Non-progressive Disease Research Articles

The role of contrast-enhanced and non-contrast-enhanced MRI in the follow-up of multiple sclerosis.

Magnetic resonance imaging (MRI) is widely used in patients with multiple sclerosis (MS) for different indications. However, frequent administration of gadolinium in these patients can have some potential complications. So, a more limited approach reducing the use of gadolinium should be considered. To evaluate the additional benefits of contrast-enhanced MRI over non-contrast-enhanced MRI in routine follow-up of patients with MS. This is a retrospective cohort study including patients with MS who underwent both contrast-enhanced and non-contrast-enhanced MRI for two time-points with an interval of at least six months. Non-contrast-enhanced images were compared for each patient and interpreted as non-progressive or progressive disease. Then, rate and type of enhancing lesions were analyzed and compared between the groups. All images were reviewed and compared visually by two radiologists. A total of 462 patients (392 women; mean age = 36 years) were included. Of these patients, 352 were in the non-progressive group and 112 were in progressive group. Comparison of baseline and follow-up contrast-enhanced MRIs revealed that 13 (3.7%) patients in the non-progressive group and 58 (51.8%) patients in progressive group developed enhancing lesions (P < 0.001). All 58 patients in the progressive group developed new enhancing lesions, whereas all those in the non-progressive group revealed persistent or reactivated enhancing lesions without evidence of new lesions. According to the very low incidence rate of new enhancing lesions in patients with non-progressive disease on follow-up non-contrast-enhanced MRI, routine administration of contrast in follow-up studies is not suggested.

Integrative Analysis of Multi-omics Data Identified EGFR and PTGS2 as Key Nodes in a Gene Regulatory Network Related to Immune Phenotypes in Head and Neck Cancer.

Malignant progression exhibits a tightly orchestrated balance between immune effector response and tolerance. However, underlying molecular principles that drive the establishment and maintenance of the tumor immune phenotype remain to be elucidated. We trained a novel molecular classifier based on immune cell subsets related to programmed death-ligand 1 (PD-L1) and interferon γ (IFNγ) expression, which revealed distinct subgroups with higher (cluster A) or lower (subcluster B3) cytotoxic immune phenotypes. Integrative analysis of multi-omics data was conducted to identify differences in genetic and epigenetic landscapes as well as their impact on differentially expressed genes (DEG) among immune phenotypes. A prognostic gene signature for immune checkpoint inhibition (ICI) was established by a least absolute shrinkage and selection operator (LASSO)-Cox regression model. Mutational landscape analyses unraveled a higher frequency of CASP8 somatic mutations in subcluster A1, while subcluster B3 exhibited a characteristic pattern of copy-number alterations affecting chemokine signaling and immune effector response. The integrative multi-omics approach identified EGFR and PTGS2 as key nodes in a gene regulatory network related to the immune phenotype, and several DEGs related to the immune phenotypes were affected by EGFR inhibition in tumor cell lines. Finally, we established a prognostic gene signature by a LASSO-Cox regression model based on DEGs between nonprogressive disease and progressive disease subgroups for ICI. Our data highlight a complex interplay between genetic and epigenetic events in the establishment of the tumor immune phenotype and provide compelling experimental evidence that a patient with squamous cell carcinoma of the head and neck at higher risk for ICI treatment failure might benefit from a combination with EGFR inhibition.

Obinutuzumab is Effective for the Treatment of Refractory Membranous Nephropathy

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in nondiabetic adults. Left untreated, two-thirds of patients with MN can develop nonprogressive chronic kidney disease or progress to end-stage renal disease in 10 years.1 The recognition of MN as an autoimmune disease has paved the way for the use of anti–B-cell therapy in its management.2 Over the last decade, rituximab has been successfully used to treat MN and was shown to be noninferior to cyclosporine in the Membranous Nephropathy Trial of Rituximab study.

Seroprevalence of hepatitis E virus in liver transplant patients in Turin, Italy.

