Nivolumab for locally advanced and metastatic cutaneous squamous cell carcinoma (NIVOSQUACS study)-Phase II data covering impact of concomitant haematological malignancies.

BACKGROUND: Monoclonal antibodies, such as cemiplimab and pembrolizumab, against the programmed death receptor (PD)-1 have become the current standard of care and first-line treatment of advanced cutaneous squamous cell carcinoma (cSCC), proving remarkable clinical benefit and acceptable safety. OBJECTIVES: To assess efficacy and safety of the anti-PD-1 antibody nivolumab in patients with locally advanced and metastatic cSCC. METHODS: Patients received open-label nivolumab 240 mg intravenously every 2 weeks for up to 24 months. Patients with concomitant haematological malignancies (CHMs), either non-progressing or stable under active therapy, were eligible for inclusion. RESULTS: Of 31 patients with a median age of 80 years, 22.6% of patients achieved an investigator assessed complete response, resulting in an objective response rate (ORR) of 61.3% and a disease control rate (DCR) of 64.5%. Progression-free survival (PFS) was 11.1 months, and the median overall survival (OS) was not reached after 24 weeks of therapy. Median follow-up was 23.82 months. Subgroup analysis of the CHM cohort (n = 11; 35%) revealed an ORR of 45.5%, a DCR of 54.5%, a median PFS of 10.9 months, and median OS of 20.7 months. Treatment related adverse events were reported in 58.1% of all patients (19.4% grade 3, the remaining grade 1 or 2). PD-L1 expression and CD-8+ T-cell infiltration did not significantly correlate with clinical response, although a trend towards a shorter PFS of 5.6 months was observed with PD-L1 negativity and low CD8+ intratumoral infiltration. CONCLUSION: This study demonstrated robust clinical efficacy of nivolumab in patients with locally advanced and metastatic cSCCs and a tolerability comparable to data of other anti-PD-1 antibodies. Favourable outcomes were obtained despite involving the oldest hitherto reported study cohort for anti-PD-1 antibodies and a significant proportion of CHM patients prone to high risk tumours and an aggressive course otherwise typically excluded from clinical trials.

Perspectives on COVID-19 prevention and treatment using herbal medicine in Vietnam: A cross-sectional study.

Introduction: The significance of herbal medicine (HM) during the COVID-19 pandemic has been confirmed. Nevertheless, limited studies have included the people perspectives on COVID-19 prevention/treatment using herbal medicine in Vietnam. Thus, this study tackled the aforementioned issue. Methods: Online-based cross-sectional study was conducted in Vietnamese adults between February-April 2021. Descriptive analysis, regression and Chi-squared tests were implemented for the statistical purposes. Results: total of 787 respondents attended the study, 368 (46.8%) confirmed that they use herbal medicine/nutritional supplements for COVID-19 prevention/treatment. Over 50% of the respondents possessed positive perspective on vitamin C ingestion. Using herbal medicine for external use as a disinfectant was mostly preferred. Respondents who had a 'very good' health self-perception or who lived in rural areas, were more likely to have a positive opinion in the COVID-19 prevention/treatment using herbal medicine. The main barrier for herbal medicine utilization was the deficiency of personal experience or expert advice. Conclusion: The Vietnamese people commonly utilize herbal medicine for the COVID-19 prevention/treatment. These data might help policy-makers in managing the public knowledge and practice on herbal medicine use in Vietnam.

