Studies on peroxidase through Moringa oleifera Lam foliage

e findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.Auristatins, a class of clinically validated anti-tubulin agents utilized as payloads in antibody-drug conjugates, are generally classified by their membrane permeability and the extent of cytotoxic bystander activity on neighboring cells after targeted delivery. The drugs typically fall within two categories membrane permeable monomethyl auristatin E-type molecules with high bystander activities and susceptibility to efflux pumps, or charged and less permeable monomethyl auristatin F (MMAF) analogs with low bystander activities and resistance to efflux pumps. Herein, we report the development of novel auristatins that combine the attributes of each class by having both bystander activity and cytotoxicity on multidrug-resistant (MDR+) cell lines. Structure-based design focused on the hydrophobic functionalization of the N-terminal N-methylvaline of the MMAF scaffold to increase cell permeability. The resulting structure-activity relationships of the new auristatins demonstrate that optimization of hydrophobicity and structure can lead to highly active free drugs and antibody-drug conjugates with in vivo bystander activities.Light sensing has been extensively characterized in the human pathogen Acinetobacter baumannii at environmental temperatures. However, the influence of light on the physiology and pathogenicity of human bacterial pathogens at temperatures found in warm-blooded hosts is still poorly understand. In this work, we show that Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa (ESKAPE) priority pathogens, which have been recognized by the WHO and the CDC as critical, can also sense and respond to light at temperatures found in human hosts. Most interestingly, in these pathogens, light modulates important pathogenicity determinants as well as virulence in an epithelial infection model, which could have implications in human infections. In fact, we found that alpha-toxin-dependent hemolysis, motility, and growth under iron-deprived conditions are modulated by light in S. aureus Light also regulates persistence, metabolism, and the ability to kill competitors in some of these microorganisms. Fin In this work, we show that these pathogens sense natural light and respond to it by modulating aspects related to their ability to cause disease; in the presence of light, some of them become more aggressive, while others show an opposite response. Overall, we provide new understanding on the behavior of these pathogens, which could contribute to the control of infections caused by them. Since the response is distributed in diverse pathogens, this notion could prove a general concept.The Yersinia genus comprises pathogens that can adapt to an environmental life cycle stage as well as to mammals. Yersinia enterocolitica strain W22703 exhibits both insecticidal and nematocidal activity conferred by the tripartite toxin complex (Tc) that is encoded on the 19-kb pathogenicity island Tc-PAI Ye All tc genes follow a strict temperature regulation in that they are silenced at 37°C but activated at lower temperatures. Four highly conserved phage-related genes, located within the Tc-PAI Ye , were recently demonstrated to encode a biologically functional holin-endolysin gene cassette that lyses its own host W22703 at 37°C. Conditions transcriptionally activating the cassette are not yet known. In contrast to Escherichia coli, the overproduction of holin and endolysin did not result in cell lysis of strain W22703 at 15°C. When the holin-endolysin genes were overexpressed at 15°C in four Y. enterocolitica biovars and in four other Yersinia spp., a heterogenous pattern of phenotypes was observed, rangihanisms underlying the activation of determinants at body temperature have been analyzed in detail, the molecular basis of low-temperature-dependent phenotypes is largely unknown. Here, we demonstrate that a novel phage-related lysis cassette, which is part of the insecticidal and nematocidal pathogenicity island of Y. enterocolitica, does not lyse its own host following overexpression at 15°C and that the Lon protease is involved in this phenotype.Characterizing the mycobacterial transporters involved in the uptake and/or catabolism of host-derived nutrients required by mycobacteria may identify novel drug targets against tuberculosis. Here, we identify and characterize a member of the amino acid-polyamine-organocation superfamily, a potential γ-aminobutyric acid (GABA) transport protein, GabP, from Mycobacterium smegmatis The protein was expressed to a level allowing its purification to homogeneity, and size exclusion chromatography coupled with multiangle laser light scattering (SEC-MALLS) analysis of the purified protein showed that it was dimeric. We showed that GabP transported γ-aminobutyric acid both in vitro and when overexpressed in E. coli Additionally, transport was greatly reduced in the presence of β-alanine, suggesting it could be either a substrate or inhibitor of GabP. Using GabP reconstituted into proteoliposomes, we demonstrated that γ-aminobutyric acid uptake is driven by the sodium gradient and is stimulated by membrane potential. Mde the host, this could be an attractive target for the development of new drugs against tuberculosis.Protein phosphorylation is a universal mechanism for transducing cellular signals in prokaryotes and eukaryotes. The histidine kinase CckA, the histidine phosphotransferase ChpT, and the response regulator CtrA are conserved throughout the alphaproteobacteria. In Rhodobacter capsulatus, these proteins are key regulators of the gene transfer agent (RcGTA), which is present in several alphaproteobacteria. Using purified recombinant R. capsulatus proteins, we show in vitro autophosphorylation of CckA protein, and phosphotransfer to ChpT and thence to CtrA, to demonstrate biochemically that they form a phosphorelay. The secondary messenger cyclic di-GMP changed CckA from a kinase to a phosphatase, resulting in reversal of the phosphotransfer flow in the relay. The substitutions of two residues in CckA greatly affected the kinase or phosphatase activity of the protein in vitro, and production of mutant CckA proteins in vivo confirmed the importance of kinase but not phosphatase activity for the lytic release of Rcange of bacterial regulatory networks.Caulobacter crescentus is a Gram-negative alphaproteobacterium that commonly lives in oligotrophic fresh- and saltwater environments. C. crescentus is a host to many