Acute E hepatitis is usually a self-limited non-progressive disease; however, acute liver failure and death can occur in the presence of conditions such as pregnancy and chronic liver diseases. In immunocompromised individuals, such as transplant patients, acute hepatitis E virus (HEV) infection may evolve to chronic hepatitis with rapid progression to liver decompensation. At our center, serology for HEV is not routinely performed in transplant patients and serological status is investigated only based on clinical judgement. In this study, seroprevalence of HEV was evaluated in 217 patients (120 liver transplant recipients and 97 individuals diagnosed with acute or chronic hepatitis). Molecular evaluation of HEV-RNA was also performed. Thirteen patients (6%) showed positivity for HEV-IgG; in particular, 10/120 (8.3%), with concomitant presence of IgM and IgG in six and 3/97 (3.1%). None of the plasma samples tested by HEV-RNA was positive. As the detectable RNA window is narrow and an undetectable HEV-RNA result does not exclude recent infection and the transplant context per se represents a risk factor for chronic infection in patients infected with HEV, a routine diagnostic workflow including HEV should be taken into consideration, increasing awareness and knowledge of the basic and clinical aspects of the disease.

Factors That Drive Heterogeneity of Response-to-Treatment of Different Metastatic Deposits Within the Same Patients as Measured by RECIST 1.1 Analyses

This study uses the rate of between-reader variability under Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 as a metric to estimate the prevalence of biologic heterogeneity of individual metastases, and to determine whether this prevalence is modulated by the type of primary tumor, or type of treatment administered. Three radiologists independently used dedicated oncologic response-assessment software (MintLesion) to prospectively determine RECIST1.1 treatment response in contrast-enhanced computed tomography studies of 355 patients with metastatic disease of different primaries between 07/2015 and 12/2017. In 200 patients, readers had chosen different sets of target lesions; these cases were used for further analysis. Clinically significant heterogeneity of response was considered to be present when RECIST1.1 results differed regarding the distinction of progressive versus non-progressive disease. Rates of response heterogeneity were compared for different types of primary cancers, and different types of systemic treatment. Heterogeneous treatment response was observed in 67 of 200 (34%) patients. Breast cancer was the only primary tumor associated with statistically significantly increased odds for heterogeneity of treatment response (Odds Ratio: 3.972, 0.95 Confidence Interval: 1.275-12.376, p = 0.017). No association was found between type of systemic treatment and rate of biologic heterogeneity. Clinically significant heterogeneity of response-to-treatment is a frequent phenomenon, observed in about one-third of patients undergoing contemporary systemic therapies. Patients with breast cancer are more likely to exhibit such heterogeneity. Type of systemic treatment did not modulate the likelihood of exhibiting metastases with diverging treatment response.

The effect of trunk kinesio taping on static and dynamic balance and functional mobility in children with cerebral palsy

Cerebral palsy (CP) is a non-progressive neurological disease that causes the loss of normal motor function. The aim of this study was to investigate the effect of trunk kinesio taping on static and dynamic balance and functional mobility in children with CP. In an experimental study with pre-test and post-test, 38 children with spastic CP were randomly divided into intervention (n = 19) and control (n = 19) groups. In the intervention group, kinesio taping was applied on the thoracic and lumbar regions. Taping was employed in control group in a sham mode. Berg balance scale (BBS), forward functional reach (FFR), and timed up and go (TUG) tests were used prior to taping application, immediately, 2 days after taping application, and 2 days after removed kinesio tape. Results showed a significant increase in BBS (P < 0.001) and TUG (P < 0.001) short time after application and after remove of taping in the intervention group. However, non-significant changes perceived in BBS (P = 0.58), FFR (P = 0.32), and TUG (P = 0.32) immediately after application of kinesio taping in intervention group. No significant change has been observed in the control group in any different interval application. According to the results of this study, kinesio taping seems to be effective in improving dynamic balance and functional mobility in children with spastic CP. Therefore, kinesio taping can be used in the neurorehabilitation of CP as a complementary therapy.

