Increase of pseudoprogression and other treatment related effects in low-grade glioma patients treated with proton radiation and temozolomide.

INTRODUCTION: Concurrent radiotherapy and temozolomide (TMZ) is associated with radiographic pseudoprogression (PsP) in glioblastoma. The occurrence of PsP and other treatment effects is less well understood in low-grade gliomas (LGG). The purpose of this study is to evaluate whether the addition of TMZ to radiotherapy increases the incidence of PsP in adults with LGG treated with proton radiotherapy (PRT). METHODS: Chart review and volumetric MRI-analysis was performed on radiotherapy-naive adults with WHO grade II or IDH mutant WHO grade III gliomas treated with PRT between 2005 and 2015. Progression was defined by histology, new chemotherapy initiation, or progressive increase in lesion volume beyond 40% from baseline. Post treatment related effects (PTRE) were defined as new/increased T2/FLAIR or abnormal enhancement which eventually resolved or stabilized without evidence of progression for a period of 6-12 months. PsP was defined as the subset of PRTE suspicious for progression or volumetrically increased at least 40% from baseline. Pearson's chi-squared test and Cox-proportional hazards models were used for statistical analysis. RESULTS: There were 119 patients meeting inclusion criteria. There was an increased risk of PsP following PRT + TMZ versus PRT-alone (HR = 2.2, p = 0.006, on Cox univariate analysis). Presence of PsP was associated with improved OS (p = 0.02 with PsP as time-varying covariate). CONCLUSIONS: TMZ use, when added to PRT, was associated with increased PsP in patients with LGG; however, patients with PsP tended to achieve longer survival.

Clinical Linear Accelerator-Based Electron FLASH: Pathway for Practical Translation to FLASH Clinical Trials.

PURPOSE: Ultrahigh-dose-rate (UHDR) radiation therapy (RT) has produced the FLASH effect in preclinical models: reduced toxicity with comparable tumor control compared with conventional-dose-rate RT. Early clinical trials focused on UHDR RT feasibility using specialized devices. We explore the technical feasibility of practical electron UHDR RT on a standard clinical linear accelerator (LINAC). METHODS AND MATERIALS: We tuned the program board of a decommissioned electron energy for UHDR electron delivery on a clinical LINAC without hardware modification. Pulse delivery was controlled using the respiratory gating interface. A short source-to-surface distance (SSD) electron setup with a standard scattering foil was configured and tested on an anthropomorphic phantom using circular blocks with 3- to 20-cm field sizes. Dosimetry was evaluated using radiochromic film and an ion chamber profiler. RESULTS: UHDR open-field mean dose rates at 100, 80, 70, and 59 cm SSD were 36.82, 59.52, 82.01, and 112.83 Gy/s, respectively. At 80 cm SSD, mean dose rate was ∼60 Gy/s for all collimated field sizes, with an R80 depth of 6.1 cm corresponding to an energy of 17.5 MeV. Heterogeneity was <5.0% with asymmetry of 2.2% to 6.2%. The short SSD setup was feasible under realistic treatment conditions simulating broad clinical indications on an anthropomorphic phantom. CONCLUSIONS: Short SSD and tuning for high electron beam current on a standard clinical LINAC can deliver flat, homogenous UHDR electrons over a broad, clinically relevant range of field sizes and depths with practical working distances in a configuration easily reversible to standard clinical use.

Impact of enteral prophylactic antibiotics on the trends of inflammatory markers following laparoscopic colorectal cancer surgery: A retrospective and prospective Cohort Study.

BACKGROUND: The study aimed to assess the effect of oral prophylactic antibiotics (OAB) with mechanical bowel preparation (MBP) on the serial measurement of postoperative inflammatory markers and clinical outcomes of the patients undergoing laparoscopic colorectal cancer resection surgery. METHODS: A retrospective and prospective data collection was carried out from January 2019 to March 2020 for the patients undergoing laparoscopic colorectal cancer resection. Daily measurements of inflammatory markers were obtained up to 7 days following surgery. The measurements of inflammatory markers were compared between patients who received a 1 week course of OAB along with MBP to those who only received MBP. RESULTS: There were a total of 110 patients that were divided into 2 groups: patients who received OAB and MBP (n = 44, 40%) and those who had MBP only (n = 66, 60%). There was no significant difference between the patient characteristics and preoperative staging of the cancer between the 2 groups. The overall length of stay was significantly lower in the patients who received OAB (9.09 days [SD 7.94] vs. 6.63 days [SD 4.96], P 0.02). The patients with OAB and MAP had persistently and significantly low levels of white blood cell count, CRP, and neutrophil count throughout the postoperative period as compared to those who only had MBP. CONCLUSION: The study demonstrated reduction in serial measurement of inflammatory markers throughout postoperative stay for the patients receiving preoperative OAB. The use of OAB helps in physiological recovery of the patient by reducing the inflammatory process postoperatively.

