[Checkpoint inhibitors in Hodgkin lymphoma]. / Checkpoint-Inhibitoren bei Hodgkin-Lymphom.

BACKGROUND: Checkpoint blockade contributes to the immunosuppressive microenvironment in classical Hodgkin lymphoma (cHL) and in particular the interaction of Hodgkin cells and macrophages with T­cells and natural killer cells via programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1). OBJECTIVES: The aim of this article is the evaluation the role and potential of checkpoint blockade in cHL as compared with the results of standard chemo- and radiotherapy. METHODS: We analyzed preclinical and clinical data from phase I and phase II studies with checkpoint blockade in cHL. RESULTS AND DISCUSSION: In 60-70% of patients with chemotherapy-refractory cHL, PD­1 blockade results in responses. Overall survival is excellent and a small number of patients achieve persistent response. Thus, the use of anti-PD­1 monoclonal antibodies has become an important treatment approach in relapsed cHL in line with the label. The results of first-line therapy are still preliminary; initial phase II studies using nivolumab in combination with doxorubicin (=adriamycin), vinblastin and dacarbazin (AVD) in early unfavorable or advanced stages showed response rates of up to 90%. Thus, implementing immunomodulatory approaches using PD 1­blockade have resulted in a significant reduction of chemotherapy. This might represent a paradigm shift in the therapy of cHL.

[Biological therapies in otology. German version]. / Biologische Therapien in der Otologie.

Millions of people worldwide suffer from hearing loss. Current treatment for patients with severe to profound hearing loss consists of cochlear implants. Providing the cochlear nerve is intact, patients generally benefit enormously from this intervention, frequently achieving significant improvements in speech comprehension. There are, however, some cases where current technology does not provide patients with adequate benefit. New therapeutic concepts based on cell transplantation and gene therapy are developing rapidly, at least in the research sector. Compared to the wealth of basic research available in this area, translation of these new experimental approaches into clinical application is presently at a very early stage. The current review focuses on translatable treatment concepts and discusses the barriers that need to be overcome in order to translate basic scientific research into clinical reality. Furthermore, the first examples of clinical application of biological therapies in severe hearing loss are presented, particularly in connection with cochlear implants.

Biological therapies in otology.

Hearing loss is present in millions of people worldwide. Current treatment for patients with severe to profound hearing loss consists of cochlear implantation. Providing the cochlear nerve is intact, patients generally benefit greatly from this intervention, frequently achieving significant improvements in speech comprehension. There are, however, some cases where current technology does not provide patients with adequate benefit. Ongoing research in cell transplantation and gene therapy promises to lead to new developments that will improve the function of cochlear implants. Translation of these experimental approaches is presently at an early stage. This review focuses on the application of biological therapies in severe hearing loss and discusses some of the barriers to translating basic scientific research into clinical reality. We emphasize the application of these novel therapies to cochlear implantation.

Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin's lymphoma.

BACKGROUND: To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL). PATIENTS AND METHODS: One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible. RESULTS: At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4). CONCLUSION: Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

Inhibition of glycosphingolipid biosynthesis induces cytokinesis failure.

Although cells undergo dramatic shape changes during cytokinesis, the role of the plasma membrane and lipids is poorly understood. We report that inactivation of glucosyl ceramide synthase (GCS), either by RNAi or with the small molecule PPMP, causes failure of cleavage furrow ingression. Using mass-spectrometry-based global lipid profiling, we identify individual lipids that are enhanced or depleted due to GCS inhibition. We show that GCS inhibition results in the mislocalization of actin and the ERM proteins, key cytoskeletal proteins that connect the plasma membrane to the actin cortex. Our data suggest that ceramides participate in mediating the interactions between the membrane and the cortex.

Acute and chronic effects of ferret odor exposure in Sprague-Dawley rats.

This manuscript describes several behavioral and functional studies evaluating the capacity of ferret odors to elicit a number of acute and long-term responses in male Sprague-Dawley rats. Acute presentation elicits multiple responses, suggesting that ferret odor, likely from skin gland secretions, provides an anxiogenic-like stimulus in this strain of rats. Compared to cat odor, however, ferret odor did not produce rapid fear conditioning, a result perhaps attributable to methodological factors. Inactivation of the olfactory system and medial nucleus of the amygdala, combined with induction of the immediate-early gene c-fos, suggest the necessity of the accessory olfactory system in mediating the effects of ferret odor. Repeated exposures to ferret odor produce variable habituation of neuroendocrine and behavioral responses, perhaps indicative of the lack of control over the exact individual origin or concentration of ferret odor. Ferret odor induces rapid and long-term body weight regulation, thymic involution, adrenal hyperplasia and facilitation of the neuroendocrine response to additional challenges. It is argued that the use of such odors is exquisitely suited to investigate the brain regions coordinating anxiety-like responses and the long-term changes elicited by such stimuli.