Effects of adaptive immune cell therapy on the immune cell profile in patients with advanced gastric cancer.

BackgroundImmunotherapy for cancer patients has been the subject of attention in recent years. In this study, we investigated whether αβT‐cell therapy causes changes in the host's immune cell profile, and if so, the effect of these changes on prognosis.MethodsPeripheral blood mononuclear cells (PBMCs) from 30 gastric cancer patients who had completed one course of αβT‐cell therapy were analyzed. The peripheral blood immune cell profile was established using PBMCs by counting the frequency of CD4+ helper T cells, CD8+ killer T cells, regulatory T cells (Tregs), and myeloid‐derived suppressor cells and measuring the expression of their surface markers. The changes after treatment and their association with response to treatment were investigated.ResultsImmune cell profiles changed greatly after treatment. The frequency of CD4+ helper T cells decreased, but that of CD8+ killer T cells increased. The frequency of programmed cell death 1 (PD‐1)+ effector Tregs increased significantly, but only in the non‐progressive disease (non‐PD) group, in which it was significantly higher compared with the PD group. Patients in whom the frequency of PD‐1+ effector Tregs increased had a significantly better prognosis than those in whom it decreased.ConclusionOur results suggested that αβT‐cell therapy changes the host's immune cell profile, and an increase in PD‐1+ effector Tregs may help improve prognosis.

MicroRNA profile in stage I clear cell renal cell carcinoma predicts progression to metastatic disease

ObjectiveThis study sought to identify microRNA (miRNA) profiles of small, pathologically confirmed stage 1 clear cell renal cell carcinoma (ccRCC) tumors that are associated with progression to metachronous metastatic disease. Materials and methodsFifty-five pathologic stage 1 ccRCC tumors ≤5cm, from 2 institutions, were examined in a miRNA screening, followed by a validation study. For the screening phase 752 miRNA were evaluated on each sample to identify those with differential expression between tumors that subsequently did (n = 10) or did not (n = 10) progress to metastatic disease. For the validation, 35 additional samples (20 nonprogressors and 15 with distant progression) were utilized to investigate 20 miRNA to determine if a miRNA panel could differentiate aggressive tumors: associations of miRNA expression with cancer specific survival was also investigated. ResultsIn the screening analysis, 35 miRNA were differentially expressed (P < 0.05, FDR < 0.1) between the groups. In the validation, 11 miRNA were confirmed to have differential expression. The miRNA -10a-5p, -23b-3p, and -26a-5p differentiated nonprogressive and distant progressive disease with a sensitivity of 73.3% and a specificity of 85% (AUC=0.893). In addition, levels of miR-30a-3p and -145-5p were identified as independent prognostic factors of cancer specific survival. ConclusionsThis investigation identified miRNA biomarkers that may differentiate between non-progressive ccRCC tumors and those that progress to metastatic disease in this group of stage I tumors. The miRNA profiles determined in this study have the potential to identify patients with small renal masses who are likely to have progressive ccRCC. Such information may be valuable to incorporate into predictive models.

Activity and tolerability of maintenance avelumab immunotherapy after first line polychemotherapy including platinum in patients with locally advanced or metastatic squamous cell penile carcinoma: PULSE

Background Metastatic Squamous cell Penile Carcinoma (mSCPC) is an orphan disease with a virally induced oncogenesis. PD-L1 expression rate is around 60% with a strong correlation between PD-L1 in the primary tumour and metastases. The first line systemic treatment relies on platinum-based chemotherapies with a median progression free survival and overall survival around 7.5 and 16 months, respectively. Immunotherapies targeting PD-1/PD-L1 axis are effective in other squamous cell or HPV related cancers. Methods PULSE is a prospective multicenter open label single arm phase II study. Thirty-two patients will be enrolled after a radiological assessment showing a non-progressive disease after 3 to 6 cycles of a first line platinum-based polychemotherapy. Patients will receive Avelumab injections 10mg/ kg every two weeks until progression or unacceptable toxicity. The primary endpoint will be the progression free survival (PFS) according to RECIST v1.1 criteria. Secondary endpoints will include PFS according to iRECIST criteria, overall survival, quality of life, safety. Ancillary explorations will include assessing blood and tissue biomarkers for association with clinical benefit. Discussion After the first line, the prognosis remains poor with no consensus on a second line systemic treatment in locally advanced or mSCPC. PULSE trial is the first study that assess an anti PD-L1 immunotherapy in maintenance among patients with locally advanced or mSCPC. NCT NUMBER : NCT03774901.