bacteriophages, including ϕCbK and ϕCbK-like bacteriophages, which require interaction with the bacterial flagellum and pilus complexes during adsorption. It is commonly thought that the six paralogs of the flagellin gene present in C. crescentus are important for bacteriophage evasion. Here, we show that deletion of specific flagellins in C. crescentus can indeed attenuate ϕCbK adsorption efficiency, although no single deletion completely ablates ϕCbK adsorption. Thus, the bacteriophage ϕCbK likely recognizes a common motif among the six known flagellins in C. crescentus with various degrees of efficiency. Interestingly, we observe that most deletion strains still generate flagellar filaments, with the exception of a strain that contains only the most divergent flagellin, FljJ, or a strain that contains only FljN and FljO. To visualize the surfaThis study characterizes the importance of the six flagellin genes in C. crescentus for infection by bacteriophage ϕCbK. We find that filaments containing the FljK flagellin are the preferred substrate for bacteriophage ϕCbK. We also present a high-resolution structure of a flagellar filament containing only the FljK flagellin, which provides a platform for future studies on determining how bacteriophage ϕCbK attaches to flagellar filaments at the molecular level.Pseudomonas aeruginosa is a major nosocomial pathogen that presents high-level resistance to antibiotics. Its ability to cause infections relies on the production of multiple virulence factors. Quorum sensing (QS) regulates the expression of many of these virulence factors through three QS systems Las, Rhl, and PQS. The Las system positively regulates the other two systems, so it is at the top of a hierarchized regulation. Nevertheless, clinical and environmental strains that lack a functional Las system have been isolated, and, surprisingly, some of them still have the ability to produce virulence factors and infect animal models, so it has been suggested that the hierarchy is flexible under some conditions or with atypical strains. Here, we analyze the PAO1 type strain and its ΔlasR-derived mutant and report, for the first time, a growth condition (phosphate limitation) where LasR absence has no effect either on virulence factor production or on the gene expression profile, in contrast to a condition of phong infections.
To determine whether intraoperative handover of patient care from one anaesthesia clinician to another was associated with an increased risk of adverse postoperative outcomes during paediatric surgeries.
A retrospective, population-based cohort study (1 April 2013-1 June 2018) at an academic medical centre.
Intraoperative handover of care between pairs of anaesthesia clinicians from one care provider to another compared with no handover of anaesthesia care.
The primary outcome was a composite of all-cause mortality and major postoperative morbidity within 30 days after surgery. Secondary outcomes included individual components of the primary outcome and 30-day hospital readmission. Inverse probability of exposure weighting using propensity scores for intraoperative handovers was calculated. Weighted logistic regression was used to determine the association between intraoperative anaesthesia handovers and outcomes.
78 321 paediatric surgical cases (n=5411 with handovers) were included for analysis. Ptes. These findings provide a preliminary perspective on the role of intraoperative handovers as a care-neutral event, with implications for improving safety.
We aimed to determine the lifetime genetic risk for anterior cruciate ligament (ACL) rupture.
We used a twin study approach, linking the Swedish Twin Register with national healthcare data to form a 30 year, population wide, longitudinal twin cohort. We studied ACL rupture in this cohort of 88 414 identical and fraternal twins, aged ≥17 years, to determine the familial risk and heritability of ACL rupture.
The incidence rate of ACL rupture was 70 (95% CI 66 to 74) per 100 000 person years. The familial risk, which is the excess risk ratio (RR) of the second twin having ACL rupture given that the first twin has had such a rupture, was higher in identical twin pairs (RR=8.6, 95% CI 6.2 to 11.0) than in fraternal twin pairs (RR=1.9, 95% CI 0.9 to 3.0). The overall heritability of ACL rupture was high, 69% (95% CI 47 to 91), increasing from 60% at age 17 years to 80% at age 60 years. Women and men had similar familial risk and heritability of ACL rupture.
The genetic contribution to ACL rupture of ~69% is high and suggests strong familial clustering. If clinicians recognise the high genetic risk of such injury, they may be better able to counsel athletes whose near relatives have had ACL rupture.
The genetic contribution to ACL rupture of ~69% is high and suggests strong familial clustering. If clinicians recognise the high genetic risk of such injury, they may be better able to counsel athletes whose near relatives have had ACL rupture.
To examine the effect of gender affirming hormones on athletic performance among transwomen and transmen.
We reviewed fitness test results and medical records of 29 transmen and 46 transwomen who started gender affirming hormones while in the United States Air Force. We compared pre- and post-hormone fitness test results of the transwomen and transmen with the average performance of all women and men under the age of 30 in the Air Force between 2004 and 2014. We also measured the rate of hormone associated changes in body composition and athletic performance.
Participants were 26.2 years old (SD 5.5). Prior to gender affirming hormones, transwomen performed 31% more push-ups and 15% more sit-ups in 1 min and ran 1.5 miles 21% faster than their female counterparts. After 2 years of taking feminising hormones, the push-up and sit-up differences disappeared but transwomen were still 12% faster. Prior to gender affirming hormones, transmen performed 43% fewer push-ups and ran 1.5 miles 15% slower than their male counterparts. After 1 year of taking masculinising hormones, there was no longer a difference in push-ups or run times, and the number of sit-ups performed in 1 min by transmen exceeded the average performance of their male counterparts.
The 15-31% athletic advantage that transwomen displayed over their female counterparts prior to starting gender affirming hormones declined with feminising therapy. However, transwomen still had a 9% faster mean run speed after the 1 year period of testosterone suppression that is recommended by World Athletics for inclusion in women's events.