Clinical diversity and treatment approaches to blastic plasmacytoid dendritic cell neoplasm: a retrospective multicentre study.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive type of haematologic precursor malignancy primarily often manifesting in the skin. We sought to provide a thorough clinical characterization and report our experience on therapeutic approaches to BPDCN. METHODS: In the present multicentric retrospective study, we collected all BPDCN cases occurring between 05/1999 and 03/2018 in 10 secondary care centres of the German-Swiss-Austrian cutaneous lymphoma working group. RESULTS: A total of 37 BPDCN cases were identified and included. Almost 90% of the patients had systemic manifestations (bone marrow, lymph nodes, peripheral blood) in addition to skin involvement. The latter presented with various types of cutaneous lesions: nodular (in more than 2/3) and bruise-like (in 1/3) skin lesions, but also maculopapular exanthema (in circa 1/6). Therapeutically, 22 patients received diverse combinations of chemotherapeutic regimens and/or radiotherapy. Despite initial responses, all of them ultimately relapsed and died from progressive disease. Eleven patients underwent haematopoietic stem cell transplantation (HSCT; autologous HSCT n = 3, allo-HSCT n = 8). The mortality rate among HSCT patients was only 33.33% with a median survival time of 60.5 months. CONCLUSION: Our study demonstrates the clinical diversity of cutaneous BPDCN manifestations and the positive development observed after the introduction of HSCT.

[Adverse effects of immunotherapy : Clinical aspects, radiological and nuclear medicine results]. / Unerwünschte Wirkungen der Immuntherapie : Klinik, radiologische und nuklearmedizinische Befunde.

BACKGROUND: The increasing use of immunotherapy in oncology increases the need for radiologic evaluation of frequent and severe immune-related adverse events. OBJECTIVE: Determination of the incidence and manifestation of radiologic and nuclear medicine findings of immune-related adverse events. MATERIAL AND METHODS: Literature review of clinical and imaging findings of immune-related adverse events induced by the immune checkpoint inhibitors ipilimumab, nivolumab and pembrolizumab. Findings are illustrated with pictorial examples and contrasted to other relevant differential diagnoses. RESULTS: The most frequent imaging manifestations are colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, arthritis and sarcoid-like lymphadenopathy. Severe to life-threatening complications may result from colitis, pneumonitis and hypophysitis. A clear differentiation from other autoimmune diseases and discrimination of immune-related and infectious pulmonary findings can be very difficult and need close multidisciplinary collaboration. CONCLUSION: Knowledge of clinical and imaging findings of adverse events induced by immunotherapy is essential for timely and adequate therapeutic decisions. In addition to staging and follow-up imaging, identification and monitoring of immune-related adverse events adds to the radiologic responsibility in oncologic care.

Quantitative and large-format histochemistry to characterize peripheral artery compositional gradients.

The femoropopliteal artery (FPA) is a long, flexible vessel that travels down the anteromedial compartment of the thigh as the femoral artery and then behind the kneecap as the popliteal artery. This artery undergoes various degrees of flexion, extension, and torsion during normal walking movements. The FPA is also the most susceptible peripheral artery to atherosclerosis and is where peripheral artery disease manifests in 80% of cases. The connection between peripheral artery location, its mechanical flexion, and its physiological or pathological biochemistry has been investigated for decades; however, histochemical methods remain poorly leveraged in their ability to spatially correlate normal or abnormal extracellular matrix and cells with regions of mechanical flexion. This study generates new histological image processing pipelines to quantitate tissue composition across high-resolution FPA regions-of-interest or low-resolution whole-section cross-sections in relation to their anatomical locations and flexions during normal movement. Comparing healthy ovine femoral, popliteal, and cranial-tibial artery sections as a pilot, substantial arterial contortion was observed in the distal popliteal and cranial tibial regions of the FPA which correlated with increased vascular smooth muscle cells and decreased elastin content. These methods aim to aid in the quantitative characterization of the spatial distribution of extracellular matrix and cells in large heterogeneous tissue sections such as the FPA. RESEARCH HIGHLIGHTS: Large-format histology preserves artery architecture. Elastin and smooth muscle content is correlated with distance from heart and contortion during flexion. Cell and protein analyses are sensitive to sectioning plane and image magnification.

Morphological inversion of complex diffusion.