Phase II study of consolidative intensity-modulated radiation therapy following first-line palliative systemic chemotherapy for de novo previously untreated metastatic (M1) nasopharyngeal carcinoma.

6524 Background: The prognosis of de novo previously untreated metastatic (M1) nasopharyngeal carcinoma (NPC) at diagnosis is poor, and the role of consolidative intensity-modulated radiation therapy (IMRT) to the primary tumor and the neck following first-line palliative chemotherapy remains unknown. We report a phase II study of consolidative IMRT after first-line chemotherapy in previously untreated M1 NPC. Methods: Consolidative IMRT was given in prospectively recruited patients whose previously untreated M1 NPC did not progress after 6 cycles of first-line chemotherapy with gemcitabine and cisplatin. The primary study objective was overall survival (OS). Secondary objectives included progression-free survival (PFS), local relapse-free survival (LRFS), regional relapse-free survival (RRFS), response and toxicity. Results: Sixty-nine consecutive patients were enrolled. Sixty-four (92.8%) patients received first-line chemotherapy, of which 8 (12.5%) developed progressive disease and another 8 (12.5%) did not receive IMRT despite non-progression to first-line chemotherapy. The remaining 48 patients whose disease controlled after chemotherapy received IMRT, including 18 (37.5%) who received concurrent chemoradiation. OS was significantly better in those who received IMRT (35.1 versus 14.2 months; P &lt; 0.001), after a median follow-up duration of 3.40 years (range 0.43 years to 12.14 years). PFS, LRFS, and RRFS were also significantly longer in those who received IMRT. Multivariable analyses revealed that IMRT was the only prognostic factor of all survival endpoints. Grade 3 adverse events were observed in 10 (20.8%) patients, mainly mucositis, dysphagia and desquamation. Conclusions: Consolidative IMRT was associated with an OS benefit and favorable tolerability among previously untreated M1 NPC patients who had non-progressive disease following first-line chemotherapy. These results support the rationale to further investigate IMRT as part of the initial treatment in this setting. Clinical trial information: NCT02476669 .

A prospective phase I trial of dendritic cell-based cryoimmunotherapy in metastatic castration-resistant prostate cancer.

