Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

Nontherapeutic Circumcision of Minors as an Ethically Problematic Form of Iatrogenic Injury.

Nontherapeutic circumcision (NTC) of male infants and boys is a common but misunderstood form of iatrogenic injury that causes harm by removing functional tissue that has known erogenous, protective, and immunological properties, regardless of whether the surgery generates complications. I argue that the loss of the foreskin itself should be counted, clinically and morally, as a harm in evaluating NTC; that a comparison of benefits and risks is not ethically sufficient in an analysis of a nontherapeutic procedure performed on patients unable to provide informed consent; and that circumcision violates clinicians' imperatives to respect patients' autonomy, to do good, to do no harm, and to be just. When due consideration is given to these values, the balance of factors suggests that NTC should be deferred until the affected person can perform his own cost-benefit analysis, applying his mature, informed preferences and values.

Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Circumcision Is Unethical and Unlawful.

The foreskin is a complex structure that protects and moisturizes the head of the penis, and, being the most densely innervated and sensitive portion of the penis, is essential to providing the complete sexual response. Circumcision-the removal of this structure-is non-therapeutic, painful, irreversible surgery that also risks serious physical injury, psychological sequelae, and death. Men rarely volunteer for it, and increasingly circumcised men are expressing their resentment about it.Circumcision is usually performed for religious, cultural and personal reasons. Early claims about its medical benefits have been proven false. The American Academy of Pediatrics and the Centers for Disease Prevention and Control have made many scientifically untenable claims promoting circumcision that run counter to the consensus of Western medical organizations.Circumcision violates the cardinal principles of medical ethics, to respect autonomy (self-determination), to do good, to do no harm, and to be just. Without a clear medical indication, circumcision must be deferred until the child can provide his own fully informed consent.In 2012, a German court held that circumcision constitutes criminal assault. Under existing United States law and international human rights declarations as well, circumcision already violates boys> absolute rights to equal protection, bodily integrity, autonomy, and freedom to choose their own religion. A physician has a legal duty to protect children from unnecessary interventions. Physicians who obtain parental permission through spurious claims or omissions, or rely on the American Academy of Pediatrics' position, also risk liability for misleading parents about circumcision.

Cell Association in Rous Sarcoma Virus (RSV) Rescue and Cell Infection.

In my article I tried to present the results of early experiments suggesting a significant role for cell association in Rous sarcoma virus transformation of non-permissive cells and revealing that infectious virus can be efficiently rescued from such cells by their fusion with permissive chicken fibroblasts.

Analysis of the complete sequences of two biologically distinct Zucchini yellow mosaic virus isolates further evidences the involvement of a single amino acid in the virus pathogenicity.

The complete genome sequences of two Slovak Zucchini yellow mosaic virus isolates (ZYMV-H and ZYMV-SE04T) were determined. These isolates differ significantly in their pathogenicity, producing either severe or very mild symptoms on susceptible cucurbit hosts. The viral genome of both isolates consisted of 9593 nucleotides in size, and contained an open reading frame encoding a single polyprotein of 3080 amino acids. Despite their different biological properties, an extremely high nucleotide identity could be noted (99.8%), resulting in differences of only 5 aa, located in the HC-Pro, P3, and NIb, respectively. In silico analysis including 5 additional fully-sequenced and phylogenetically closely-related isolates known to induce different symptoms in cucurbits was performed. This suggested that the key single mutation responsible for virus pathogenicity is likely located in the N-terminal part of P3, adjacent to the PIPO.

Circumcision of male infants as a human rights violation.

Every infant has a right to bodily integrity. Removing healthy tissue from an infant is only permissible if there is an immediate medical indication. In the case of infant male circumcision there is no evidence of an immediate need to perform the procedure. As a German court recently held, any benefit to circumcision can be obtained by delaying the procedure until the male is old enough to give his own fully informed consent. With the option of delaying circumcision providing all of the purported benefits, circumcising an infant is an unnecessary violation of his bodily integrity as well as an ethically invalid form of medical violence. Parental proxy 'consent' for newborn circumcision is invalid. Male circumcision also violates four core human rights documents-the Universal Declaration of Human Rights, the Convention on the Rights of the Child, the International Covenant on Civil and Political Rights, and the Convention Against Torture. Social norm theory predicts that once the circumcision rate falls below a critical value, the social norms that currently distort our perception of the practice will dissolve and rates will quickly fall.

Out of step: fatal flaws in the latest AAP policy report on neonatal circumcision.