The 15-31% athletic advantage that transwomen displayed over their female counterparts prior to starting gender affirming hormones declined with feminising therapy. However, transwomen still had a 9% faster mean run speed after the 1 year period of testosterone suppression that is recommended by World Athletics for inclusion in women's events.
The prognosis of cholangiolocarcinoma, a rare malignant liver tumor derived from hepatic progenitor or stem cells, is considered relatively good; however, it frequently recurs. We herein present the diagnosis, histological findings, and treatment of cholangiolocarcinoma.
A 65-year-old woman with a large liver tumor (70 mm in diameter) was referred. Hepatocellular carcinoma was suspected based on strong early enhancement and delayed washout by enhanced computed tomography. The patient underwent curative left tri-sectionectomy. Histologically, she was diagnosed with pure cholangiolocarcinoma in a slightly fibrous liver. Three metachronous recurrent lesions (all ≤10 mm in diameter) were found between fifteen and twenty months after the initial hepatectomy. One lesion and the remaining two lesions were treated with hepatectomy and radiofrequency ablation, respectively. Two years after the initial diagnosis, she was doing well without recurrence.
Repeated hepatectomy and radiofrequency ablation might be useful for small intrahepatic recurrences of cholangiolocarcinoma.
Repeated hepatectomy and radiofrequency ablation might be useful for small intrahepatic recurrences of cholangiolocarcinoma.
Previous reviews of Social determinants of health in lung cancer patients have not examined essential factors such as social isolation and loneliness. This study aimed to explore the factors affecting social isolation and loneliness among lung cancer patients.
A cross-sectional study was conducted. Social isolation, loneliness, and the presence of dementia were measured using Japanese adaptations of the Lubben Social Network Scale, UCLA Loneliness Scale, and Life Function Evaluation for Care Provision, respectively.
From March 2019 to March 2020, 264 patients were included. Social isolation was significantly higher for patients receiving welfare (adjusted OR=5.28, 95% CI=2.24-12.4). Loneliness was significantly higher for patients receiving welfare (beta coefficient=0.52, 95% Cl=0.13-0.90) with symptoms of dementia (beta coefficient=0.28, 95% Cl=0.03-0.54).
Results showed that receiving welfare was associated with experiencing social isolation. Receiving welfare and symptoms of dementia were associated with experiencing loneliness.
Results showed that receiving welfare was associated with experiencing social isolation. Receiving welfare and symptoms of dementia were associated with experiencing loneliness.
To clarify the differences in overall survival (OS) depending on the presence or absence of hypomagnesemia and the type of epidermal growth factor receptor antibody as first-line therapy for metastatic colorectal cancer (mCRC).
We retrospectively compared the OS in 68 patients who received cetuximab or panitumumab for mCRC at Ogaki Municipal Hospital (Ogaki, Japan) between January 2010 and December 2019.
The complete and partial response rates in the cetuximab and panitumumab groups were 60.0% and 72.0%, respectively (p=0.470). The OS was significantly longer in the panitumumab group (median=1,007 days, range=208-1,433 days) than in the cetuximab group (median=735 days, range=181-2,391 days; p=0.047). Hypomagnesemia did not contribute to differences in OS in the two groups.
Panitumumab may lead to a longer OS than cetuximab as first-line treatment of mCRC. The presence or absence of hypomagnesemia in cetuximab- or panitumumab-treated patients did not affect OS.
Panitumumab may lead to a longer OS than cetuximab as first-line treatment of mCRC. The presence or absence of hypomagnesemia in cetuximab- or panitumumab-treated patients did not affect OS.
Signet-ring cell carcinoma (SRCC) is an uncommon histological variant of colorectal cancer (CRC). Knowledge is scarce due to its rarity. Our aim was to better evaluate the clinicopathologic and prognostic features of this little-known malignancy.
Thirty-nine consecutive patients with non-metastatic colorectal SRCC undergoing curative resection at University Hospital of Parma between 2000 and 2018 were examined in this retrospective analysis.
Mean overall (OS) and disease-free survival (DFS) were 33.6 and 31.5 months, respectively. At univariate analysis, the lymph-related parameters (nodal status, Stage III, metastatic lymph node ratio and lymphovascular invasion) were significantly associated with shorter OS and poorer DFS. At multivariate analysis, Stage III and a metastatic lymph node ratio ≥25% were found to be the only independent prognostic factors significantly correlated with worse OS and DFS.
Nodal and lymphatic status should be carefully pondered when planning the most appropriate management of patients with colorectal SRCC.
Nodal and lymphatic status should be carefully pondered when planning the most appropriate management of patients with colorectal SRCC.
Extraordinary restrictions aimed to limit Sars-CoV-2 spreading; they imposed a total reorganization of the health-system. Oncological treatments experienced a significant slowdown. The aim of our multicentric retrospective study was to evaluate screening suspension and surgical treatment delay during COVID-19 and the impact on breast cancer presentation.
All patients who underwent breast surgery from March 11, 2020 to May 30, 2020 were evaluated and considered as the Lockdown group. These patients were compared with similar patients of the previous year, the Pre-Lockdown group.
A total of 432 patients were evaluated; n=223 and n=209 in the Lockdown and Pre-lockdown-groups, respectively. At univariate analysis, waiting times, lymph-nodes involvement and cancer grading, showed a statistically significant difference (p<0.05). Multivariate analysis identified waiting-time on list (OR=1.07) as a statistically significant predictive factor of lymph node involvement.
Although we did not observe a clinically evident difference in breast cancer presentation, we reported an increase in lymph node involvement.