3029 Background: Dendritic cell (DC)-based cryoimmunotherapy (CryoIT) was used to treat metastatic castration-resistant prostate cancer in a Phase I clinical trial. Primary objective was safety of treatment. Secondarily, clinical, radiological and immunological treatment responses were investigated. Methods: In 18 patients cryoablation by a freeze-thaw process under general anesthesia was performed, followed by intratumoral autologous immature DC injection. In the last 9 patients checkpoint inhibition of either CTLA-4 or PD-1 was added. Subjects had minimum 46 weeks follow-up. Adverse events (AEs) and blood analyses were registered at all visits. Disease progression was determined by three imaging modalities according to (i)RECISTv1.1 and progression-free survival (PFS) by Kaplan-Meier method. Circulating tumor cells (CTC/7.5 mL, CellSearch) and ultradeep T-cell receptor (TCR) b-chain sequences (TCRSafe) were enumerated. Patients were separated by CTC into none (n=10), 1-4 (n=4) and ≥ 5 (n=4). Health related quality of life (HRQoL) measured by EORTC-QLQ C30 questionnaire were answered at inclusion, and 10, 22 and 46 weeks post CryoIT. Scores were calculated according to the EORTC manual. Results: Subjects progressing within 22 weeks had higher PSA (p=0.03). AE profile of the total cohort (n=18) was comparable with interim reports (n=13); of 20 possible DC-related AEs one was severe (urinary retention) and 19 mild-to-moderate, and spread independent of treatment regime. Maximum tolerated dose of DC was not reached. By 46 weeks, imaging showed 6 patients partial response or stable disease. Median PFS was 150 days in total cohort. Pretreatment CTC counts ≥5 indicated higher progression rates and recurring CTC. Ultradeep TCR-sequencing showed more prevalent and higher expressed (&gt;5-fold) new TCR clonotypes at 2-6 weeks in men without progression. Participants reported high and stable HRQoL scores throughout the study. However, presence of CTC was associated with worse HRQoL scores at week 10 (p=0.031) and 22 (p=0.005). Conclusions: DC treatment seems safe and well tolerated, also combined with checkpoint inhibitors. Effect is indicated in subjects with moderate pre-treatment PSA levels. Immune responses are suggested by higher number of novel TCR clonotypes in men with non-progressive disease. Clinical trial information: NCT02423928 .

Explorative study of emerging blood biomarkers in progressive multiple sclerosis (EmBioProMS): Design of a prospective observational multicentre pilot study

BackgroundDefining clinical and subclinical progression in multiple sclerosis (MS) is challenging. Patient history, expanded disability status scale (EDSS), and magnetic resonance imaging (MRI) all have shortcomings and may underestimate disease dynamics. Emerging serum biomarkers such as glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) proved useful in many cross-sectional studies. However, longitudinal data on patients with progressive MS is scarce. ObjectivesTo assess whether the serum biomarkers GFAP and NfL might differentiate between patients with progressive vs. non-progressive disease stages and predict the disease course according to the Lublin criteria. MethodsEmBioProMS is a pilot, observational, prospective, multicentric study funded by the German Multiple Sclerosis Society (DMSG). 200 patients with MS according to the 2017 McDonald criteria and history of relapse-independent progression at any time (progressive MS, PMS), younger than 65 years, and with EDSS ≤ 6.5 will be recruited in 6 centres in Germany. At baseline, month 6, and 18, medical history, EDSS, Nine-Hole-Peg-Test (9-HPT), Timed-25-Foot-Walk-Test (T-25FW), Symbol-Digit-Modalities-Test (SDMT), serum GFAP, and NfL, MRI (at least baseline and month 18) and optional optical coherence tomography (OCT) will be performed. Disease progression before and during the study is defined by confirmed EDSS progression, increase by ≥ 20% in 9-HPT or T-25FW time. ConclusionsThis longitudinal multicentre study will reveal to what extent the prediction of disease progression in patients with PMS will be improved by the analysis of serum biomarkers in conjunction with routine clinical data and neuroimaging measures.

18F-FDG Pet Parameters and Radiomics Features Analysis in Advanced Nsclc Treated with Immunotherapy as Predictors of Therapy Response and Survival.