Patterns of Failure Among Patients With Low-grade Glioma Treated With Proton Radiation Therapy.

PURPOSE: Proton treatment may be a useful radiation therapy modality for long-term surviving patients with glioma to reduce normal tissue toxicities. Photon studies demonstrate that most low-grade glioma (LGG) failures occur within the radiation field, supporting the use of more conformal treatment plans, yet it is unclear whether this can be translated to proton radiation therapy (PRT). Our objective is to examine our institutional experience to determine patterns of failure in patients with LGG with respect to the volume irradiated with PRT. METHODS AND MATERIALS: Patients with World Health Organization 2007 grade I to II or isocitrate dehydrogenase 1-positive mutation grade III LGG treated with PRT between 2005 and 2015 were retrospectively reviewed. Patients with documented local recurrences on magnetic resonance imaging after receipt of PRT underwent a comparison with the initial treatment plan dosimetry to evaluate patterns of failure. A total of 141 patients were included in the final cohort. RESULTS: The median follow-up time was 46.7 months (range, 2.8-144 months), and 5-year overall survival was 84%. The median PRT dose delivered was 54 Gy (relative biological effectiveness) (range, 45-60 Gy). There were 42 failures after PRT (30%). The median time to progression after treatment was 32.7 months (range, 4.8-93.6 months). Thirty-one patients (74%) failed in-field (defined as within the 95% isodose volume), 5 patients (12%) failed out-of-field, and 5 patients (12%) had marginal failures (defined as within the 50%-95% isodose volume). The 5-year freedom from progression after PRT was 60.1% (95% confidence interval, 48.7-70.0). The 5-year cumulative incidence of overall survival was 33% among those with recurrence after PRT and 96% among those without recurrence after PRT (P < .001). CONCLUSIONS: Of the patients with LGG who had documented failures after PRT, most recurred within the radiation field with few marginal failures, indicating that even with PRT, which often can have steeper dose gradients, coverage is adequate. Survival was poor for patients whose tumors recurred.

Long-term outcomes and late adverse effects of a prospective study on proton radiotherapy for patients with low-grade glioma.

BACKGROUND: Patients with low-grade gliomas (LGG) can survive years with their illness. Proton radiotherapy (PRT) can reduce off-target dose and decrease the risk of treatment-related morbidity. We examined long-term morbidity following proton therapy in this updated prospective cohort of patients with LGG. METHODS: Twenty patients with LGG were enrolled prospectively and received PRT to 54 Gy(RBE) in 30 fractions. Comprehensive baseline and longitudinal assessments of toxicity, neurocognitive and neuroendocrine function, quality of life, and survival outcomes were performed up to 5 years following treatment. RESULTS: Six patients died (all of disease) and six had progression of disease. Median follow-up was 6.8 years for the 14 patients alive at time of reporting. Median progression-free survival (PFS) was 4.5 years. Of tumors tested for molecular markers, 71% carried the IDH1-R132H mutation and 29% had 1p/19q co-deletion. There was no overall decline in neurocognitive function; however, a subset of five patients with reported cognitive symptoms after radiation therapy had progressively worse function by neurocognitive testing. Six patients developed neuroendocrine deficiencies, five of which received Dmax ≥20 Gy(RBE) to the hypothalamus-pituitary axis (HPA). Most long-term toxicities developed within 2 years after radiation therapy. CONCLUSIONS: The majority of patients with LGG who received proton therapy retained stable cognitive and neuroendocrine function. The IDH1-R132H mutation was present in the majority, while 1p/19q loss was present in a minority. A subset of patients developed neuroendocrine deficiencies and was more common in those with higher dose to the HPA.

In silico modeling of Itk activation kinetics in thymocytes suggests competing positive and negative IP4 mediated feedbacks increase robustness.

