Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience.

BACKGROUND: Reed-Sternberg cells of classical Hodgkin's lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. PATIENTS AND METHODS: We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. RESULTS: Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. CONCLUSIONS: Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity.

Is Cytomegalovirus Surveillance Necessary for Patients With Low Reactivation Risk in an Autologous Hematopoietic Cell Transplantation Setting?

BACKGROUND: In an autologous hematopoietic cell transplantation (AHCT) setting, routine cytomegalovirus (CMV) surveillance is not indicated except in high-risk situations. On the other hand, some studies reported increased CMV reactivation in AHCT setting as a result of incorporation of novel agents into treatment algorithms, such as bortezomib and rituximab. We retrospectively analyzed CMV reactivation and infection rates in patients with no high-risk features, who were treated with AHCT. METHODS: During January 2010 to November 2015, all consecutive, CMV-seropositive patients were included. The viral copy numbers were measured twice a week from the start of the conditioning regimen until engraftment, once a week for the remaining time period until day 30 after AHCT and once weekly only for patients who had been diagnosed with CMV reactivation before and who developed primary/secondary engraftment failure during 31 to 60 days after AHCT. RESULTS: One hundred one (61.6%) men and 63 (38.4%) women were included in the study. The median age of study cohort was 51 years (range, 16-71 years). The indications for AHCT were Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma in 44 (26.8%), 41 (25%), and 79 (48.2%) patients, respectively. CMV reactivation occurred in 60 (37%) patients, and 13 patients (8%) received pre-emptive ganciclovir treatment. CONCLUSIONS: On the basis of our results, it might be stated that CMV surveillance may be recommended during 40 days after AHCT in countries with a high CMV prevalence, even in patients without high-risk features regarding reactivation. Additionally, the risky conditions necessitating CMV screening after AHCT must be re-defined in the era of novel agents.

Bilateral peninsula-shaped linear craniectomy for mild degrees of craniosynostosis: indication, technique and long-term results.

OBJECTIVE: The goals of surgery in craniosynostosis are to reduce increased intracranial pressure and to achieve a good aesthetic result with minimal mortality and morbidity. A new type of strip craniectomy according to these principles is presented. PATIENTS: The technique was applied to seven cases of oxycephaly and three cases of scaphocephaly under 5 years of age. None of them had major cranial base involvement, facial deformity or marked psychomotor retardation. There was no syndromic case of craniosynostosis included in this group. METHODS: A curvilinear parasagittal craniectomy was combined with coronal and lambdoid craniectomies bilaterally. These craniectomies were curved postero- and antero-inferiorly, respectively, in order to create bilateral 'peninsula-shaped' parieto-temporal bones with their neck still attached to the temporal bone. A linear craniectomy, crossing the superior sagittal sinus and combining right and left curvilinear craniectomies was added. RESULTS: The operative time varied between 45 min and 1h, without any complications. Correction of the skull shape was successful in all cases. CONCLUSION: This technique is simple and effective. But, it is only applicable to a minority of craniosynostoses. Patient selection is the key to better results.

Two cases of neuro-Behcet's disease mimicking cerebral tumor.

Two cases of neuro-Behcet's disease with isolated, solitary fronto-temporal and mesencephalic lesions respectively are reported. The cases were misdiagnosed as cerebral tumor. The postoperative outcome of the first patient was not satisfactory as he developed hemispheric edema. The second patient, with mesencephalic lesion, was treated only with corticosteroids, and the patient improved significantly. The lesion in this case resolved completely at six-month follow-up. We conclude that distinguishing the isolated solitary cerebral lesion of the Behcet's disease from a tumor may prevent surgical intervention.

Experimental study of rapid versus slow sagittal sinus occlusion in dogs.

BACKGROUND: Clinical, radiological, postmortem and experimental studies are not enough for the definition of pathophysiological differences between rapid and slow-progressing cerebral venous system obstruction. AIMS: An experimental study was conducted to set some physiopathological differences between rapid and slow occlusion of the superior sagittal sinus. SETTINGS AND DESIGN: Eighteen dogs categorized into 3 groups were chosen as test subjects. The three groups were the rapid occlusion, slow occlusion and the control study groups and each group had six subjects. MATERIAL AND METHODS: Intracranial pressure values, histopathological findings, and the degree of cerebral edema formation, estimated by measuring the water content ratio of the brain and the angiographic results in the 2 different groups of subjects that underwent rapid and slow superior sagittal sinus obstruction were compared with that of the control subjects. STATISTICAL ANALYSIS: Statistical analysis was performed using GraphPad Prisma V.3 statistical software. Variables of the 3 groups were compared using non-parametric Kruskal Wallis ANOVA test and multiple comparisons were made using Dunn's multiple test. The comparison of initial and terminal intracranial pressure values obtained before and after the sinus occlusion, was made using the Wilcoxon test. A probability value of less than 0.05 was regarded as significant. RESULTS AND CONCLUSIONS: Comparison of the water content ratio of the brain in the 3 groups, the difference between the initial and terminal intracranial pressure values of the rapid occlusion study group, and the difference between the terminal intracranial pressure values of the 3 groups was statistically significant (P<0.05). Dunn's Multiple Comparison Test yielded significant differences in the water content ratio of the brain and in the intracranial pressure values between the rapid occlusion study group and the control group (P<0.05). Moreover, histopathological and radiological examination disclosed more prominent brain edema findings, and less apparent collateral venous flow in the rapid occlusion study group than in the slow occlusion one. To conclude, the clinical severity of sinus occlusion seems directly related to the quickness of the occlusion and the capacity of the collateral venous system.