The American Academy of Pediatrics recently released a policy statement and technical report on circumcision, in both of which the organisation suggests that the health benefits conferred by the surgical removal of the foreskin in infancy definitively outweigh the risks and complications associated with the procedure. While these new documents do not positively recommend neonatal circumcision, they do paradoxically conclude that its purported benefits 'justify access to this procedure for families who choose it,' claiming that whenever and for whatever reason it is performed, it should be covered by government health insurance. The policy statement and technical report suffer from several troubling deficiencies, ultimately undermining their credibility. These deficiencies include the exclusion of important topics and discussions, an incomplete and apparently partisan excursion through the medical literature, improper analysis of the available information, poorly documented and often inaccurate presentation of relevant findings, and conclusions that are not supported by the evidence given.

Potential prolongation of PFS in mantle cell lymphoma after R-HyperCVAD: auto-SCT consolidation or rituximab maintenance.

We retrospectively analyzed 44 patients undergoing first-line treatment for mantle cell lymphoma with R-HyperCVAD, with or without rituximab (R) maintenance or auto-SCT. The primary study end point was PFS; secondary end point was overall survival.Median follow up for all patients was 3.3 years. Median age was 54 years, and 95% (n=42) were stage III or IV at diagnosis. In all, 17 patients underwent consolidative auto-SCT and 12 patients received R maintenance. The overall response rate was 95%, with 91% achieving complete response (CR). Median PFS for all patients was 3.5 years. Median PFS was 2.3 years for patients treated with R-HyperCVAD alone vs 3.9 years (P=0.02) with R-HyperCVAD+ R maintenance and 4.5 years (P=0.01) with R-HyperCVAD+ auto-SCT. For patients who did not achieve CR at interim staging, PFS for R-HyperCVAD alone was 1.4 years vs not reached for R-HyperCVAD+ consolidation (either R maintenance or auto-SCT) (P=0.02). PFS for patients with CR at interim staging was 3.3 years vs not reached (P=0.04) after consolidation. Our data suggest potential improvement in PFS when R-HyperCVAD is consolidated with either R maintenance or auto-SCT. This benefit appears particularly significant in those patients who do not achieve CR at interim restaging.

SU-E-T-19: Fitting a Multiple Source Photon Model for Monte Carlo Treatment Plan Verification.

PURPOSE: To assess and reduce the difficulty of fitting a multiple source photon model for monte carlo treatment plan verification. METHODS: The EGS4 user code MCSIM, from Fox Chase Cancer Center, was chosen for its support of a multiple source photon model, of which the point and secondary (extrafocal) photon sources were utilized. A described method of fitting the secondary source to in-air output factors was implemented. Additionally, a method to fit the point source to a single large field dose distribution was explored. The point source fitter utilizes a database of pre-simulated mono-energetic fanlines to build distributions from arbitrary spectra. Perturbations are made to fanline spectra to reduce the errors along them. In this study the energy spectrum for each fanline has been limited to the log-normal distribution, which reduces the number of parameters for each to two. RESULTS: It was found that one spectral parameter could be set to a constant for all fanlines and the other restricted to linearity with respect to off-axis position. The model matched the outputs and distributions in non-superficial areas to within 2% for 6MV and 15MV Varian iX field sizes between 4 and 40 cm. Various types of treatment plans were then successfully verified, including 3D, VMAT, IMRT, and an iPlan Monte Carlo stereotactic lung to within 3% (tumor dose). CONCLUSION: With such tools it is practical for a non-research physicist to fit a two source photon model for the purpose of monte carlo treatment plan verification. The only commissioning data needed are in-air output factors, a single large field dose distribution, and the usual machine parameters provided by LINAC vendors for clinical second check programs. Even when only photons are simulated and spectra are greatly simplified it is possible to achieve acceptable results for non-superficial tumors. Furthermore, this is achieved without proprietary machine specifications.

CD161 receptor participates in both impairing NK cell cytotoxicity and the response to glycans and vimentin in patients with rheumatoid arthritis.