Objectives: (1.1) to evaluate the association between baseline 18F-FDG PET/CT semi-quantitative parameters of the primary lesion with progression free survival (PFS), overall survival (OS) and response to immunotherapy, in advanced non-small cell lung carcinoma (NSCLC) patients eligible for immunotherapy; (1.2) to evaluate the application of radiomics analysis of the primary lesion to identify features predictive of response to immunotherapy; (1.3) to evaluate if tumor burden assessed by 18F-FDG PET/CT (N and M factors) is associated with PFS and OS. Materials and Methods: we retrospectively analyzed clinical records of advanced NCSLC patients (stage IIIb/c or stage IV) candidate to immunotherapy who performed 18F-FDG PET/CT before treatment to stage the disease. Fifty-seven (57) patients were included in the analysis (F:M 17:40; median age = 69 years old). Notably, 38/57 of patients had adenocarcinoma (AC), 10/57 squamous cell carcinoma (SCC) and 9/57 were not otherwise specified (NOS). Overall, 47.4% patients were stage IVA, 42.1% IVB and 8.8% IIIB. Immunotherapy was performed as front-line therapy in 42/57 patients and as second line therapy after chemotherapy platinum-based in 15/57. The median follow up after starting immunotherapy was 10 months (range: 1.5–68.6). Therapy response was assessed by RECIST 1.1 criteria (CT evaluation every 4 cycles of therapy) in 48/57 patients or when not feasible by clinical and laboratory data (fast disease progression or worsening of patient clinical condition in nine patients). Radiomics analysis was performed by applying regions of interest (ROIs) of the primary tumor delineated manually by two operators and semi-automatically applying a threshold at 40% of SUVmax. Results: (1.1) metabolic tumor volume (MTV) (p = 0.028) and total lesion glycolysis (TLG) (p = 0.035) were significantly associated with progressive vs. non-progressive disease status. Patients with higher values of MTV and TLG had higher probability of disease progression, compared to those patients presenting with lower values. SUVmax did not show correlation with PD status, PFS and OS. MTV (p = 0.027) and TLG (p = 0.022) also resulted in being significantly different among PR, SD and PD groups, while SUVmax was confirmed to not be associated with response to therapy (p = 0.427). (1.2) We observed the association of several radiomics features with PD status. Namely, patients with high tumor volume, TLG and heterogeneity expressed by “skewness” and “kurtosis” had a higher probability of failing immunotherapy. (1.3) M status at 18F-FDG PET/CT was significantly associated with PFS (p = 0.002) and OS (p = 0.049). No significant associations were observed for N status. Conclusions: 18F-FDG PET/CT performed before the start of immunotherapy might be an important prognostic tool able to predict the disease progression and response to immunotherapy in patients with advanced NSCLC, since MTV, TLG and radiomics features (volume and heterogeneity) are associated with disease progression.

Predictive value of integrated 18F-FDG PET/MRI in the early response to nivolumab in patients with previously treated non-small cell lung cancer

BackgroundThe early response to treatment with immune-checkpoint inhibitors is difficult to evaluate. We determined whether changes in integrated [18F]-fluoro-2-deoxy-D-glucose positron emission tomography/MRI (18F-FDG PET/MRI) parameters after the first 2 weeks...

Serial circulating tumor DNA (ctDNA) measurement to predict progression in patients (pts) with advanced urothelial carcinoma (aUC).

558 Background: Next-generation sequencing (NGS) of plasma ctDNA is a promising non-invasive method to detect somatic genomic alterations (GAs). We investigated whether serial ctDNA measurements can predict disease progression and map the molecular evolution of advanced UC (aUC) through successive treatments. Methods: We analyzed cohorts from 2 academic centers, WCM and UNLV, with serial (≥2) ctDNA targeted NGS using the Guardant360 panel of 73 genes, ctDNA was collected within four weeks of restaging scans. Non-progressive disease (non-PD) was defined as stable disease or radiological response. Results: Our cohort included 176 individual ctDNA samples (median 3/patient) from 52 patients (38 men), the median age was 69 (range 38-88), 38 pts (73%) had metastatic disease, 20 pts (38.5%) had visceral metastases and 35 pts (67%) received first-line platinum-based combination chemotherapy for aUC. The median number of lines of therapy was 2. 49 pts (94%) had detectable GAs in at least one ctDNA sample. Most commonly identified GAs involved TP53 (67%), PIK3CA, EGFR, and ERBB2 (each in 19%). FGFR3 GAs were identified in 9 pts (17%, 2 FGFR3-TACC3 fusions, and 7 SNVs, including two novel mutations P250R and K650M). The mean variant allele fraction (VAF) significantly decreased in pts with non-PD (80 non-PD events) compared to pts with PD (45 PD events) with a mean VAF decrease of 2.06 % (p&lt; 0.0001). This effect was consistent independent of the number of prior lines of therapy. The mean number of GAs per patient at each time point was significantly decreased in non-PD vs. PD group (2.8 vs. 4.4, p=0.004). Pts with detectable VAF in somatic alterations at any time point during the disease course had shorter overall survival (HR 1.18, 95% CI: 1.08 – 1.28, p&lt;0.0001). Pts with sustained partial or complete responses were more likely to have VAF ≤0.2% suggesting that molecular remission was associated with clinical remission. Conclusions: Serial ctDNA testing is a promising dynamic tool to assess clonal evolution and predict progression in aUC pts.

