show more adhesion and clustering of platelets on the NF surfaces as compared to PCL and NW surfaces. Platelet activation studies reveal that NW surfaces have the highest percentage of unactivated platelets, whereas NF surfaces have the highest percentage of fully activated platelets. Whole blood clotting results indicate that NW surfaces maintain an increased amount of free hemoglobin during the clotting process compared to PCL and NF surface, indicating less clotting and slower rate of clotting on their surfaces.
Hemocompatibility; nanowire surfaces; nanofiber surfaces; platelets
Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte-colony stimulating factor (G-CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G-CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just-in-time plerixafor in combination with chemotherapy and G-CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin’s and non-Hodgkin’s) and multiple myeloma who underwent chemomobilization and high-dose G-CSF and just-in-time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but 1 patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 × 106/kilogram of body weight). The median CD34+ cell dose collected in patients with non-Hodgkin lymphoma was 4.93 × 106/kilogram of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 × 106/kilogram of body weight. Plerixafor was well tolerated; no grade 2 or higher non- hematologic toxic effects were observed.
Just-in-time plerixafor; chemomobilization
The t(11;14)(q13;q32) is seen in 15–20% patients with multiple myeloma (MM). In general, it is not associated with worse outcome. We studied the impact of t(11;14)(q13;q32) on the outcome of patients with MM who received high-dose chemotherapy followed by an autologous hematopoietic stem cell transplantation (auto-HCT).
Eligible patients underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between February 2000 and August 2010, and had conventional cytogenetic (CC) or fluorescent in situ hybridization (FISH) results available prior to auto-HCT. The cohort is divided into three groups of patients: (1) normal (diploid by CC, and negative by FISH); (2) t(11;14)(q13;q32) by CC or FISH; and (3) high-risk (HR) abnormalities by CC or FISH. The primary objective was to compare the outcome of patients with t(11;14)(q13;q32) to patients with diploid or HR markers by CC or FISH studies.
CC or FISH studies were available for 993 patients in the 3 groups described above. Eight-hundred and sixty-nine patients had normal, 27 patients had t(11;14)(q13;q32) and 97 patients HR markers by CC or FISH studies. Of the 27 patients with t(11;14)(q13;q32), 18 had isolated t(11;14)(q13;q32) while 9 patients had concurrent HR abnormalities. We compared the outcome of patients with t(11;14)(q13;q32) to patients with normal or HR markers. Median follow up in surviving patients was 37 months. 3-year PFS for normal, t(11;14)(q13;q32) and HR groups were 47%, 27% and 13%, respectively (p=<0.00001). 3-year OS for normal, t(11;14)(q13;q32) and HR groups were 83%, 63% and 34%, respectively (p=<0.00001). On multivariate analyses, t(11;14)(q13;q32) and HR abnormalities by CC or FISH, and relapsed disease at auto-HCT were associated with shorter PFS, while t(11;14)(q13;q32) and HR abnormalities by CC or FISH, β2 microglobulin of >3.5 and relapsed disease at auto-HCT were associated with shorter OS.
Patients with t(11;14)(q13;q32) had worse outcome than patients with normal CC or FISH, but better than patients with HR markers by CC or FISH studies.
Detection of the ALK rearrangement in a solid tumor gives these patients the option of crizotinib as an oral form of anticancer treatment. The current test of choice is fluorescence in situ hybridization (FISH), but various cheaper and more convenient immunohistochemical (IHC) assays have been proposed as alternatives.
Fifteen FISH-positive cases from patients, seven with data on crizotinib therapy and clinical response, were evaluated for the presence of ALK protein using three different commercially available antibodies: D5F3, using the proprietary automated system (Ventana), ALK1 (Dako), and 5A4 (Abcam). A further 14 FISH-negative and three uncertain (<15% rearrangement detected) cases were also retrieved. Of the total 32 specimens, 17 were excisions and 15 were computed tomography-guided biopsies or cytological specimens. All three antibodies were applied to all cases. Antibodies were semiquantitatively scored on intensity, and the proportion of malignant cells stained was documented. Cutoffs were set by receiver operating curve analysis for positivity to optimize correct classification.
All three IHC assays were 100% specific but sensitivity did vary: D5F3 86%, ALK 79%, 5A4 71%. Intensity was the most discriminating measure overall, with a combination of proportion and intensity not improving the test. No FISH-negative IHC-positive cases were seen. Two FISH-positive cases were negative with all three IHC assays. One of these had been treated with crizotinib and had failed to show clinical response. The other harbored a second driving mutation in the EGFR gene.