A systematic review of national policies for the management of persons exposed to tuberculosis.

OBJECTIVE: To describe mandates and policy gaps in tuberculosis (TB) contact investigation and management. DESIGN: We conducted a systematic review of national TB policy documents obtained using a systematic internet search and by contacting national TB programs. We included policies published in English, Spanish, and French, and abstracted data using a standardized form. RESULTS: We reviewed policy documents for 68 of 216 (31%) countries and territories. All countries recommended performing contact investigations, but 40% did not specify how contacts enter the health system for evaluation or who was responsible for this process. All countries recommended preventive therapy for contacts, but in 14 (21%) countries only young children were eligible. While four preventive therapy regimens exist, 48 (71%) countries recommended only isoniazid monotherapy. In addition, 28 (41%) countries lacked guidance on whether to give preventive therapy to contacts exposed to drug-resistant TB. Policies in 28 (41%) countries lacked recommendations for managing contacts with the human immunodeficiency virus (HIV) after new TB exposure. CONCLUSION: Policies recommending contact investigation and preventive therapy for contacts are widespread, but policy gaps exist in the areas of ensuring accountability and the management of vulnerable populations such as people living with HIV and those exposed to drug-resistant TB.

High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study).

To investigate immuno-chemotherapy for elderly immuno-competent patients (⩾65 years) with newly diagnosed primary central nervous system lymphoma, we conducted a multicentre single-arm trial. One cycle consisted of rituximab (375 mg/m2, days 1, 15, 29), high-dose methotrexate (3 g/m2 days 2, 16, 30), procarbazine (60 mg/m2 days 2-11) and lomustine (110 mg/m2, day 2)-R-MPL protocol. Owing to infectious complications, we omitted lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary end point was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). In all, 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared with R-MPL (37.7%), but respective 2-year progression-free survival (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and overall survival (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less ⩾grade 3 toxicities compared with R-MPL (71.1% vs 87.0%). R-MP is more feasible while still associated with similar efficacy compared with R-MPL and warrants further improvement in future studies.

Human angiogenin fused to human CD30 ligand (Ang-CD30L) exhibits specific cytotoxicity against CD30-positive lymphoma.

A number of different immunotoxins composed of cell-specific targeting structures coupled to plant or bacterial toxins have increasingly been evaluated for immunotherapy. Because these foreign proteins are highly immunogenic in humans, we have developed a new CD30 ligand-based fusion toxin (Ang-CD30L) using the human RNase angiogenin. The completely human fusion gene was inserted into a pET-based expression plasmid. Transformed Escherichia coli BL21(DE3) were grown under osmotic stress conditions in the presence of compatible solutes. After isopropyl beta-D-thiogalactoside induction, the M(r) 37,000 His(10)-tagged Ang-CD30L was directed into the periplasmic space and functionally purified by a combination of metal ion affinity followed by enterokinase cleavage of the His(10)-Tag and molecular size chromatography. The characteristics of the recombinant protein were assessed by ELISA, flow cytometry, and toxicity assays showing specific activity against CD30(+) Hodgkin-derived cells. Specific binding activity of Ang-CD30L was verified by competition with anti-CD30 monoclonal antibody Ki-4 and commercially available CD30L-CD8 chimeric protein. Ang-CD30L showed RNase activity in vitro. The human recombinant immunotoxin showed significant toxicity toward several CD30-positive cell lines (HDLM-2, L1236, KM-H2, and L540Cy) and exhibited highest cytotoxicity against L540 cells (IC(50) = 8 ng/ml) as determined by cell proliferation assays. CD30 specificity was confirmed by competitive toxicity assays. This is the first report on the specific cytotoxicity of a recombinant completely human fusion toxin with possibly largely reduced immunogenicity for the treatment of CD30-positive malignancies.

Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma: An updated review of published data from the named patient program.