Epidemics, neural cascades, power failures, and many other phenomena can be described by a diffusion process on a network. To identify the causal origins of a spread, it is often necessary to identify the triggering initial node. Here, we define a new morphological operator and use it to detect the origin of a diffusive front, given the final state of a complex network. Our method performs better than algorithms based on distance (closeness) and Jordan centrality. More importantly, our method is applicable regardless of the specifics of the forward model, and therefore can be applied to a wide range of systems such as identifying the patient zero in an epidemic, pinpointing the neuron that triggers a cascade, identifying the original malfunction that causes a catastrophic infrastructure failure, and inferring the ancestral species from which a heterogeneous population evolves.

Reduced turn-around time for Mycobacterium tuberculosis drug susceptibility testing with a proportional agar microplate assay.

Multidrug-resistant tuberculosis is a major issue worldwide; however, accessibility to drug susceptibility testing (DST) is still limited in developing countries, owing to high costs and complexity. We developed a proportion method on 12-well microplates for DST. The assay reduced the time to results to <12 days and <10 days when bacterial growth was checked with the naked eye or a microscope, respectively. Comparison with the Canetti-Grosset method showed that the results of the two assays almost overlapped (kappa index 0.98 (95% CI 0.91-1.00) for isoniazid, rifampicin, streptomycin; and kappa index 0.92 (95% CI 0.85-0.99) for ethambutol). The sequencing of genes involved in drug resistance showed similar level of phenotype-genotype agreement between techniques. Finally, measurement of the MICs of rifampicin and ethambutol suggests that the currently used critical ethambutol concentration should be revised, and that the current molecular drug susceptibility tests for rifampicin need to be re-evaluated, as in vitro rifampicin-sensitive isolates could harbour drug resistance-associated mutation(s).

IL-10 attenuates IFN-alpha-activated STAT1 in the liver: involvement of SOCS2 and SOCS3.

Interleukin-10 (IL-10) has been used in the treatment of viral hepatitis in interferon-alpha (IFN-alpha) non-responders while patients who have high levels of IL-10 are poorly responsive to IFN-alpha. The mechanism underlying such controversial functions of IL-10 remains unknown. Here we demonstrated that injection of IL-10 into mice attenuated IFN-alpha-induced signal transducer and activator transcription factor (STAT)1 tyrosine phosphorylation in the liver. Reverse transcriptase-polymerase chain reaction assay demonstrated that mouse liver expressed high levels of IL-10 receptor 2 (IL-10R2) but low levels of IL-10R1. Injection of IL-10 into mice activated STAT3 but not STAT1 tyrosine phosphorylation and induced suppressor of cytokine signal 2 (SOCS2), SOCS3, and cytokine-inducible SH2 protein (CIS) mRNA expression in the liver. Furthermore, overexpression of SOCS2 or SOCS3 inhibited IFN-alpha-induced reporter activity in hepatic cells. These findings suggest that IL-10 inhibits IFN-alpha-activated STAT1 in the liver, at least in part, by inducing SOCS2, SOCS3, and CIS expression, which may be responsible for the resistance of IFN-alpha therapy in patients who have high levels of IL-10 and recommends that IL-10 treatment for viral hepatitis should be cautious.

Synthesis of the marine natural product barbamide.

The first total synthesis of the trichlorinated natural product barbamide is described. The convergent approach involves coupling (S)-3-trichloromethylbutanoyl chloride with Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) to give 15 followed by addition of the novel secondary amine N-methyl-(S)-dolaphenine 2 (prepared in 6 steps and 24% overall yield from N-Cbz-L-phenylalanine) to give the beta-keto amide 16 which was converted directly to the required (E)-enol ether.

Controlling binocular rivalry.

Binocular rivalry is the alternating perception that occurs when the two eyes are presented with incompatible stimuli. We have developed a new method for controlling binocular rivalry and measuring its progress. One eye views a static grating while the fellow eye views a grating that smoothly and cyclically varies between two orientations, one the same as the static grating and the other orthogonal. Contrast sensitivity was tested monocularly a number of times during the stimulus cycle. When the eye viewing the static grating was tested, sensitivity varied between maximum and minimum values as the conditioning stimulus varied from binocularly compatible to incompatible. The interocular suppression thus demonstrated was limited to the eye viewing the static grating; variations in the fellow eye's sensitivity were due to interocular masking alone.