IHC with all three antibodies is especially highly specific (100%) although variably sensitive (71%-86%), specifically in cases with scanty material. D5F3 assay was most sensitive in these latter cases. Occasional cases are IHC-positive but FISH-negative, suggesting either inaccuracy of one assay or occasional tumors with ALK rearrangement that do not express high levels of ALK protein.
Pulmonary adenocarcinoma; ALK; Immunohistochemistry; Fluorescence in situ hybridization; Crizotinib
Approximately 20% of patients with multiple myeloma (MM) have renal failure at diagnosis, and about 5% are dialysis-dependent. Many of these patients are considered ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) because of a high risk of treatment-related toxicity. We evaluated the outcome of 46 patient with MM and renal failure, defined as serum creatinine >2 mg/dL sustained for >1 month before the start of preparative regimen. Patients received auto-HSCT at our institution between September 1997 and September 2006. Median serum creatinine and creatinine clearance (CrCl) at auto-HSCT were 2.9 mg/dL (range: 2.0–12.5) and 33 mL/min (range: 8.7–63), respectively. Ten patients (21%) were dialysis-dependent. Median follow-up in surviving patients was 34 months (range: 5–81). Complete (CR) and partial responses (PR) after auto-HSCT were seen in 9 (22%) and 22 (53%) of the 41 evaluable patients, with an overall response rate of 75%. Two patients (4%) died within 100 days of auto-HSCT. Grade 2–4 nonhematologic adverse events were seen in 18 patients (39%) and included cardiac arrythmias, pulmonary edema, and hyperbilirubinemia. Significant improvement in renal function, defined as an increase in flomerular filtration rate (GFR) by 25% above baseline, was seen in 15 patients (32%). Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 36% and 64%, respectively. In conclusion, auto HSCT can be offered to patients with MM and renal failure with acceptable toxicity and with a significant improvement in renal function in approximately one-third of the transplanted patients. In this analysis, a melphalan (Mel) dose of 200 mg/m2 was not associated with an increase in toxicity or nonrelapse (Mel) mortality (NRM).
Myeloma; Renal failure; Autologous
Most candidates for hematopoietic stem cell transplantation (HSCT) lack a human leukocyte antigen (HLA)-identical sibling donor. Some patients may have a related donor with whom they are mismatched at 1 antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We evaluated the outcomes (survival, relapse, nonrelapse mortality [NRM]) of all 28 patients with a single HLA antigen/allele mismatch identified through high-resolution HLA typing at HLA-A, -B, -C, -DRB1, and -DQB1, and all 318 patients with myeloid malignancies who received transplants from a 10/10 MUD treated during the same period of time at a single institution. Overall, outcomes for patients treated from a 1-antigen/allele mismatch related donor were significantly worse than from a MUD, primarily because of increased NRM. Overall survival (OS) rates at 3 years for 1-antigen/allele mismatched related donor and MUD transplant recipients were 19% and 45% (P =.007), and NRM rates were 40% and 26% (P =.05), respectively. Patients with class I mismatches appeared to have poorer OS than did patients with class II mismatches. A higher incidence of graft rejection was identified in the mismatched related donor group (P =.02). These results indicate that transplant outcomes are better with a MUD than with a 1 antigen/allele-mismatched related donor.
Hematopoietic stem cell transplantation; HLA matched unrelated donors; 9/10 matched related donors; Class I HLA mismatch; Class II HLA mismatch
A high risk of regimen-related toxicity with allogeneic hematopoietic stem cell transplantation (allo-HSCT) limits this potentially curative treatment for patients with a left ventricular ejection fraction (LVEF) of ≥50%. We evaluated the frequency of cardiac complications and 100-day nonrelapse mortality (NRM) in 56 patients with a LVEF of ≤45%, who received allo HCTat our institution. The results were retrospectively compared with a matched control group with LVEF of ≥50%, which received an allogeneic stem cell transplantation (allo-SCT). After a median follow-up of 29 months in the study group, grade ≥2 cardiac complications were seen in 7 of 56 (12.5%) patients and cumulative incidence of 100-day NRM was 12.5% with no deaths from cardiac causes. In contrast, after a median follow-up of 49 months in the control group, grade >2 cardiac complications were seen in 19 of 161 patients (11.8%; P = 1.00) and cumulative incidence of 100-day NRM was 14.9% (P =.82). The presence of at least 1 of the 7 pretransplant cardiac risk factors (past history of smoking, hypertension, hyperlipidemia, coronary artery disease, arrhythmia, prior myocardial infarction, and congestive heart failure) was associated with a higher cardiac complication rate in the study group (P = .03). In conclusion, selected patients with a LVEF of ≤45% can safely receive allo-HCT without a significant increase in cardiac toxicity or NRM.
Allogeneic hematopoietic stem cell transplantation; Low ejection fraction