Brentuximab vedotin was available via named patient program (NPP) to patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma in ∼60 non-US/Canadian countries, before local approval. Published results were examined recently; through systematic literature review, we identified 12 new NPP publications. Most (10/12) publications included new NPP data describing 8 unique cohorts (N=480; all R/R HL) and new participating countries. Overall response rates were 58-80%, and complete remission rates were 10-40%. With median follow-up of 9.5-26 months, median progression-free survival was 5-10.5 months and median overall survival (OS) had not been reached in most cohorts; 1- and 2-year OS was 67-76% and 58-67%, respectively. Tolerability was as expected from previous reports. Despite intrinsic bias and heterogeneous cohorts, this update supports previous findings showing comparable efficacy and tolerability of brentuximab vedotin between real-world practice and phase 2 trial results in R/R HL.

Two-dimensional and 3-dimensional optical coherence tomographic imaging of the airway, lung, and pleura.

BACKGROUND: Methods for obtaining real-time in vivo histologic resolution by means of noninvasive endoscopic optical imaging would be a major advance for thoracic surgical diagnostics and treatment. Optical coherence tomography is a rapidly evolving technology based on near-infrared interferometry that might provide these capabilities. The purpose of this study is to investigate the feasibility of real-time 2- and 3-dimensional optical coherence tomographic imaging of airway, pleural, and subpleural lung tissues in normal, inflammatory, and malignant animal models and patients with known or suspected airway malignancy. METHODS: Freshly excised lungs and pleural tissue obtained from rabbits with inhalation lung injury and induced empyema, metastatic sarcomas, and pleural sarcomas and from patients with airway disease were imaged by using 2- and 3-dimensional optical coherence tomography with a prototype superluminescent diode optical coherence tomographic system constructed in our laboratory. Lungs and pleural tissue were subsequently processed for standard hematoxylin and eosin histology for comparison with optical coherence tomography. RESULTS: Optical coherence tomographic imaging achieved an ex vivo resolution of 10 microm and an in vivo resolution of about 30 microm with a depth penetration of 1 to 2 mm with 2- and 3- dimensional reconstruction capabilities. Tumors as small as 500 microm were detectable with optical coherence tomography. The acquired images closely matched histologic images, demonstrating details at the level of mucosal layers, glands, alveoli, and respiratory bronchioles. CONCLUSIONS: Optical coherence tomography with near-infrared interferometric methods enables near real-time in vivo near-histologic resolution optical imaging. With further advances, optical coherence tomography has the potential for real-time accurate and early pleural and subpleural diagnostics by using small-diameter flexible fiberoptic endoscopic probes for a wide range of thoracic surgical applications.

Experience of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma and relapsed/refractory systemic anaplastic large-cell lymphoma in the Named Patient Program: Review of the literature.

Brentuximab vedotin was made available via a Named Patient Program (NPP) to non-US/Canadian patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL) until approval in their respective countries. We re-evaluated the efficacy and safety NPP data in a pooled analysis. Through a systematic literature review, 21 NPP publications were identified describing 14 cohorts (N=245). Among patients with a specified diagnosis, 207 had HL, 28 had ALCL, and one had CD30+ T-cell lymphoma (not specified). In cohorts reporting response, overall response and complete remission rates were 67% and 26%, respectively, in R/R HL, and 75% and 74%, respectively, in R/R ALCL. Incidences of grade 3/4 neurologic and hematologic toxicities were 6% and 12%, respectively; 5% of patients discontinued because of toxicity. In real-world practice, response rates and tolerability to brentuximab vedotin are similar to those reported in the two pivotal phase 2 trials in these settings.

Selection of scFv phages on intact cells under low pH conditions leads to a significant loss of insert-free phages.

Display of functional antibody fragments on the surface of filamentous bacteriophages allows fast selection of specific phage antibodies against a variety of target antigens. However, enrichment of single chain variable fragment (scFv)-displaying phages is often hampered by the abundance of bacteriophages lacking antibody fragments. Moderate adhesive binding activities and production advantages of these "empty" phages results in their subsequent enrichment during selection on target cells. To date, very limited effort has been made to develop strategies removing nonspecific binding phages during the selection processes. To efficiently reduce insert-free phages when panning on intact cells, we increased the washing stringency by lowering the pH of the buffer with citric acid. Under standard washing procedures (pH 7.4), only approximately 73% of recovered phages were insert-free after three rounds of selection. Using stringent washing procedures (pH 5.0), approximately 12% of recovered phages contained no scFv. Using this protocol, we have cloned an antibody fragment from a mouse/human hybridoma cell line directed against the disialoganglioside GD2. This study confirms that selection of phage antibodies on cells is efficiently enhanced by assays augmenting the stringency to remove nonspecific binding phages.

