Novel approaches to treatment of leptomeningeal metastases.

PURPOSE OF REVIEW: The incidence of leptomeningeal metastases is increasing in the setting of improved survival from systemic cancers. In more recent years, our understanding of leptomeningeal metastasis pathogenesis, how to diagnose and treat has been evolving. RECENT FINDINGS: Diagnosing leptomeningeal metastasis has been challenging due to the limitations of cytology and neuroimaging; However, newer techniques detecting circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) have shown potential advantage with diagnosis, quantification and detection of oncogenic mutations. The use of small molecule inhibitors and immunotherapy has shown some promise in specific leptomeningeal metastasis subtypes. SUMMARY: These new discoveries have improved clinical trials' ability to assess treatment response and thereby more optimally compare different treatments. Furthermore, they have helped the individual clinician better diagnose, monitor the disease and provide novel therapies.

Role of immunotherapy in chondrosarcoma: A case report and review of the literature.

Chondrosarcomas (CSs) consist of a heterogenous group of primary bone cancers arising from malignant cells which produce cartilaginous matrix. As the second most common primary bone cancer, CS are often resistant to systemic chemotherapy due to poor vascularization, slow proliferation, and expression of multidrug-resistant pumps. Immune checkpoint inhibitors have transformed the field of oncology and are now designated as frontline therapy for many solid tumor cancers. Several studies have demonstrated increased expression of programed cell death 1 (PD-1) and PD-L1 in CS tissue in vitro, which has led to the development of multiple clinical trials for immunotherapy in patients with aggressive CS. In this review, we highlight the ongoing investigation into the role for immunotherapy in CS. We also report the case of a 44-year-old female with a history of stage IV primary CS of the right shoulder who underwent radical resection with recurrence and demonstrated a spectacular sustained response to pembrolizumab at our center. Our review highlights the need for further studies investigating the role of immunotherapy in the treatment of aggressive bone sarcomas that are resistant to standard surgical resection, chemotherapy, and radiation treatment.

Chondrosarcoma is a cancer of the cells that make cartilage and is often removed surgically. However, when the cancer spreads to other organs such as the lungs or are in areas unreachable by surgeons, there are not many effective treatments. While targeted treatments are in development, many of them have unclear effectiveness. A new and rapidly growing area of cancer treatment is known as immunotherapy, which uses the body's own immune system to kill cancer cells. In this review, we discuss trials in using immunotherapy against aggressive forms of chondrosarcoma. We also present the case of a patient where an immunotherapy agent called pembrolizumab was highly effective in preventing disease progression.

Modern Management and Diagnostics in HER2+ Breast Cancer with CNS Metastasis.

Patients with HER2-positive breast cancer have seen improved survival and outcomes over the past two decades. As patients live longer, the incidence of CNS metastases has increased in this population. The authors' review outlines the most current data in HER2-positive brain and leptomeningeal metastases and discuss the current treatment paradigm in this disease. Up to 55% of HER2-positive breast cancer patients go on to experience CNS metastases. They may present with a variety of focal neurologic symptoms, such as speech changes or weakness, and may also have more diffuse symptoms related to high intracranial pressure, such as headaches, nausea, or vomiting. Treatment can include focal treatments, such as surgical resection or radiation (focal or whole-brain radiation), as well as systemic therapy options or even intrathecal therapy in the case of leptomeningeal disease. There have been multiple advancements in systemic therapy for these patients over the past few years, including the availability of tucatinib and trastuzumab-deruxtecan. Hope remains high as clinical trials for CNS metastases receive greater attention and as other HER2-directed methods are being studied in clinical trials with the goal of better outcomes for these patients.

Postinfective bowel dysfunction following Campylobacter enteritis is characterised by reduced microbiota diversity and impaired microbiota recovery.