Although we did not observe a clinically evident difference in breast cancer presentation, we reported an increase in lymph node involvement.
The aim of this study was to evaluate the impact of laparoscopic gastrectomy (LG) for gastric cancer on long-term survival in patients with postoperative infectious complications (PIC).
A total of 608 patients who underwent gastrectomy were classified into two groups based on the surgical approach LG (385 patients) and open gastrectomy (OG 211 patients). Long-term survival after gastrectomy was compared between patients with and without PIC in both LG and OG groups.
Although the patients with PIC in OG group tended to have worse overall survival (OS) than those without PIC, the OS was not significantly different between the patients with and without PIC in LG group. Although multivariate analysis demonstrated that nodal involvement and PIC were significantly associated with OS in OG group, age and tumor depth, and not PIC, were associated with OS in LG group.
PIC were negative predictors of clinical outcomes in patients with gastric cancer, particularly those who underwent OG, and long-term prognosis may be impacted less by PIC in patients undergoing LG.
PIC were negative predictors of clinical outcomes in patients with gastric cancer, particularly those who underwent OG, and long-term prognosis may be impacted less by PIC in patients undergoing LG.
It has been reported that some adverse events (AEs) of enzalutamide (ENZ) occur more frequently in Japanese patients with castration-resistant prostate cancer (CRPC) due to higher steady-state trough plasma concentrations of ENZ (C
) and its active metabolite (NDE), (C
). Thus, we investigated the efficacy, safety, and pharmacokinetics of ENZ in Japanese patients with CRPC.
Fourteen patients were administered ENZ at a standard dose (160 mg/day) or reduced doses (80 or 120 mg/day). Prostate-specific antigen (PSA), AEs, C
, and C
were examined.
A maximum PSA decrement of ≥50% from baseline was achieved in 92% of patients. AEs were few (>20%) and mild. No differences in C
and C
between other ethnic groups in previous literature and our subjects was observed.
ENZ shows adequate efficacy and safety in Japanese patients with CRPC, even if administered at reduced doses in real-world conditions.
ENZ shows adequate efficacy and safety in Japanese patients with CRPC, even if administered at reduced doses in real-world conditions.
Nivolumab is an immune checkpoint inhibitor with high antitumor activity in selected neoplasms. The aim of the study was to evaluate the efficacy and safety of nivolumab in pediatric patients with various types of highly malignant advanced tumors.
Ten patients with a median age of 15.1 years were included in the study. The indications for treatment were malignant skin melanoma (n=5), brain tumor (n=2), malignant melanoma of the brain (n=1), Hodgkin lymphoma (n=1) and soft tissue sarcoma (n=1).
Complete disease remission was observed in 4 patients. Overall survival at 24 months from diagnosis for the entire group was 0.36. Two patients receiving combination therapy of nivolumab and ipilimumab did not achieve a remission. Adverse events of immunotherapy were observed in 4/10 patients.
Nivolumab is a promising option in pediatric advanced malignancies. Treatment with immunotherapy was relatively well tolerated, and emerging side-effects were manageable.
Nivolumab is a promising option in pediatric advanced malignancies. Treatment with immunotherapy was relatively well tolerated, and emerging side-effects were manageable.
We investigated the relationship between solid component size (SS), carcinoembryonic antigen (CEA), and standardized uptake value (SUVmax) as continuous variables and postoperative clustered circulating tumor cell (C-CTC) detection in patients with pulmonary adenocarcinoma who underwent surgery.
C-CTC detection was the main evaluation item, which was analyzed using the receiver operating characteristic curve to calculate areas under the curves (AUCs) for the variables. Additionally, the two-year recurrence-free survival rates (2Y-RFSRs) were analyzed.
Among the 84 patients examined, SS, CEA, and SUVmax had AUCs>0.7, and were independent. Their thresholds were 2.1 cm, 7.5 ng/ml, and 2.9, respectively. The 2Y-RFSR were significantly better in the non-C-CTC group (n=58) and in the group of patients without high levels of these predictors (n=32).
SS, CEA level, and SUVmax predicted postoperative CTC detection in pulmonary adenocarcinoma patients.
SS, CEA level, and SUVmax predicted postoperative CTC detection in pulmonary adenocarcinoma patients.
The accuracy of axillary ultrasound (AUS) with fine-needle aspiration with varying patient body mass index (BMI) is still unclear. The aim of our study was to evaluate whether the US features of axillary lymph nodes changes with BMI of patients.
A retrospective review was performed involving 144 out of 270 patients with early breast cancer who underwent breast surgery with sentinel lymph node biopsy. Diagnostic efficacy of AUS in preoperative axillary nodal staging was assessed in relation to BMI.
Negative predictive values of AUS for the overweight and obese groups were statistically significantly lower compared to the normal/underweight group (p=0.02 and p=0.003, respectively). Additionally, Spearman's correlation coefficient R between BMI and positive sentinel lymph node biopsy was 0.257, suggesting a significantly positive linear relationship between the two variables in the cohort overall.
Our results demonstrate how in our cohort the negative predictive value of AUS was significantly influenced by adipose tissue and that the selection of the most suitable instrumental diagnostic technique might contribute to improving heterogeneous results.
Our results demonstrate how in our cohort the negative predictive value of AUS was significantly influenced by adipose tissue and that the selection of the most suitable instrumental diagnostic technique might contribute to improving heterogeneous results.
Patients requiring re-irradiation for recurrent glioblastoma multiforme (GBM) may benefit from individualized therapy. This study aimed to identify predictors of survival and contribute to treatment personalization.