Components of visual acuity loss in strabismus.

Strabismus, the misalignment of the visual axis of one eye relative to that of the other eye, reduces visual acuity in the affected eye. Several processes contributing to that loss are: amblyopia, which results in a chronic acuity loss whether or not the fellow eye is viewing; strabismic deviation, which shifts the image of an acuity target onto more peripheral, and therefore less acute, retina when the fellow eye fixates; interocular suppression and binocular masking, which reduce visibility in the strabismic eye due to neural influences from the other eye. We measured the losses due to these processes in nine small-angle strabismic subjects. Amblyopia reduced acuity by a median of 34% relative to its value in subjects with normal binocular vision, and strabismic deviation produced a loss of 44%. Suppression and masking together reduced acuity by 20%, and therefore had substantially less effect than the other factors.

Balloon angioplasty with intraluminal stenting as the initial treatment modality in aorto-iliac occlusive disease.

PURPOSE: We retrospectively evaluated balloon angioplasty with intraluminal stenting to define applicability, early results, cost, and length of stay. METHODS: Seventy-three patients underwent 94 aorto-iliac angioplasties with intraluminal stents from October 1991 through July 1993. All had disabling claudication or rest ischemia. RESULTS: Mean follow-up was 10.2 months and was 90.4% complete. Ninety percent of procedures were immediately successful. There were no deaths within 30 days of surgery. Complications occurred in 13%. The ankle:brachial indices improved in all groups. Functional class improved in all groups. In class 4, limb salvage or a benefit on level of amputation was universal. Length of stay ranged 33% to 82% less than when aorto-iliac or aortofemoral bypass were undertaken (diagnosis-related group 39.25). Hospital charges for stent procedures ranged 25% to 66% less than for aorto-iliac or aortofemoral bypass (diagnosis-related group 39.25). CONCLUSION: The procedure is widely applicable, with an apparent initial advantage in mortality, morbidity, charges, and length of stay. Durability is unproven.

Multiple tolerance of Rhodotorula glutinis R-1 to acid, aluminum ion and manganese ion, and its unusual ability of neutralizing acidic medium.

A red yeast isolated from the acidic water of Kusatsu hot spring could grow in an acidic medium of pH 1.5 and was identified as Rhodotorula glutinis. Electron microscope observations (scanning electron microscopy [SEM] and transmission electron microscopy [TEM]) showed that cell envelope became wrinkled and thick as the pH values of media became lower. The cell membrane grown at pH 1.5 was about four times as thick as that grown at pH 6.0. It was suggested that the change of cell envelope plays an important role in the acid tolerance. Cellular proteins at pH 1.5 appeared to be different from those at pH 6.0 and the amounts of phospholipids and non-phospholipids increased and decreased under low pH conditions, respectively. The acid-tolerant yeast also showed strong resistance to both aluminum and manganese ions. An acidic medium (pH 3.0) containing these ions (100 mM) was shifted to neutral pH by long-term cultivation of the red yeast, suggesting the potential of using this yeast in the bioremediation of acidic soil containing these ions at a high level.

Acute pulmonary edema, capillaritis and alveolar hemorrhage: pulmonary manifestations coexistent in antiphospholipid syndrome and systemic lupus erythematosus?

Pulmonary capillaritis and alveolar hemorrhage are rare yet serious and life threatening complications of systemic lupus erythematosus (SLE). Pulmonary manifestations of antiphospholipid syndrome (APS) are similar and include, apart from pulmonary embolism and pulmonary hypertension, pulmonary capillaritis, diffuse alveolar hemorrhage and respiratory insufficiency in patients with catastrophic APS. Herein, we described the radiological features of three patients with pulmonary and SLE-associated APS, manifested with pulmonary edema, capillaritis and alveolar hemorrhage. We observed that the radiological features of pulmonary APS shared close resemblance to those of pulmonary SLE. Based on these findings, we conclude that both entities are not only histologically, but also radiologically indistinguishable from each other, suggesting a mutual pathogenetic mechanism. This raises the question of whether some of the reported lupus pneumonitis cases in the past might be manifestations of APS rather than of SLE.