OBJECTIVES: Persistent bowel dysfunction following gastroenteritis (postinfectious (PI)-BD) is well recognised, but the associated changes in microbiota remain unclear. Our aim was to define these changes after gastroenteritis caused by a single organism, Campylobacter jejuni, examining the dynamic changes in the microbiota and the impact of antibiotics. DESIGN: A single-centre cohort study of 155 patients infected with Campylobacter jejuni. Features of the initial illness as well as current bowel symptoms and the intestinal microbiota composition were recorded soon after infection (visit 1, <40 days) as well as 40-60 days and >80 days later (visits 2 and 3). Microbiota were assessed using 16S rRNA sequencing. RESULTS: PI-BD was found in 22 of the 99 patients who completed the trial. The cases reported significantly looser stools, with more somatic and gastrointestinal symptoms. Microbiota were assessed in 22 cases who had significantly lower diversity and altered microbiota composition compared with the 44 age-matched and sex-matched controls. Moreover 60 days after infection, cases showed a significantly lower abundance of 23 taxa including phylum Firmicutes, particularly in the order Clostridiales and the family Ruminoccocaceae, increased Proteobacteria abundance and increased levels of Fusobacteria and Gammaproteobacteria. The microbiota changes were linked with diet; higher fibre consumption being associated with lower levels of Gammaproteobacteria. CONCLUSION: The microbiota of PI-BD patients appeared more disturbed by the initial infection compared with the microbiota of those who recovered. The prebiotic effect of high fibre diets may inhibit some of the disturbances seen in PI-BD. TRIAL REGISTRATION NUMBER: NCT02040922.

Omaveloxolone attenuates squamous cell carcinoma growth and disease severity in an Epidermolysis Bullosa mouse model.

Patients with epidermolysis bullosa (EB) are susceptible to development of squamous cell carcinomas (SCC) at sites of chronic inflammation and fibrosis. While triterpenoids such as RTA 408 (Omaveloxolone) have been shown to reduce inflammation and inhibit tumour growth in various cancer models, the utility of this class of drugs in the treatment of SCC has not been investigated. Given the dual anti-inflammatory and anti-neoplastic properties of triterpenoids, we hypothesized RTA 408 would be an effective treatment for SCCs that arise in the chronic inflammatory setting in EB. We tested the effects of topical RTA 408 on a mouse model of non-Herlitz, junctional EB. RTA 408 significantly reduced phenotypic severity in the affected ears of Lamc2jeb mice. In cultures, RTA 408 reduced cell viability in EB-associated SCC cell lines and normal human epidermal keratinocytes. When administered in vivo, RTA 408 inhibited SCC tumour growth in mice without cutaneous or systemic toxicity. These results suggest that RTA 408 can be a promising new therapy to reduce inflammation and inhibit SCC growth in patients with EB.

Interactive Timeline Approach for Contextual Spatio-Temporal ECT Data Investigation.

This paper presents a novel approach to a complex process of electrical capacitance tomography (ECT) measurement data analysis. ECT is frequently employed for non-invasive monitoring of industrial process phenomena. Proposed methodology is based on the premeditated integration of the spatial and temporal relations inherent in the measurement records into the workflow of the analysis procedure. We propose a concept of interactive timeline that enables arranging data visualization according to the user's current focus along the process of analysis. We evaluated the proposed method using a prototype system in a task-based user study conducted with a group of domain experts. The evaluation is based on gravitational silo flow measurement datasets. Proposed prototype system enables diverse data manipulation in a more natural way allowing the user to switch back and forth between space and time domains along the data analysis trail. Experiments with the prototype system showed that the accuracy and completion times have significantly improved in comparison to the performance measured in the baseline condition. Additionally, the participants reported decreased physical load with improved efficiency measured with NASA task load index. Finally, a short discussion coupled with directions for the future of interactive spatio-temporal ECT measurement data analysis conclude the paper.

Linear basal cell nevus with a novel mosaic PTCH1 mutation.

The patched tumor suppressor gene (PTCH1) encodes a receptor, which is a key component of the hedgehog signalling pathway. Mutations in PTCH1 are implicated in the development of sporadic basal cell carcinomas (BCC), as well as those in Gorlin Syndrome. Rarely, BCCs may develop in a linear pattern along lines of Blaschko due to cutaneous mosaicism. In cases in which there are other features of Gorlin syndrome, genomic analysis has demonstrated lesional mutations in the Hedgehog signalling pathway. Causative mutations, however, have not been firmly demonstrated in the cases of linear and segmental BCCs in otherwise healthy individuals. Herein, we report a case of a 31 year-old Caucasian woman with linear development of multiple superficial BCCs in a Blaschkoid distribution without other characteristic findings of Gorlin syndrome. Genomic analysis of lesional skin by whole-exome sequencing identified a novel heterozygous mutation PTCH1: NM_000264.3, Exon 15, c.2336-2337insGGTAGGA, p.Asp779Glufs*13 in PTCH1, shared by two discrete samples within the lesion, while no mutations were found in the non-lesional skin or peripheral blood. Given the young age of our patient and linear distribution of BCCs on non-sun exposed skin, our findings suggest segmental mosaicism. The patient was treated with topical 5% imiquimod with histologically confirmed clearance of BCCs in 2 months.

MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer.

BACKGROUND: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. METHODS: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. RESULTS: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. CONCLUSION: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.

Gastrointestinal peptides and small-bowel hypomotility are possible causes for fasting and postprandial symptoms in active Crohn's disease.

BACKGROUND: Crohn's disease (CD) patients suffer postprandial aversive symptoms, which can lead to anorexia and malnutrition. Changes in the regulation of gut hormones and gut dysmotility are believed to play a role. OBJECTIVES: This study aimed to investigate small-bowel motility and gut peptide responses to a standard test meal in CD by using MRI. METHODS: We studied 15 CD patients with active disease (age 36 ± 3 y; BMI 26 ± 1 kg/m 2) and 20 healthy volunteers (HVs; age 31 ± 3 years; BMI 24 ± 1 kg/m 2). They underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling following a 400-g soup meal (204 kcal). Small-bowel motility, other MRI parameters, and glucagon-like peptide-1 (GLP-1), polypeptide YY (PYY), and cholecystokinin peptides were measured. Data are presented as means ± SEMs. RESULTS: HVs had significantly higher fasting motility indexes [106 ± 13 arbitrary units (a.u.)], compared with CD participants (70 ± 8 a.u.; P ≤ 0.05). Postprandial small-bowel water content showed a significant time by group interaction (P < 0.05), with CD participants showing higher levels from 210 min postprandially. Fasting concentrations of GLP-1 and PYY were significantly greater in CD participants, compared with HVs [GLP-1, CD 50 ± 8 µg/mL versus HV 13 ± 3 µg/mL (P ≤ 0.0001); PYY, CD 236 ± 16 pg/mL versus HV 118 ± 12 pg/mL (P ≤ 0.0001)]. The meal challenge induced a significant postprandial increase in aversive symptom scores (fullness, distention, bloating, abdominal pain, and sickness) in CD participants compared with HVs (P ≤ 0.05). CONCLUSIONS: The decrease in fasting small-bowel motility noted in CD participants can be ascribed to the increased fasting gut peptides. A better understanding of the etiology of aversive symptoms in CD will facilitate identification of better therapeutic targets to improve nutritional status. This trial was registered at clinicaltrials.gov as NCT03052465.

The Effect of Psyllium Husk on Intestinal Microbiota in Constipated Patients and Healthy Controls.

Psyllium is a widely used treatment for constipation. It traps water in the intestine increasing stool water, easing defaecation and altering the colonic environment. We aimed to assess the impact of psyllium on faecal microbiota, whose key role in gut physiology is being increasingly recognised. We performed two randomised, placebo-controlled, double-blinded trials comparing 7 days of psyllium with a placebo (maltodextrin) in 8 healthy volunteers and 16 constipated patients respectively. We measured the patients' gastrointestnal (GI) transit, faecal water content, short-chain fatty acid (SCFA) and the stool microbiota composition. While psyllium supplement had a small but significant effect on the microbial composition of healthy adults (increasing Veillonella and decreasing Subdoligranulum), in constipated subjects there were greater effects on the microbial composition (increased Lachnospira, Faecalibacterium, Phascolarctobacterium, Veillonella and Sutterella and decreased uncultured Coriobacteria and Christensenella) and alterations in the levels of acetate and propionate. We found several taxa to be associated with altered GI transit, SCFAs and faecal water content in these patients. Significant increases in three genera known to produce butyrate, Lachnospira, Roseburia and Faecalibacterium, correlated with increased faecal water. In summary, psyllium supplementation increased stool water and this was associated with significant changes in microbiota, most marked in constipated patients.

Cine MRI assessment of motility in the unprepared small bowel in the fasting and fed state: Beyond the breath-hold.