Poly-axial screw removal.

As the use of instrumentation in spinal surgery has become common, the need for revision surgery has increased. During revision surgery one of the most difficult steps is removal of poly-axial pedicle screws, especially if no suitable revision set is available. We describe here an easy method for poly-axial screw removal. Leaving or placing a small piece of rod, attached firmly by a nut, tightens the head of the poly-axial screw. It can no longer move freely from the distal part of the screw and the screw can be removed by turning it counterclockwise with a big clamp or needle driver, which is available in almost every surgery set.

Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning.

The second enzyme in the heme biosynthetic pathway, delta-aminolevulinate dehydratase (ALAD), is a homooctameric protein encoded by a gene localized to human chromosome 9q34. Expression of the two common alleles, ALAD1 (p = .9) and ALAD2 (q = .1), results in a polymorphic enzyme system with three distinct charge isozymes, designated 1-1, 1-2, and 2-2. Individuals heterozygous (2pq = .18) or homozygous (q2 = .01) for the ALAD2 allele have significantly higher blood lead levels than do ALAD1 homozygotes, when exposed to low or high levels of lead in the environment. To investigate the molecular nature of this common polymorphism, total RNA from an ALAD2 homozygote was oligo-dT primed and reverse transcribed, and then the ALAD2 cDNA was amplified, subcloned, and sequenced. Compared with the ALAD1 sequence, the only difference in the ALAD2 cDNA was a G-to-C transversion of nucleotide 177 in the coding region, which created an MspI restriction site. This base substitution predicted the replacement of a positively charged lysine by a neutral asparagine (K59N), an amino acid change consistent with the more electronegative charge of the ALAD-2 subunit. The ALAD1 and ALAD2 alleles were easily detected by amplification of a 916-bp region of genomic DNA and MspI digestion which results in 582- and 511-bp products, respectively. Molecular analysis of 85 ALAD1/ALAD2 heterozygotes and of eight ALAD2 homozygotes revealed no discrepancy between the predicted genotype and the erythrocyte isozyme phenotype, indicating that all the ALAD2 alleles analyzed had the G-to-C transversion.(ABSTRACT TRUNCATED AT 250 WORDS)

Human delta-aminolevulinate dehydratase (ALAD) gene: structure and alternative splicing of the erythroid and housekeeping mRNAs.

Genomic clones containing human delta-aminolevulinate dehydratase (ALAD), the second enzyme in the heme pathway, were isolated, and the entire sequence was determined in both orientations (15,913 bp; GenBank Accession No. X64467). The gene contained two alternative noncoding exons, 1A and 1B, and 11 coding exons, 2-12. Ten Alu-repetitive elements were within the gene, including an inverted repeat that may have resulted from gene conversion. The housekeeping transcript, which included exon 1A and not 1B, was identified in a human adult liver cDNA library, while an erythroid-specific transcript, which contained exon 1B and not 1A, was detected in a human K562 erythroleukemia cDNA library. The promoter region upstream of housekeeping exon 1A was GC-rich and contained three potential Sp1 elements and a CCAAT box. Further upstream, there were three potential GATA-1 binding sites and an AP1 site. The promoter region upstream of erythroid-specific exon 1B had several CACCC boxes and two potential GATA-1 binding sites. To assess the tissue-specific expression of exons 1A and 1B, HeLa and K562 cells were transduced with CAT constructs containing either exon 1A or 1B and their respective upstream promoter region. Two housekeeping CAT constructs, with 450 and 1400 bp upstream of exon 1A, were expressed at similar levels in HeLa cells, whereas the erythroid-specific construct, containing the entire 450-bp promoter region upstream of exon 1B, was not. In contrast, the housekeeping and erythroid constructs were both expressed in K562 cells.(ABSTRACT TRUNCATED AT 250 WORDS)