We investigated the role of natural killer (NK) cells and CD161, their primary C-type-lectin-like receptor in rheumatoid arthritis (RA). Samples were compared with healthy donors (HD), dermatomyositic (DM), polymyositic (PM), and osteoarthritic (OA) patients. RA, PM, and DM NK cell cytotoxicities significantly decreased relative to the HD and OA NK cells (p<0.0001). These results correlated with an increased expression of NK cell inhibitory receptor CD161, in active disease RA patients. We demonstrated that NK cells are able to respond to mutated citrullinated vimentin (MCV), an RA-specific autoantigen, leading to increases in both PAD4 enzyme and CD161 mRNA expression. MGAT5 glycosidase involvement was detected in GlcNAc metabolism within the synoviocytes of RA patients. Our findings reveal a functional relationship between CD161 expression and NK cell cytotoxicity as well as reactivity to glycans and MCV, thus providing new insight into the pathogenesis of RA and confirming the involvement of surface glycosylation.

NK cell-mediated cytotoxicity modulation by A(2) adenosine receptor agonist in different mammalian species.

Adenosines, endogenous purine nucleosides, appear in the extracellular space under metabolically stressful conditions associated with ischemia, inflammation, and cell damage. Their activity on innate immunity is prevalently inhibitory and can develop both in infectious and neoplastic diseases. During cancer development, tumor cells that release high concentrations of adenosines can impair the function of tumor-infiltrating lymphocytes and assist tumor growth by neo-angiogenesis. We evaluated the influence of A(2) adenosine receptor (A(2)AR) agonist on cytotoxic-cell response comparing human with other mammalian species (rodents, pigs, goats), both in healthy and in cancer conditions. The A(2)AR agonist developed dose-dependent inhibition of the cytotoxic activity of immune effector cells in all studied species. However, variability of the response was observed in relation to the species and the target cells that were used. Altogether, our data indicate that the A(2)AR plays a central role in adenosine-mediated inhibition of immune response to tumors.

EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial.

While EBV PCR is used in the management of PTLD, the optimal primer set, relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population remains unclear. We performed a prospective 2-arm trial utilizing an EBV PCR panel measuring LMP-1, EBER-1 and EBNA-1 in both free plasma as well as intracellular whole blood. Control Arm A consisted of 31 lung transplant patients and Arm B consisted of 35 transplant patients being evaluated for possible PTLD. In Arm A, 1/31 (3%) patients developed a transient plasma EBV load. Thirteen of 31 (42%) had detectable intracellular EBV. In Arm B, 17 (49%) patients were diagnosed with PTLD. Thirteen (76%) had EBV-positive PTLD with 12/13 (92%) having detectable EBV by PCR. The EBV PCR panel had a high sensitivity (92%), specificity (72%), positive predictive value (PPV) (71%) and negative predictive value (NPV) (93%) for diagnosing EBV-positive PTLD and followed patients' clinical course well (p < 0.001). Comparing the individual PCR assays, plasma EBNA PCR was superior with high sensitivity (77%), specificity (100%), PPV (100%) and NPV (86%). We conclude that EBV PCR is a useful test for managing PTLD patients. While plasma EBNA PCR is the best single assay for diagnosing and monitoring PTLD, the complete PCR panel is superior for ruling out its presence.

Immunological response in the mouse melanoma model after local hyperthermia.

Our study was aimed to characterize the phenotype and functional endpoints of local microwave hyperthermia (LHT, 42 degrees C) on tumor infiltrating and spleen leukocytes. The effectiveness of LHT applied into the tumor of B16F10 melanoma-bearing C57/BL6 mice was compared with anesthetized and non-treated animals. Subpopulations of leukocytes were analyzed using the flow cytometry, and the cytotoxic activity of splenocytes against syngeneic B16F10 melanoma and NK-sensitive YAC-1 tumor cell lines was evaluated in (51)Cr-release assay. Similarly, the in vitro modification of the heat treatment was performed using healthy and melanoma-bearing splenocytes. We found a 40 % increase of activated monocytes (CD11b+CD69+) infiltration into the tumor microenvironment. In the spleen of experimental animals, the numbers of cytotoxic T lymphocytes (CTLs-CD3+CD8+) and NK cell (CD49b+NK1.1+) raised by 22 % and 14 %, respectively, while the NK1.1+ monocytes decreases by 37 %. This was accompanied by an enhancement of cytotoxic effector function against B16F10 and YAC-1 targets in both in vivo and in vitro conditions. These results demonstrate that LHT induces better killing of syngeneic melanoma targets. Furthermore, LHT evokes the homing of activated monocytes into the tumor microenvironment and increases the counts of NK cells and CTL in the spleen.

[An unusual cause of duodenal obstruction--a case report]. / Neobvyklá prícina obstrukce duodena--kazuistika.