Variability of arterial blood gas values over time in stable medical ICU patients.

The spontaneous variability of arterial blood gas and pH values (ABGs) was examined in a group of 28 typical stable medical ICU patients under a variety of ventilatory conditions. In each patient, 13 ABG specimens were measured at 5-min intervals during a 1-h study period using a new bedside, extravascular fluorescent blood gas monitor. For all patients, the mean coefficient of variation (C) was 6.1 percent for PO2 and 4.7 percent for PCO2. The average SD for pH was 0.012. We conclude that the spontaneous variability for ABG values over a 1-h period is substantial and that this variability should be taken into account when making clinical decisions based on ABG values.

The utility of daily therapeutic thoracentesis for the treatment of early empyema.

STUDY OBJECTIVES: To determine if therapeutic thoracentesis is as effective as early chest tube placement or no drainage procedure in the treatment of early empyema in rabbits. DESIGN AND INTERVENTIONS: An empyema, as evidenced by gross pleural pus and a decreased pleural fluid pH and glucose level, was induced in 49 rabbits. The rabbits were divided into three groups: 16 underwent daily therapeutic thoracentesis starting at 48 h, 14 underwent chest tube placement at 48 h, and 19 served as controls. RESULTS: The mortality rate in the therapeutic thoracentesis group (0/16) did not differ significantly from that in the chest tube group (3/14) or that in the control group (6/19). At autopsy at 10 days, the gross empyema score in the therapeutic thoracentesis group (2.1 +/- 0.3) was significantly lower (p < 0.05) than that in the chest tube group (2. 8 +/- 0.3) or the control group (3.5 +/- 0.2). The mean pleural peel score of 5.8 +/- 1.1 in the therapeutic thoracentesis group was significantly less (p < 0.05) than the score for the nonintervention control group (13.4 +/- 1.6). CONCLUSIONS: From this study, we conclude that therapeutic thoracentesis is at least as effective as early chest tube placement for the treatment of early empyema using our rabbit model of empyema.

The effects of pentoxifylline on oxygenation, diffusion of carbon monoxide, and exercise tolerance in patients with COPD.

Pentoxifylline has been reported previously in an unblinded study to improve oxygen saturation, treadmill walk time, and resting diffusion of carbon monoxide (Dco) in patients with COPD. We recruited 12 patients with moderate to severe COPD whose exercise capacity was limited by ventilation or who developed hypoxemia with exercise. Patients were randomized to receive pentoxifylline or placebo, each for a 12-week period in a prospective, double-blind, crossover design study, to assess the effects of pentoxifylline on oxygenation, resting Dco, and exercise tolerance using arterial blood gas analysis. Eleven patients with a mean FEV1 of 0.94 L and a mean Dco of 9.85 mL/min/mm Hg completed the study. One patient withdrew from the study after developing pneumonia. There were no significant differences in resting oxygenation, resting Dco, or spirometry after 12 weeks of pentoxifylline relative to placebo. The 12-min walk test and dyspnea index for activities of daily living were also not significantly different while taking pentoxifylline. Finally, at maximal exercise, there were no differences in workload attained, exercise duration, oxygen consumption, carbon dioxide production, minute ventilation, oxygen saturation, PO2, alveolar-arterial oxygen pressure difference, or Borg score while taking pentoxifylline relative to placebo. We conclude that pentoxifylline does not improve oxygenation, resting Dco, exercise tolerance, or dyspnea in patients with moderate to severe COPD.

Hemoptysis due to migration of a fractured Kirschner wire.

We report a rare complication related to the insertion of Kirschner wires for stabilization of an acromioclavicular separation. Five years after placement of the Kirschner wires, the patient presented with hemoptysis. On review of chest radiographs, a fractured wire was found to have migrated from the acromioclavicular joint, through the hemithorax and into the trachea.

Arterial blood gas changes during breath-holding from functional residual capacity.

