Phase I trial of single-photon emission computed tomography-guided liver-directed radiotherapy for patients with low functional liver volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

Novel Clinical Tool to Estimate Risk of False-Negative KRAS Mutations in Circulating Tumor DNA Testing.

PURPOSE: In metastatic colorectal cancer, the detection of RAS mutations by circulating tumor DNA (ctDNA) has emerged as a valid and noninvasive alternative approach to determining RAS status. However, some RAS mutations may be missed, that is, false negatives can occur, possibly compromising important treatment decisions. We propose a statistical model to assess the probability of false negatives when performing ctDNA testing for RAS. METHODS: Cohorts of 172 subjects with tissue and multipanel ctDNA testing from MD Anderson Cancer Center and 146 subjects from Massachusetts General Hospital were collected. We developed a Bayesian model that uses observed frequencies of reference mutations (the maximum of APC and TP53) to provide information about the probability of KRAS false negatives. The model was alternatively trained on one cohort and tested on the other. All data were collected on Guardant assays. RESULTS: The model suggests that negative KRAS findings are believable when the maximum of APC and TP53 frequencies is at least 8% (corresponding posterior probability of false negative <5%). Validation studies demonstrated the ability of our tool to discriminate between false-negative and true-negative subjects. Simulations further confirmed the utility of the proposed approach. CONCLUSION: We suggest clinicians use the tool to more precisely quantify KRAS false-negative ctDNA results when at least one of the reference mutations (APC, TP53) is observed; usage may be especially important for subjects with a maximum reference frequency of <8%. Extension of the methodology to predict false negatives of other genes is possible. Additional reference genes can also be considered. Use of personal training data sets is supported. An open-source R Shiny application is available for public use.

Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.

PURPOSE: To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Eight randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS: Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)-positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Polymeric fiber sensors for insertion forces and trajectory determination of cochlear implants in hearing preservation.

The level of hearing restoration in patients with severe to profound sensorineural hearing loss by means of cochlear implants (CIs) has drastically risen since the introduction of these neuroprosthetics. The proposed CI integrated with polymer optical fiber Bragg gratings (POFBGs) enables real-time evaluation of insertion forces and trajectory determination during implantation irrespective of the speed of insertion, as well as provides high signal quality, low stiffness levels, minimum induced stress even under forces of high magnitudes and exhibits significant reduction of the risk of fiber breakage inside the constricted cochlear geometry. As such, the proposed device opens new avenues towards atraumatic cochlear implantations and provides a direct route for the next generation of CIs with intraoperative insertion force assessment and path planning capacity crucial for surgical navigation. Hence, adaptation of this technology to clinical reality holds promising prospects for the hearing impaired.

Dysbiosis of the Beneficial Gut Bacteria in Patients with Parkinson's Disease from India.

Objectives: Recent advancement in understanding neurological disorders has revealed the involvement of dysbiosis of the gut microbiota in the pathophysiology of Parkinson's disease (PD). We sequenced microbial DNA using fecal samples collected from PD cases and healthy controls (HCs) to evaluate the role of gut microbiota. Methods: Full-length bacterial 16S rRNA gene sequencing of fecal samples was performed using amplified polymerase chain reaction (PCR) products on the GridION Nanopore sequencer. Sequenced data were analyzed using web-based tools BugSeq and MicrobiomeAnalyst. Results: We found that certain bacterial families like Clostridia UCG 014, Cristensenellaceae, and Oscillospiraceae are higher in abundance, and Lachinospiracea, Coriobacteriaceae and genera associated with short-chain fatty acid production, Faecalibacterium, Fusicatenibacter, Roseburia and Blautia, are lower in abundance among PD cases when compared with the HC. Genus Akkermansia, Dialister, Bacteroides, and Lachnospiraceae NK4A136 group positively correlated with constipation in PD. Conclusion: Observations from this study support the other global research on the PD gut microbiome background and provide fresh insight into the gut microbial composition of PD patients from a south Indian population. We report a higher abundance of Clostridia UCG 014 group, previously not linked to PD.

Exploring the multifactorial aspects of Gut Microbiome in Parkinson's Disease.

Advanced research in health science has broadened our view in approaching and understanding the pathophysiology of diseases and has also revolutionised diagnosis and treatment. Ever since the establishment of Braak's hypothesis in the propagation of alpha-synuclein from the distant olfactory and enteric nervous system towards the brain in Parkinson's Disease (PD), studies have explored and revealed the involvement of altered gut microbiota in PD. This review recapitulates the gut microbiome associated with PD severity, duration, motor and non-motor symptoms, and antiparkinsonian treatment from recent literature. Gut microbial signatures in PD are potential predictors of the disease and are speculated to be used in early diagnosis and treatment. In brief, the review also emphasises on implications of the prebiotic, probiotic, faecal microbiota transplantation, and dietary interventions as alternative treatments in modulating the disease symptoms in PD.

A Novel Perception Framework for Automatic Laparoscope Zoom Factor Control Using Tool Geometry.

In conventional Minimally Invasive Surgery, the surgeon conducts the operation while a human or robot holds the laparoscope. Laparoscope control is returned to the surgeon in teleoperated camera holding robots, but simultaneously controlling the laparoscope and surgical tools might be cognitively demanding. On the other hand, fully automated camera holders are still limited in their performance. To help the surgeon to better focus on the main operation while maintaining their control authority, we propose an automatic laparoscope zoom factor control framework for Robot-Assisted Minimally Invasive Surgery. In this paper, we present the perception section of the framework. It extracts and uses the surgical tool's geometric characteristics to adjust the laparoscope's zoom factor, without any artificial markers. The acceptable range and tooltip's position frequency during operations are analysed based on the gallbladder removal surgery dataset (Cholec80). The common range and tooltip's heatmap are identified and presented quantitatively.