Cosmc-dependent mucin-type O-linked glycosylation is essential for podocyte function.

Mucin-type O-linked glycosylation, a posttranslational modification affecting the stability and biophysical characteristics of proteins, requires C1GalT1 (T synthase) and its obligate, X-linked chaperone Cosmc. Hypomorphic C1GalT1 mutations cause renal failure via not yet established mechanisms. We hypothesize that impaired Cosmc-dependent O-glycosylation in podocytes is sufficient to cause disease. Podocyte-specific Cosmc knockout mice were generated and phenotyped to test this hypothesis. Female heterozygous mice displaying mosaic inactivation of Cosmc in podocytes due to random X-linked inactivation were also examined. Mice with podocyte-specific Cosmc deletion develop profound albuminuria, foot process effacement, glomerular sclerosis, progressive renal failure, and impaired survival. Glomerular transcriptome analysis reveals early changes in cell adhesion, extracellular matrix organization, and chemokine-mediated signaling pathways, coupled with podocyte loss. Expression of the O-glycoprotein podoplanin was lost, while Tn antigen, representing immature O-glycans, was most abundantly found on podocalyxin. In contrast to hemizygous male and homozygous female animals, heterozygous female mosaic animals developed only mild albuminuria, focal foot process effacement, and nonprogressive kidney disease. Ultrastructurally, Cosmc-deficient podocytes formed Tn antigen-positive foot processes interdigitating with those of normal podocytes but not with other Cosmc-deficient cells. This suggests a cell nonautonomous mechanism for mucin-type O-glycoproteins in maintaining podocyte function. In summary, our findings demonstrated an essential and likely cell nonautonomous role for mucin-type O-glycosylation for podocyte function.

Allo-HSCT in transplant-naïve patients with Hodgkin lymphoma: a single-arm, multicenter study

AbstractWe evaluated the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in transplant-naïve patients with relapsed/refractory Hodgkin lymphoma (HL) who failed to attain metabolic complete response (mCR) to 1 to 2 lines of salvage chemotherapyThose with residual but nonprogressive disease assessed by positron emission tomography/computed tomography scanning were eligible. An additional 1 to 2 cycles of salvage therapy were permissible in those with progressive disease or when required to bridge to allo-HSCT, with additional imaging at baseline before transplantation. Conditioning consisted of carmustine, etoposide, cytarabine, melphalan, and alemtuzumab. Donor lymphocyte infusions (DLI) were administered for mixed chimerism or residual or relapsed disease. Eleven patients had sibling donors, 13 had HLA-matched unrelated donors, and 7 had HLA-mismatched unrelated donors. There were no graft failures, and no episodes of grade 4 acute graft-versus-host disease (GVHD); only 19.4% of patients had grade 2 to 3 GVHD, and 22.2% had extensive chronic GVHD. The non-relapse mortality rate was 16.1% (95% confidence interval [CI], 7.1%-34.5%). Relapse incidence was 18.7% (95% CI, 8.2%-39.2%). The study met its primary objective, with a 3-year progression-free survival of 67.7% (95% CI, 48.4%-81.2%). Survival outcomes were equivalent in those with residual metabolically active disease immediately before transplantation (n = 24 [70.8%; 95% CI, 17.2%-83.7%]). Two of the 5 patients who relapsed received DLI and remained in mCR at latest follow-up, with a 3-year overall survival of 80.7% (95% CI, 61.9%-90.8%). We demonstrate encouraging results that establish a potential role for allo-HSCT in selected high-risk patients with HL. This trial was registered at www.clinicaltrials.gov as #NCT00908180.