In 28 patients with recurrent GBM, nine factors were analyzed for associations with survival Main location and type of recurrence, Karnofsky performance score (KPS), age, gender, interval between primary radiotherapy and recurrence, gross total resection (GTR), equivalent dose in 2-Gy fractions (EQD2) of re-irradiation and cumulative EQD2 of primary and re-irradiation.
On univariate analyses, GTR (p=0.047), EQD2 ≥30 Gy (p=0.029) and cumulative EQD2 ≥90 Gy (p=0.023) were significantly associated with better survival; frontal location (p=0.119) and KPS 80-100% (p=0.067) showed trends. In multivariate analyses, frontal location (p=0.032) and cumulative EQD2 ≥90 Gy (p=0.038) were significant; KPS 80-100% (p=0.110) and EQD2 ≥30 Gy (p=0.083) showed trends.
Predictors of survival after re-irradiation for recurrent GBM were identified that can help when designing personalized treatments. Use of irradiation with EQD2 ≥30 Gy appeared superior to lower doses.
Predictors of survival after re-irradiation for recurrent GBM were identified that can help when designing personalized treatments. Use of irradiation with EQD2 ≥30 Gy appeared superior to lower doses.
Nivolumab is effective against advanced gastric cancer (AGC) refractory to or in patients intolerant of standard chemotherapy. This study was designed to clarify the impact of cancer cachexia in patients with AGC who received nivolumab.
We recruited AGC patients who were treated with nivolumab from October 2017 to December 2019. Clinical outcomes were compared between patients with and without cancer cachexia at the start of nivolumab. Cancer cachexia was defined as weight loss >5%; weight loss >2% and body mass index (BMI) <20; or sarcopenia and BMI <20. Primary endpoints were median overall survival (OS) and median time to treatment failure (TTF), while secondary endpoints were overall response rate (ORR) and incidence of adverse events.
The study enrolled 44 patients. Median OS and TTF were significantly shorter in patients with cancer cachexia than in those without cancer cachexia (OS 6.6 vs. 2.3 months; HR=2.65; 95%CI=1.28-5.49; p=0.008, TTF 2.6 vs. 1.9 months; HR=2.17; 95%CI=1.09-4.32, p=0.027). On Cox proportional hazards analysis, cancer cachexia was significantly associated with shorter OS. The incidence of adverse events did not differ between the two groups. Nivolumab was associated with better OS and TTF outcomes in AGC patients without cachexia than in those with cachexia, albeit there was no difference in the incidence of adverse events.
Cancer cachexia may be associated with worse clinical outcomes in patients with AGC treated with nivolumab.
Cancer cachexia may be associated with worse clinical outcomes in patients with AGC treated with nivolumab.
This study was conducted to evaluate the clinical usefulness of panel next-generation sequencing (NGS) and to investigate the spectrum of genetic alterations and their clinical implications in neuroblastoma.
Formalin-fixed, paraffin-embedded archival samples from 41 cases of neuroblastoma were used for targeted sequencing.
A total of 145 somatic mutations were identified, including 51 synonymous, 86 missense, 3 nonsense, 2 frameshift deletion, 2 splice-site, and 1 in-frame deletion mutations. The most frequently mutated gene was ALK (9 missense mutations). The common copy number variations (CNVs) were amplification at 2p24.2 and deletion at 11q22.3 and 1p36.21. ALK mutations were more frequent in patients with stage 4 or 4S (0% vs. 33.3%, p=0.017). Among 27 patients with high-risk disease, the 5-year overall survival was inferior in patients with ALK mutations to those without (25.0% vs. 67.0%, p=0.009).
Genetic analysis using targeted NGS was feasible and helpful in detecting point mutations and CNVs in neuroblastoma. Targeted NGS could predict prognosis and be used to find molecular target-based therapies for neuroblastoma.
Genetic analysis using targeted NGS was feasible and helpful in detecting point mutations and CNVs in neuroblastoma. Targeted NGS could predict prognosis and be used to find molecular target-based therapies for neuroblastoma.
The synchronous diagnosis of two or more primary malignancies in a patient is overall rare.
We report such a case of a 67-year-old male smoker with a history of laryngeal squamous cell carcinoma. He was incidentally identified through follow up computed tomography to have three masses in the lung, rectum and jejunum, respectively. Biopsies were performed and demonstrated synchronous lung small cell carcinoma (pT1bN0) and rectal adenocarcinoma. The patient underwent fractionated stereotactic radiation (FSRT) to the pulmonary tumor and chemotherapy with cisplatin and etoposide followed by laparoscopic rectum low anterior resection and small bowel segmental resection. Final pathology diagnoses confirmed synchronous microsatellite stable (MMS) moderately differentiated adenocarcinoma of the rectum (pT3N1b) and jejunal gastrointestinal stromal tumor (GIST), spindle cell type (pT2N0). At 8 months follow up postsurgery, the patient was doing well and no tumor recurrences were identified.
To the best of our knowledge, this is the first documented case of synchronous primary small cell lung carcinoma, rectal adenocarcinoma, and GIST in the English literature. The rarity, diagnosis and treatment challenges of these entities are discussed.
To the best of our knowledge, this is the first documented case of synchronous primary small cell lung carcinoma, rectal adenocarcinoma, and GIST in the English literature. The rarity, diagnosis and treatment challenges of these entities are discussed.
The lungs are the second most common site of cancer dissemination. The aim of this study was to analyze a cohort of patients operated for pulmonary metastases from colorectal carcinoma over a period of 18 years.
In a group of 104 patients, relations were sought between overall survival or disease-free survival and preoperative levels of selected biomarkers, number of metastases and the condition of the intrathoracic lymphatic nodes. Median observation period was 63 months.