The inositol-phosphate messenger inositol(1,3,4,5)tetrakisphosphate (IP4) is essential for thymocyte positive selection by regulating plasma-membrane association of the protein tyrosine kinase Itk downstream of the T cell receptor (TCR). IP4 can act as a soluble analog of the phosphoinositide 3-kinase (PI3K) membrane lipid product phosphatidylinositol(3,4,5)trisphosphate (PIP3). PIP3 recruits signaling proteins such as Itk to cellular membranes by binding to PH and other domains. In thymocytes, low-dose IP4 binding to the Itk PH domain surprisingly promoted and high-dose IP4 inhibited PIP3 binding of Itk PH domains. However, the mechanisms that underlie the regulation of membrane recruitment of Itk by IP4 and PIP3 remain unclear. The distinct Itk PH domain ability to oligomerize is consistent with a cooperative-allosteric mode of IP4 action. However, other possibilities cannot be ruled out due to difficulties in quantitatively measuring the interactions between Itk, IP4 and PIP3, and in generating non-oligomerizing Itk PH domain mutants. This has hindered a full mechanistic understanding of how IP4 controls Itk function. By combining experimentally measured kinetics of PLCγ1 phosphorylation by Itk with in silico modeling of multiple Itk signaling circuits and a maximum entropy (MaxEnt) based computational approach, we show that those in silico models which are most robust against variations of protein and lipid expression levels and kinetic rates at the single cell level share a cooperative-allosteric mode of Itk regulation by IP4 involving oligomeric Itk PH domains at the plasma membrane. This identifies MaxEnt as an excellent tool for quantifying robustness for complex TCR signaling circuits and provides testable predictions to further elucidate a controversial mechanism of PIP3 signaling.

Dramatic reduction of dimensionality in large biochemical networks owing to strong pair correlations.

Large multi-dimensionality of high-throughput datasets pertaining to cell signalling and gene regulation renders it difficult to extract mechanisms underlying the complex kinetics involving various biochemical compounds (e.g. proteins and lipids). Data-driven models often circumvent this difficulty by using pair correlations of the protein expression levels to produce a small number (fewer than 10) of principal components, each a linear combination of the concentrations, to successfully model how cells respond to different stimuli. However, it is not understood if this reduction is specific to a particular biological system or to nature of the stimuli used in these experiments. We study temporal changes in pair correlations, described by the covariance matrix, between concentrations of different molecular species that evolve following deterministic mass-action kinetics in large biologically relevant reaction networks and show that this dramatic reduction of dimensions (from hundreds to less than five) arises from the strong correlations between different species at any time and is insensitive to the form of the nonlinear interactions, network architecture, and to a wide range of values of rate constants and concentrations. We relate temporal changes in the eigenvalue spectrum of the covariance matrix to low-dimensional, local changes in directions of the system trajectory embedded in much larger dimensions using elementary differential geometry. We illustrate how to extract biologically relevant insights such as identifying significant timescales and groups of correlated chemical species from our analysis. Our work provides for the first time, to our knowledge, a theoretical underpinning for the successful experimental analysis and points to a way to extract mechanisms from large-scale high-throughput datasets.

Extruded Filshie clip presenting as an ischiorectal abscess.

This report adds to the small, but significant, literature base describing late complications following laparoscopic sterilisation. In women with recalcitrant peri-anal sepsis (who have previously undergone a sterilisation procedure) the possibility of tubal clip migration should be borne in mind. This is also an important learning point from a medicolegal point of view as patients presenting with the sequelae of clip migration will need to be counselled, and possibly investigated, with respect to the efficacy of their sterilisation procedure.

Choriocarcinoma of the colon: report of a case and review of the literature.

Primary choriocarcinoma of the colon is a very rare tumor, with only six reported cases in the world literature, all but one of which was associated with an adjacent adenocarcinoma. This has led to the suggestion that colonic choriocarcinomas may arise from the more typical adenocarcinoma a process of further dedifferentiation. This article reviews the above cases and adds a further case from a 73-year-old male in whom no associated adenocarcinoma could be found despite careful postmortem examination. This finding gives support to the hypothesis that, rather than arising as a result of further dedifferentiation of an existing tumor, primary choriocarcinomas may also develop in the large intestine.