Acetalization of glycerol and benzaldehyde to synthesize biofuel additives using SO4 2-/CeO2-ZrO2 catalyst.

Synthesis of 1,3- dioxane and 1,3-dioxolane, using sulfated CeO2-ZrO2 catalyst for acetalization of glycerol with benzaldehyde, is the focus of present work. SO4 2-/CeO2-ZrO2 catalyst was synthesized using combustion method. Experiments were carried out to analyze the effect of various solvents (n-hexane, toluene, tert-butyl alcohol, pentanol), molar ratios (1:3, 1:5, 1:7), catalyst loadings (3 wt%, 5 wt%, 9 wt %) and temperatures (80 °C, 90 °C, 100 °C) on glycerol conversion and selectivity of the products. Selectivity of 87.20% dioxolane and 12.80% dioxane was obtained at molar ratio of 1:3, 9 wt% catalyst loading and temperature of 100 °C.Strong NH3 desorption peak from NH3-TPD study indicated the high acidic strength of sulphated catalyst. Strong surface acidity and surface porosity (observed from TEM and SEM analysis) contributed to an enhanced activity of the catalyst for glycerol acetalization reaction. The kinetics of the reaction was studied using an elementary kinetic law. A correlation coefficient of 0.98 from the selected kinetic model proved that the rate of acetalization reaction was dependent on glycerol concentration and acetal formation was instantaneous. The study demonstrated the application of an environmentally benign, inexpensive, thermally stable, active SO4 2-/CeO2-ZrO2 catalyst for glycerol acetalization reaction to synthesize 1,3-dioxolane as the desired product.

Integrated Force Sensor in a Cochlear Implant for Hearing Preservation Surgery.

Cochlear Implant is used for patients with severe hearing loss. It is a neural-prosthesis that stimulates the nerve endings within the cochlea, which is the organ of hearing. The surgical technique involves inserting the electrode array of the implant into a very small "snail-like" spiral structure. During this insertion process, the surgeon's finger tip is not able to perceive the resistance from the contact of the implant and the cochlea's internal structure, below the internal rupture threshold. This can potentially damage vital structures and result in the worsening of residual hearing and poor speech perception. Currently, there is no clinically and commercially available intra-operative force feedback system. A custom made sensor is therefore proposed, integrated within the implant to enable real-time force readings. The device will provide surgeons with the vital force feedback information related to the implants' position within the cochlea. This paper concentrates on demonstrating that the proposed sensor is capable of measuring the contact force below the rupture threshold of the cochlea's internal structure.

Significance of antibody detection in the diagnosis of cryptococcal meningitis.

Cryptococcus neoformans is the causative agent of Cryptococcosis, a chronic and life-threatening infection common in AIDS patients. Sonicated proteins of cryptococci were reported to contain antigenic properties. In the present study antigens are prepared from cryptococcal culture filtrate and by sonication. Secretory antigens are prepared by precipitation of culture filtrate using saturated ammonium sulfate followed by dialysis. Prepared antigens are tested for the presence of antibodies in the CSF samples of cryptococcal meningitis cases by ELISA. Comparison is made between India ink staining, latex antigen test, and the antibodies to the sonicated and secretory antigens. The results indicate that although antigen could be detected in the majority of samples, antibody could also be detected to the extent of 80-85%. It is interesting to note that some samples that were negative for India ink staining also showed high antibody responses. Hence, antibody detection could be a valuable marker in association with India ink staining for the early diagnosis of the cryptococcal infection. This test may also counter false positivity encountered in latex antigen test. Antibody detection assay would be a viable alternative, which has 83% sensitivity and 100% specificity. Thus the presently described test aids in immunodiagnosis of cryptococcal infection.

An outbreak of extended spectrum beta-lactamase producing Klebsiella pneumoniae in a neonatal intensive care unit.

Klebsiella pneumoniae has long been a prominent cause of nosocomial infections and outbreaks have been observed in the intensive care units and in high risk groups. We present here a brief report on an outbreak of Klebsiella pneumoniae which occurred in a neonatal intensive care unit in our teaching hospital. As neonates are at highest risk for acquisition of Klebsiella pneumoniae producing extended spectrum beta-lactamase, infection control policies and procedures should be strictly followed to prevent such outbreaks.

Evidence-based management of Mastalgia: a meta-analysis of randomised trials.

Several agents have been utilised for therapy of mastalgia based on data from small trials. No meta-analysis of trials on mastalgia exists. We have conducted a meta-analysis on trials on mastalgia published in the English language. Study was restricted to randomised controlled trials comparing Bromocriptine, Danazol, Evening primrose oil (EPO) and Tamoxifen with placebo. The analysis was carried out on the REVMAN statistical package. Weighted mean difference in the pain score in favour of Bromocriptine was -16.31(95% CI -26.35 to -6.27). Danazol produced a significant benefit with a mean pain score difference -20.23(95% CI -28.12 to -12.34). EPO did not offer any advantage over placebo in pain relief, mean pain score difference being -2.78 (95% CI -7.97 to 2.40). Tamoxifen achieved a relative risk (RR) of pain relief of 1.92 (95% CI 1.42-2.58). Tamoxifen is associated with least side effects and should be the drug of first choice.