Human herpesvirus-8 infection of umbilical cord-blood-derived CD34+ stem cells enhances the immunostimulatory function of their dendritic cell progeny.

CD34(+) progenitor cells carrying human herpesvirus-8, Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV), have been described in the peripheral blood of AIDS patients suffering from Kaposi's sarcoma (KS). In this study, we investigated the influence of HHV-8 on the differentiation of CD34(+) progenitor cells. Native CD34(+) cells derived from cord blood could be infected by a laboratory strain of HHV-8, as shown by immunofluorescence staining and polymerase chain reaction, but no significant initial maturation/differentiation effects were observed. In addition, these infected cells were differentiated into immature and mature dendritic cells (DCs) using cytokine induction with recombinant human granulocyte-macrophage colony-stimulating factor (rhGm-CSF), recombinant human tumor necrosis factor (rhTNF-alpha) and recombinant human stem cell factor (rhSCF). Double immunofluorescence and flow cytometry studies demonstrated that virus infection did not impair the development of immature and mature DC populations. Subsequently, the immunostimulating capacity of DC populations was tested in a mixed lymphocyte reaction using allogeneic T-cells. The HHV-8-infected CD34(+) progenitor cell-derived mature DC population showed a significantly enhanced antigen-presenting capacity, compared to non-infected DCs, which was not observed with the immature DCs. This suggests stimulation of DC function by HHV-8 infection. Because there are only a small percentage of HHV-8-positive DCs in the preparations and because it is not clear whether infection is abortive or productive to some extent, this seems to be most likely due to an indirect viral effect.

Cross-talk between alpha(1B)-adrenergic receptor (alpha(1B)AR) and interleukin-6 (IL-6) signaling pathways. Activation of alpha(1b)AR inhibits il-6-activated STAT3 in hepatic cells by a p42/44 mitogen-activated protein kinase-dependent mechanism.

Treatment of primary rat hepatocytes or tranfected HepG2 cells with the alpha(1B)-adrenergic receptor (alpha(1B)AR) agonist phenylephrine (PE) significantly inhibited interleukin 6 (IL-6)-induced STAT3 binding, tyrosine phosphorylation, and IL-6-induced serum amyloid A mRNA expression. Western analyses and in vitro kinase assays indicate that this inhibition is not due to either down-regulation of STAT3 protein expression nor inactivation of upstream-located JAK1 and JAK2. Blocking the new RNA and protein syntheses antagonized the inhibitory effect of PE on IL-6-activated STAT3, suggesting synthesis of an inhibitory factor(s) is involved. The inhibitory effect of PE on IL-6 activation of STAT3 was also abolished by the tyrosine phosphatase inhibitor sodium vanadate, indicating involvement of protein tyrosine phosphatases. Furthermore, preincubation of the cells with the specific MEK1 inhibitor PD98059 or a dominant negative MEK1 reversed the inhibitory effect of PE, and expression of constitutively activated MEK1 alone abolished IL-6-activated STAT3. Taken together, these data indicate that PE inhibits IL-6 activation of STAT3 in hepatic cells by a p42/44 mitogen-activated protein kinase-dependent mechanism, and tyrosine phosphatases are involved. This inhibitory cross-talk between the alpha(1B)AR and IL-6 signaling pathways implicates the alpha(1B)AR involvement in regulating the IL-6-mediated inflammatory responses.

Endothelial injury in internal organs of University of California at Davis line 200 (UCD 200) chickens, an animal model for systemic sclerosis (Scleroderma).