The 5-year survival rate was 54.3%. Risk of disease progression and risk of death increases in case of occurrence of 2 or more metastases, affection of intrathoracic lymph nodes and levels of CA 19-9, TPS or CEA above cut-off value.
Prognostic factors that determine overall survival as well as disease-free survival are the number of metastases, the condition of intrathoracic lymphatic nodes and the preoperative levels of biomarkers.
Prognostic factors that determine overall survival as well as disease-free survival are the number of metastases, the condition of intrathoracic lymphatic nodes and the preoperative levels of biomarkers.
This retrospective observational study evaluated the role of hypo-fractionated stereotactic radiotherapy (SRT) in patients with oligo-progressive metastatic renal cell carcinoma (mRCC) treated with first-line oral tyrosine kinase inhibitors (TKI). Data on local control, delay of further progression, and safety are reported.
Between January 2010 and December 2016, 28 patients with mRCC who showed oligo-progressive disease while receiving first-line pazopanib were treated with hypofractionated SRT to progressive metastatic sites to delay the change of systemic therapy. First and second progression-free survival (PFS-1 and PFS-2) were recorded, as well as objective response and toxicity.
After pazopanib therapy, nine partial remissions (32%), 12 stable disease (43%) and seven progressions (25%) were recorded. The median time to progression from first-line pazopanib until oligo-progression was 9.45 months (PFS-1 range=2-30 months). Seventeen patients (61%) showed progression at pre-existing tumor sites, andomes.
Innominate grooves (IGs) in the colon are ubiquitous structures limiting anthemic folds. The histology of the crypts in anthemic folds is well known but the histology of IGs has remained unattended. In this study, IG crypts in the normal mucosa and in ulcerative colitis (UC) were analyzed.
IGs displayed a single central-lumen with merging tributary crypts. The number of merging tributary crypts, at both sides and at the bottom of the central lumen, were quantified in 60 IGs 30 in normal colons and 30 in UC.
A total of 152 (median=5) tributary crypts were found merging in the 30 IGs in the normal colon, and 170 (median=5) in the 30 IGs in UC. The difference was non-significant (p=0.08012).
Chronic inflammation did not influence the frequency of tributary crypts in IGs. The shape and the length varied considerably in the 60 IGs. Given that the chief putative physiological function of IGs is the expansion of the colon when submitted to increased intraluminal pressure, it is not inconceivable that following that demand, IGs act as hinges that permit grooves to level with the rest of the surrounding mucosa.
Chronic inflammation did not influence the frequency of tributary crypts in IGs. The shape and the length varied considerably in the 60 IGs. Given that the chief putative physiological function of IGs is the expansion of the colon when submitted to increased intraluminal pressure, it is not inconceivable that following that demand, IGs act as hinges that permit grooves to level with the rest of the surrounding mucosa.
Standard treatment of glioblastoma multiforme (GBM) includes resection, longer-course radiotherapy and chemotherapy. Some patients cannot tolerate these regimens and may benefit from personalized treatments. This study aims to contribute to treatment personalization by identifying predictors of outcomes after longer-course radiotherapy.
In 91 patients, number/site/diameter of lesions, Ki-67, MGMT promoter methylation, Karnofsky performance score (KPS), symptoms, gender, age and resection were evaluated for local control and survival.
On univariate analyses, gross resection (p=0.029) was significantly associated with improved local control. It maintained significance in the multivariate analysis [hazard ratio (HR)=1.64, p=0.025]. MGMT-methylation (p=0.004), KPS ≥80 (p=0.022) and resection (p<0.001) were significantly associated with improved survival on univariate analyses, unifocal GBM (p=0.056) showed a trend. In the multivariate analyses, MGMT-methylation (HR=3.63, p=0.009), KPS (HR=2.01, p=0.018) and resection (HR=3.29, p<0.001) were significant.
Predictors of local control and survival were identified that may guide physicians when tailoring treatments to patients with GBM.
Predictors of local control and survival were identified that may guide physicians when tailoring treatments to patients with GBM.
Surgery is an important pancreatic ductal adenocarcinoma (PDAC) treatment; existing markers are inadequate prognostic indexes. We herein evaluated the utility of the FA score (fibrinogen/albumin ratio) for predicting PDAC postoperative outcomes.
We analysed the data of 67 PDAC patients who underwent surgical resection. The relationship between postoperative outcomes and the FA score was investigated. Performance of the FA score was compared to that of other variables and prognostic indexes.
No patient with FA ≥130 survived >3 years, whereas all patients who survived longer had FA <130. The FA score was superior to all other indexes for predicting postoperative outcomes. Patients with FA ≥130 vs. <130 had significantly shorter overall and recurrence-free survival.
The FA score is useful for predicting PDAC postoperative outcomes. Preoperatively, it may detect patients likely to have poor postoperative prognoses who may benefit from adjuvant or neoadjuvant therapy, thus improving outcomes.
The FA score is useful for predicting PDAC postoperative outcomes. Preoperatively, it may detect patients likely to have poor postoperative prognoses who may benefit from adjuvant or neoadjuvant therapy, thus improving outcomes.
The delayed initiation of treatment is associated with poor clinical outcomes in patients with malignancies. However, few previous studies have investigated prognostic factors, including the delayed initiation of treatment, in soft-tissue sarcoma.
One hundred and fifty-three patients with soft-tissue sarcoma were enrolled. Univariate and multivariate analyses were performed to identify factors predicting metastasis, including factors that delay the initiation of treatment.