Breath-holding serves as a model for studying gas exchange during clinical situations in which cessation of ventilation occurs. We chose to examine the arterial blood gas changes that occurred during breath-holding, when breath-holding was initiated from functional residual capacity (FRC) while breathing room air. Eight normal subjects who had a radial artery catheter placed for another study were taught to breath-hold on command from FRC. FRC was determined using respiratory inductance plethysmography. Arterial blood gas specimens were obtained at 5-s intervals until the termination of breath-holding. The average breath-holding time (+/-SD) was 35 (+/-10 s). The PaO2, PaCO2, and pH values were plotted against time and individually fit to logistic equations for each subject. The arterial PaO2 fell by a mean of 50 mm Hg during the first 35 s of breath-holding under these conditions, while the arterial PCO2 rose by a mean of 10.2 mm Hg during the first 35 s and the pH fell by a mean of 0.07 in the first 35 s. The rapid decline in PaO2 is greater than that previously reported using different methods and should be considered in clinical situations in which there is an interruption of oxygenation and ventilation at FRC while breathing room air. The changes in PaCO2 and pH are similar to those previously reported in paralyzed apneic patients.

The effects of early chest tube placement on empyema resolution.

STUDY OBJECTIVES: The objective of this study was to determine the impact of the timing of chest tube insertion on outcome for the treatment of empyema, using a new animal model of empyema. DESIGN: A prospective, controlled randomized, blinded design was used. SETTING: The study was conducted in an animal research laboratory. PATIENTS OR PARTICIPANTS: Sixty-six 2- to 3-kg rabbits were used in this study. INTERVENTIONS: After induction of empyema, the rabbits were divided into four groups. Fourteen rabbits had chest tubes placed at 24 h after empyema induction. Seventeen rabbits had chest tubes placed at 48 h and 14 rabbits had chest tubes placed at 72 h after empyema induction. Twenty-one rabbits served as control rabbits and had no chest tubes placed. MEASUREMENTS AND RESULTS: Ten days after induction of empyema, the rabbits were killed. The pleural spaces of each rabbit were examined and a gross score, pleural peel score, and a microscopic score were calculated for each rabbit. The median gross score, mean pleural peel score, and median microscopic scores were significantly higher in the rabbits that underwent late chest tube placement (72 h) relative to those that underwent early chest tube placement (24 or 48 h). CONCLUSIONS: This study supports previous expert opinion statements and conclusions from retrospective analyses that early chest tube placement (relative to delayed chest tube placement) is beneficial for the treatment of empyema.

Comparison of the end-tidal arterial PCO2 gradient during exercise in normal subjects and in patients with severe COPD.

We undertook the present study with the following objectives: (1) to compare the difference between the end-tidal and the arterial carbondioxide concentration (P[ETa] CO2) gradients at rest and during exercise in normal subjects and patients with COPD; and (2) to analyze the factors contributing to this gradient. We studied seven normal subjects and seven patients with COPD using a symptom-limited exercise test on a cycle ergometer. Our results show that the P(ET-a)CO2 increased progressively as the individuals went from rest to higher workloads in both the normal group and in the COPD group. The P(ET-a)CO2 in patients with COPD both at rest (-3.24 +/- 2.78 mm Hg) and during exercise (1.03 +/- 2.23 mm Hg) is significantly lower than that in normal individuals at rest (1.84 +/- 3.68 mm Hg) and during exercise (10.3 +/- 6.5 mm Hg) (p < 0.01). However, the slope for the relationship between the P(ET-a)CO2 and the workload is actually significantly steeper in the patients with COPD. Although the P(ET-a)CO2 correlated significantly with the workload in both normal subjects (r = 0.63, p < 0.001) and patients (r = 0.55, p < 0.005), the P(ET-a)CO2 was much more closely correlated with the ratio of dead space to tidal volume (VD/VT) (r values of -0.86 and -0.77, respectively). Moreover, when multiple regression analysis was performed, addition of any other physiologic measure (eg, oxygen consumption [VO2], carbon dioxide production [VCO2], minute ventilation [VE], or workload) as a second independent variable after the VD/VT did not improve the correlation. This indicates that the correlation between the P(ET-a)CO2 and the workload is probably related to the dependence of the VD/VT on the workload. The PaCO2 in normal subjects and in the COPD group correlated significantly with the partial pressure of end-tidal carbon dioxide (PETCO2). Using multiple regression analysis, with the PaCO2 as the dependent variable and the PETCO2 (along with other physiologic measures) as the independent variables, we found that the standard error of the estimate was still above 2.1 mm Hg in normal subjects and in patients with COPD. We conclude that (1) during exercise, the P(ET-a)CO2 in normal subjects and in patients with COPD increases significantly, (2) the P(ET-a)CO2 gradient is more closely correlated with the VD/VT than any other physiologic variable, and (3) changes in the PETCO2 during exercise are not correlated closely with changes in the PaCO2.