Systemic sclerosis (SSc) is a multisystem disorder characterized by mononuclear cell infiltration and fibrosis. Using skin samples from human SSc and UCD 200 chickens, which spontaneously develop a hereditary disease closely resembling human SSc, we have shown previously that endothelial cell apoptosis is a primary event in the pathogenesis of SSc. The aim of the present study was to investigate the initial disease stage in visceral organs of UCD 200 chickens with special emphasis on endothelial apoptosis, mononuclear cell infiltration and collagen deposition using tissue samples from oesophagus, lung, heart, kidney and liver. Apoptotic endothelial cells were detected by terminal deoxynucleotidyl transferase-mediated FITC-dUTP nick end labeling (TUNEL), mononuclear cell infiltrates were stained with hematoxylin and eosin, and increased collagen deposition was demonstrated by Goldner staining. Apoptotic endothelial cells were detected in oesophagus, lung and kidney of UCD 200 chickens at the initial stage of the disease. No apoptotic endothelial cells were found in heart or liver of UCD 200 or in visceral organs of healthy normal UCD 058 control chickens. Oesophagus of UCD 200 chickens, which was the most affected internal organ, showed mononuclear cell infiltrations and increased deposition of collagen. Perivascular inflammatory infiltrates and collagen deposition appeared later than endothelial cell apoptosis. These data support the hypothesis that endothelial cell apoptosis initiates the disease process, followed by mononuclear cell infiltration and fibrosis.

The depth and selectivity of suppression in binocular rivalry.

Binocular rivalry occurs when the two eyes are presented with incompatible stimuli and the perceived image alternates between the two stimuli. The aim of this study was to find out whether the periodic perceptual loss of a monocular stimulus during binocular rivalry is mirrored by a comparable loss of contrast sensitivity. We presented brief test stimuli to one eye while its conditioning stimulus was dominant or suppressed. The test stimuli were varied widely across four stimulus domains--namely, the relative stimulation of medium- and long-wavelength-sensitive cones, duration, spatial frequency, and grating orientation. The result in each case was the same. Suppression depended slightly or not at all on the type of test stimulus, and contrast sensitivity during suppression was around 64% of that during dominance. The effect of suppression on sensitivity is therefore very weak, relative to its effect on the perceived image. Furthermore, suppression was largely independent of the similarity between the conditioning and the test stimuli, indicating that our results are better explained by eye suppression than by stimulus suppression. A model is presented to account for the small, monocular sensitivity loss during suppression: It assumes that test detection precedes conditioning stimulus perception in the visual pathway.

Interferons activate the p42/44 mitogen-activated protein kinase and JAK-STAT (Janus kinase-signal transducer and activator transcription factor) signalling pathways in hepatocytes: differential regulation by acute ethanol via a protein kinase C-dependent mechanism.

Interferons (IFNs) have been used in the treatment of viral hepatitis. However, their effectiveness is much reduced (<10%) in alcoholics. The mechanism underlying this resistance remains unknown. Here, we report that IFN-alpha/beta and IFN-gamma rapidly activate the JAK-STAT1 (Janus kinase-signal transducer and activator transcription factor 1) and p42/44 mitogen-activated protein kinase (p42/44 MAPK) in freshly isolated rat hepatocytes. Treatment of hepatocytes with 25-100 mM ethanol for 30 min inhibited IFN-beta- or IFN-gamma-induced STAT1 activation and tyrosine phosphorylation. The inhibitory effect of ethanol was not reversed by pretreatment with either sodium vanadate, a non-selective tyrosine phosphatase inhibitor, or with MG132, a specific proteasome inhibitor. This suggests that protein tyrosine phosphatases or the ubiquitin-proteasome pathway are not involved in the inhibitory action of ethanol. In contrast with the JAK-STAT signalling pathway, acute ethanol exposure significantly potentiated IFN-beta or IFN-gamma-induced activation of p42/44 MAPK, and caused marked activation of protein kinase C (PKC). Inhibition of PKC partially antagonized ethanol attenuation of IFN-induced STAT1 activation, suggesting that PKC may be involved. Taken together, these findings suggest that the ability of biologically relevant concentrations of ethanol (less than 100 mM) to markedly inhibit IFN-activated STAT1 is one of the cellular mechanisms responsible for the observed resistance of IFN therapy in alcoholics.