The multivariate analysis revealed that high histological grade (p<0.01), tumor located in the trunk (p=0.04), >5-month delay from symptom initiation to consultation of general practitioner (p=0.02), and >29-day delay in referral to a specialized hospital by general practitioners (p=0.03) were independently associated with metastasis of soft tissue sarcoma.
Early consultation of a general practitioner and early referral to a specialized hospital might be essential for preventing metastasis of soft-tissue sarcoma.
Early consultation of a general practitioner and early referral to a specialized hospital might be essential for preventing metastasis of soft-tissue sarcoma.
Clear cell sarcoma (CCS) is an aggressive sarcoma subtype, resistant to conventional anthracycline-based chemotherapy and radiation. The diagnosis is often challenging due to similarities with malignant melanoma.
We aimed to analyse the activity of gemcitabine-based chemotherapy in a cohort of patients with CCS treated at the Royal Marsden Hospital.
Five patients with metastatic CCS received gemcitabine as first- or second-line systemic therapy. The median time-to-progression was 10 weeks. The median number of cycles of gemcitabine-based therapy was 3 (range=2-7 cycles). Median overall survival in our cohort was 66 months from the initial diagnosis but in the metastatic setting, the overall survival was reduced to 28 months.
Gemcitabine-based therapy has modest activity in CCS. There remains a significant unmet medical need for novel, effective therapies for this disease.
Gemcitabine-based therapy has modest activity in CCS. There remains a significant unmet medical need for novel, effective therapies for this disease.
There is evidence that a unique immunomodulatory protein, known as the progesterone induced blocking factor (PIBF), is utilized by a large variety of cancers to escape immune surveillance. Mifepristone, a progesterone receptor antagonist/modulator, anecdotally, has been found to increase both length and quality of life in many different types of advanced cancers.
Though there was one previous case of pancreatic cancer that showed a significant reduction in pain for the one month she took mifepristone before changing to an experimental drug, the case presented here provided much greater evidence that this drug can markedly improve both length and quality of life, in at least some patients, with very advanced pancreatic cancer.
It is hoped that this case report will influence others to prescribe mifepristone off-label and hopefully substantiate this finding of marked palliative benefit in the majority of a larger series of patients.
It is hoped that this case report will influence others to prescribe mifepristone off-label and hopefully substantiate this finding of marked palliative benefit in the majority of a larger series of patients.
The current literature conjectures that oral squamous cell carcinoma (OSCC) in younger patients is an entirely separate entity with a different risk profile. We aimed to uncover the potential risk factors of OSCC and evaluated the long-term outcome in such patients.
This hospital-based case-control study included 40 patients with OSCC and 40 controls under the age of 46 years. Survival was analyzed via Kaplan-Meier estimates, including a follow-up of up to 24.3 years.
The patients with OSCC were prone to smoking and drinking heavily and even suffered secondary organ damage to the lungs and the liver at this young age. Early diagnosed as well as surgically treated patients had superior 5-year recurrence-free and overall survival.
Young patients with OSCC were found to have a traditional risk profile. Secondary organ damage to the liver and the lungs might be considered as a risk indicator. The meticulous screening of every age group with this risk profile is key to early diagnosis and acceptable treatment results.
Young patients with OSCC were found to have a traditional risk profile. Secondary organ damage to the liver and the lungs might be considered as a risk indicator. The meticulous screening of every age group with this risk profile is key to early diagnosis and acceptable treatment results.
This study aimed to examine survival and surgical complications in patients with anaplastic thyroid cancer (ATC) after multimodal treatment.
Since 2002, the recommended treatment strategy for ATC at our centre has been hyperfractionated accelerated radiotherapy (HART) with high doses to the neck (64 Gy), combined with weekly doxorubicin, and surgery after 4-8 weeks, if feasible.
Between 2002 and 2014, 14 patients completed HART and thyroid surgery. Eight patients had preoperative HART, and six postoperative HART. Median survival was 20 months (range=4-110 months) in all patients, 51 months (range=4-110 months) and 18.5 months (range=9-56 months) in the preoperative and postoperative HART groups, respectively. Six patients survived for more than two years, and four patients survived for more than five years. Seven patients had postoperative complications.
In this series of selected patients, an improved survival after aggressive, multimodal treatment was observed. Preoperative HART may promote survival although complications may be more frequent.
In this series of selected patients, an improved survival after aggressive, multimodal treatment was observed. Preoperative HART may promote survival although complications may be more frequent.
We retrospectively investigated the significance of pre-treatment interferon-gamma release (IGR) as a biomarker for predicting the efficacy of immune checkpoint inhibitor treatment (ICI-tx).
This study included non-small-cell lung cancer patients who received ICI-tx between January 1, 2016 and April 30, 2019. IGR was measured using the positive control of an enzyme-linked immunosorbent assay. We defined the pre-treatment cut-off level of IGR as 10 IU/ml.
Fifty-four patients were divided into two groups; those with an IGR ≤10 IU/ml (lower group LG) (n=15) and those with >10 IU/ml (higher group HG) (n=39). The time to treatment failure (TTF) in the HG was significantly longer than that in the LG. In multivariate analyses, C-reactive protein and IGR levels were significant risk factors for TTF.
Pre-treatment IGR level of >10 IU/ml is recommended to identify those patients who will respond favourably to ICI-tx.
10 IU/ml is recommended to identify those patients who will respond favourably to ICI-tx.
The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in non-small cell lung cancer (NSCLC) patients.
Thirty-four patients with NSCLC received definitive chemoradiotherapy. The endpoint of this study was receiving durvalumab within 45 days after chemoradiotherapy for NSCLC.