Efficacy and safety of first-line pembrolizumab monotherapy in elderly patients (aged ≥ 75years) with non-small cell lung cancer.

Pembrolizumab is an effective front-line treatment for advanced non-small cell lung cancer (NSCLC) in patients expressing high levels of programmed death-ligand 1 (PD-L1). However, it is unclear whether first-line pembrolizumab has similar efficacy among elderly (aged ≥ 75years) and younger patients. This study aimed to investigate the safety and efficacy of front-line pembrolizumab monotherapy in older adults with NSCLC expressing high PD-L1. A total of 128 patients with advanced NSCLC expressing high PD-L1, including 47 older adults, received first-line pembrolizumab monotherapy at ten institutions in Japan, between February 2017 and February 2018. Data related to patient characteristics, efficacy of pembrolizumab therapy, and the type and severity of adverse events were recorded. Overall, 47 patients [40 men and 7 women; median age 79 (range 75-88)years] were included in our analysis. In patients who received first-line pembrolizumab monotherapy, overall response, disease control rates, median progression-free survival (PFS), and median overall survival (OS) were 53.1%, 74.4%, 7.0months, and not reached, respectively. Common adverse events included anorexia, fatigue, skin rash, and hypothyroidism. Two treatment-related deaths were noted, due to pneumonitis and infection. First-line pembrolizumab monotherapy was associated with improved PFS in patients with non-progressive disease (PD). In patients with non-PD and good performance status (PS), pembrolizumab monotherapy improved OS. Elderly patients with NSCLC expressing high PD-L1 tolerated front-line pembrolizumab monotherapy well. Their survival outcomes were equivalent to those of younger patients. In patients with non-PD, first-line pembrolizumab monotherapy may improve PFS; in conjunction with good PS, it additionally improves OS.

Efficacy of modified FOLFOX6 chemotherapy for patients with unresectable pseudomyxoma peritonei

BackgroundPseudomyxoma peritonei (PMP) is a rare malignancy, and there is insufficient evidence about systemic chemotherapy for this disease.MethodsWe retrospectively evaluated the efficacy and safety of a chemotherapeutic regimen with 5-fluorouracil and oxaliplatin (modified FOLFOX6, mFOLFOX6) for patients with unresectable pseudomyxoma peritonei. Patients who received the therapy between April 2000 and February 2019 at the Department of Medical Oncology, Tohoku University Hospital, were enrolled in this study.ResultsEight patients were treated with mFOLFOX6. The sites of primary tumor were appendix in six patients, ovary in a patient, and urachus in a patient. Six patients received surgery. Seven patients had histologically high-grade PMP, and one patient had low-grade PMP. The median follow-up duration was 27.2 months. All the patients had non-measurable regions as the targets of tumor response. Non-complete response or non-progressive disease was observed in seven patients, with a disease control rate of 87.5%. The median progression-free survival and overall survival were 13.0 months and 27.9 months, respectively. An obvious reduction in the symptoms was observed in two patients. Five patients experienced decline in the serum tumor markers, CEA or CA19-9. The grade 3/4 toxicity that was observed was grade 4 neutropenia in one patient and grade 3 neutropenia in two patients.ConclusionsmFOLFOX6 might be an effective and tolerable treatment option for patients with unresectable PMP. To our knowledge, this is the first case series of mFOLFOX6 in patients with unresectable PMP and the first case series of systemic chemotherapy for Asian patients with unresectable PMP.

Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer

BackgroundClinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c+ myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs).MethodsIn this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria.ResultsBoth tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm+ and IFN-γ+ antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1–2 toxicity.ConclusionsImmunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome.Trial registrationClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.