The article presents a patient operated for upper gastrointestinal tract obstruction caused by a tumour of the duodenum. The histological analysis described it as hyperplasia of the Brunner's gland. The article presents the clinical manifestation, diagnostics and therapy of this tumour. A summary of related literature to Brunner's gland adenoma follows. This very rare benign pathology of the small intestine presents itself with no specific clinical symptomatology, often as dyspepsia or ulcerous disease. Diagnosis is based on endoscopy and radiographic methods. Therapy is most commonly surgical.

Prognostic value of FDG-PET scan imaging in lymphoma patients undergoing autologous stem cell transplantation.

We conducted a retrospective analysis of 50 lymphoma patients (Hodgkin's disease and non-Hodgkin's lymphoma) who had an 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) scan after at least two cycles of salvage chemotherapy and before autologous stem cell transplantation (ASCT) at our institution. The patients were categorized into FDG-PET negative (N = 32) and positive (N = 18) groups. The median follow-up after ASCT was 19 months (range: 3-59). In the FDG-PET-negative group, the median progression-free survival (PFS) was 19 months (range: 2-59) with 15 (54%) patients without progression at 12 months after ASCT. The median overall survival (OS) for this group was not reached. In the FDG-PET-positive group, the median PFS was 5 months (range: 1-19) with only one (7%) patient without progression at 12 months after ASCT. The median OS was 19 months (range: 1-34). In the FDG-PET-negative group, chemotherapy-resistant patients by CT-based criteria had a comparable outcome to those with chemotherapy-sensitive disease. A positive FDG-PET scan after salvage chemotherapy and prior ASCT indicates an extremely poor chance of durable response after ASCT.

Long-term event-free survivors after high-dose therapy and autologous stem-cell transplantation for low-grade follicular lymphoma.

Although follicular lymphoma (FL) is generally responsive to conventional-dose chemotherapy, improved survival in patients with this disease has been difficult to demonstrate. High-dose chemo/radiotherapy followed by autologous stem-cell transplantation (ASCT) can improve response rates, although its effects on survival remain controversial. Between 1990 and 2003, we transplanted 49 patients with low-grade FL at our institution. Twenty-two patients (45%) had undergone histologic transformation at the time of ASCT. In all, 44 patients (90%) had relapsed disease and five patients (10%) were resistant to chemotherapy at the time of transplantation. After ASCT, 30 patients (61%) were in complete remission (CR). The median overall survival (OS) has not been reached, while the median event-free survival (EFS) is 2.4 years. At a median follow-up of 5.5 years (longest 12.4 years), a plateau has been reached with 56% of patients remaining alive, and 35% event-free. ASCT was well tolerated except for two (4%) treatment-related deaths. In multivariable analysis, CR after ASCT and age less than 60 years are the best predictors of EFS and OS. ASCT is thus a safe therapeutic approach in FL, resulting in long-term EFS and OS for some patients, even with transformed disease.

Ultrafiltered pig leukocyte extract (UPLE, IMUNOR) potentiates hematopoiesis-stimulating effects of G-CSF in vitro and improves the outcome of treatment of hematopoietic radiation damage in mice with G-CSF.

Ultrafiltered pig leukocyte extract (UPLE, Imunor), a heterogeneous mixture of low molecular weight (<10 kD) substances released from disintegrated pig leukocytes was tested from the point of view of its hematopoiesis-modulating activities using experiments in vitro and in vivo. Attention was focused especially on evaluation of the contingent ability of UPLE to potentiate the hematopoiesis-stimulating effects of recobinant human granulocyte colony-stimulating factor (G-CSF). Experiments in vitro revealed the capability of sera from mice administered UPLE perorally (p.o.) to stimulate proliferation of progenitor cells for granulocytes and macrophages (GM-CFC) in cultures of normal bone marrow cells. In addition, UPLE, as well as sera from mice given UPLE, added to the cultures in combination with G-CSF enhanced the numbers of GM-CFC significantly over those induced by sera after administration of either of the preparations alone. In in vivo experiments, UPLE was found to increase the counts of GM-CFC per femur and femoral bone marrow cellularity in sublethally irradiated mice when administered p.o. after irradiation in combination with G-CSF in comparison with the effects of G-CSF alone. These results indicate the possibility of using UPLE, a commercially available preparation, for treatment of hematopoietic suppression of various etiology.

[Thyroid gland surgery--a contribution to the discussion on its surgical technique]. / Chirurgie stítné zlázy--príspevek k diskusi o technice operování.

The authors present their thyroid gland operation results from the point of view of the current discussion on various techniques of the thyroid surgical procedures.