Twenty-five of 34 (73%) patients received immunotherapy within 45 days after chemoradiotherapy. The reasons for not receiving immunotherapy were radiation pneumonitis (50%), radiation esophagitis (10%), and four other reasons (40%). Univariate analysis showed that significant factors for not receiving immunotherapy were elective nodal irradiation (ENI)+ and chronic obstructive pulmonary disease (COPD)+. The rate of immunotherapy was 100% (17/17 cases) in the COPD- and ENI- group, and 16% (1/6 cases) in the COPD+ and ENI+ group.
ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy.
ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy.
Although acute cholecystitis (AC) is quite a frequent clinical cause of acute abdominal pain (AAP), the accuracy of a diagnostic score (DS) in confirming AC is rarely considered. The aim of the study was to conduct a detailed analysis comparing the accuracy of common clinical findings, laboratory tests and DS in AC diagnosis.
A cohort of 1,333 patients presenting with AAP were included in the study. The clinical history and diagnostic symptoms (n= 21), signs (n=14) and laboratory tests (n=3) were recorded in each patient.
The significant independent diagnostic predictors (disclosed by multivariate logistic regression model) were used to construct the DS formulas for AC diagnosis. These formulas were tested at five different cut-off levels to establish the most optimal diagnostic performance for clinically confirmed AC. In the ROC comparison test, there was no statistically significant difference in the AUC values of i) clinical history and symptoms (AUC=0.542), and ii) signs & laboratory tests (AUC=0.580), whereas both were significantly inferior (p=0.0001) to the AUC value of the DS (AUC=0.962).
In the diagnosis of clinically confirmed AC, the DS formula is superior to clinical symptoms and signs, justifying the use of DS as an integral part of the diagnostic algorithm of AC in all patients presenting with AAP.
In the diagnosis of clinically confirmed AC, the DS formula is superior to clinical symptoms and signs, justifying the use of DS as an integral part of the diagnostic algorithm of AC in all patients presenting with AAP.
Reconstruction for soft-tissue sarcomas is complex and often uses soft-tissue flaps. To preserve critical structures, intraoperative radiotherapy (IORT) can be used to boost the total dose to these critical structures and close margins; however, there are limited data on the outcome of soft-tissue reconstruction in patients treated with IORT.
Twenty patients received IORT with soft-tissue flap coverage. There were 14 tumors of the lower extremities and six of the upper, including seven free-flaps and 13 pedicle flaps. Mean preoperative and IORT doses were 49.4 Gy and 10.4 Gy, respectively, with a mean total dose of 59.8 Gy.
Seven (35%) patients had a complication, most commonly an infection (n=4, 27%). Total flap loss occurred in one treated with pedicle flap. Four (20%) patients suffered a radiation-associated fracture. At the final follow-up, the mean Musculoskeletal Tumor Society Score was 75±11%.
Complications and postoperative fractures were common with IORT, however, there were no cases requiring amputation.
Complications and postoperative fractures were common with IORT, however, there were no cases requiring amputation.
Chemokine receptor inhibition is an immunotherapy that modulates the innate arm of the immune system. Previous work in microsatellite-stable metastatic colorectal cancer showed an exploitive loop that could be successfully targeted via C-C-motive-chemokine-receptor 5 (CCR5) specific blocking, resulting in a selective anti-tumoral activation of macrophages. In the respective trial (MARACON trial, NCT01736813) the peripheral blood laboratory markers and cytokine values were measured over time. Little is known on their role as biomarkers or stratification parameters in immunotherapy trials.
Systematic analyses of key laboratory parameters are presented, highlighting specific dynamics of lymphocyte and monocyte percentages, lactate dehydrogenase as well as interleukin-6 and interleukin-8 levels as parameters of a systemic inflammatory readout.
Specific dynamical changes of lymphocyte and monocyte compositions were noted between different patients, showing a stabilization (or increase) versus decreased numbers over time for monocytes. While lactate dehydrogenase, interleukin-6 and interleukin-8 showed almost uniformly rising levels over time, the systemic monocyte patterns prompted a further evaluation. Stabilized or increasing monocyte percentages were associated with improved overall survival (Kaplan Meier analysis, p=0.025) and with induced overt radiologic necrosis in patients.
The observed association between monocyte dynamics and imaging findings as well as overall survival suggests that analyses of dynamical parameters in the peripheral blood should be implemented in immunotherapy trials.
The observed association between monocyte dynamics and imaging findings as well as overall survival suggests that analyses of dynamical parameters in the peripheral blood should be implemented in immunotherapy trials.
Examine features of blood and lymphatic vessels in ovarian tumors and their significance to prognosis of ovarian cancer.
A total of 139 women with epithelial ovarian tumors were included 86 malignant, 17 borderline and 36 benign. Density, percentage, mean size and number of blood microvessels in tumors were measured by immunohistochemistry with antibodies against CD34 and CD105. Lymphatic vessel density was assayed using the D2-40 antibody against podoplanin.
Angiogenesis was most profuse in malignant tumors. Small size of lymph vessels predicted 26% shorter 5-year survival of ovarian cancer patients. Further, high percentage of lymphatic vessels in tumors was associated with lymph node metastasis, and high density with cancer recurrence. Lower number of microvessels, as assessed by CD34 staining, predicted shorter progression-free survival. Additionally, the large size of microvessels assessed by CD34 and the high number of vessels assessed by CD105 were related to residual tumor >1 cm at primary surgery and also, large vessel size was associated with stage III, as assessed by CD105 staining.