BACKGROUND: The symptoms of functional bowel disorders are common in postprandial but investigations are generally undertaken in the fasted state using invasive procedures. MRI provides a noninvasive tool to study the gastrointestinal tract in an unperturbed, fed state. The aim of this study was to develop a technique to assess small bowel motility from cine MRI data in the unprepared bowel in fasting and fed states. METHODS: Fifteen healthy volunteers underwent a baseline MRI scan after which they consumed a 400 g soup. Subjects then underwent a postprandial scan followed by further scans at regular intervals. Small bowel motility was assessed using single-slice bTFE cine MRI. An optimized processing technique was used to generate motility data based on power spectrum analysis of voxel-signal changes with time. Interobserver variability (n = 15) and intra-observer (n = 6) variability were assessed. Changes in the motility index were compared between fasted and immediate postprandial state. KEY RESULTS: Excellent agreement between observers was seen across the range of motility measurements acquired, with intraclass correlation coefficient (ICC) of 0.979 (P < 0.0001) and Bland-Altman limits of agreement 95% CI: -28.9 to 45.9 au. Intra-observer variability was low with ICC of 0.992 and 0.960 (2 observers, P < 0.0001). Changes from the fasted to immediately postprandial state showed an average increase of 122.4% ± 98.7% (n = 15). CONCLUSIONS & INFERENCES: This optimized technique showed excellent inter and intra observer agreement. It was sensitive to changes in motility induced feeding. This technique will be useful to study contractile activity and regional patterns along the gastrointestinal tract under physiological conditions.

An Examination of Appetite and Disordered Eating in Active Crohn's Disease.

BACKGROUND: Crohn's disease [CD] patients suffer from nutritional deficiencies when in active disease. We aim to examine calorific intake, macronutrient choice, and disordered eating behaviour in patients with active CD. METHODS: CD patients with matched healthy volunteers [HV] were recruited. Active disease was defined by faecal calprotectin >250 µg/g, C-reactive protein 83.8 ± 47.1 mg/dL, or active disease seen on endoscopy or imaging. Symptoms were quantified by Harvey­Bradshaw Index [HBI]. Calorific intake was assessed by 24-h dietary recall. Disordered eating was assessed using validated questionnaires: Binge Eating Scale [BES]; Power of Food Scale [PFS]; Control of Eating Questionnaire [CoEQ]; Dutch Eating Behaviour Questionnaire [DEBQ]; and Three Factor Eating Questionnaire [TFEQ]. RESULTS: Totals of 30 CD (18 male[M]:12 female [F], age 32.3 ± 2.19 years, body mass index [BMI] 24.9 ± 0.8) and 31 matched HV [19 M:12 F, age 32.8 ± 2.0 years, BMI 24.7 ± 0.5] were recruited. Mean faecal calprotectin was 1032.5 ± 176 µg/g, C-reactive protein 8.38 ± 4.71 mg/dL, and HBI 4.8 ± 1. There were no significant differences in calorific intake between groups. Protein intake was lower in the CD cohort [p = 0.03]. Hospital Anxiety and Depression score was higher [p = 0.01] and CoEQ-Positive Mood [p = 0.001] lower in CD. CD patients were characterised by higher BES [p = 0.01] and lower CoEQ Craving Control [p = 0.027], with greater craving for Sweet [p = 0.043] and Savoury [p = 0.021] foods. PFS food Present [p = 0.005], DEBQ Emotional [p =< 0.001], and External Eating [p = 0.022] were significantly higher than among HV. CONCLUSIONS: Reduced protein consumption and more prevalent disordered eating behaviour traits were present in CD. Greater binge eating and decreased control of cravings may be attributed to lower mood and higher anxiety observed. Patients may benefit from stronger psychological support with firm dietetic advice for healthy eating.

Analysis of the causes of false negative and false positive results of preoperative axillary ultrasound in patients with early breast cancer - a single-centre study.

INTRODUCTION: Properly planned and performed diagnostic tests allow the optimal treatment option to be chosen for the patient. They also allow qualification for the correct surgical procedure. AIM OF THE STUDY: In this study we evaluated the clinical value of preoperative ultrasound scan (USS) testing performed during primary disease staging in patients with early breast cancer qualified to sentinel lymph node biopsy (SLNB). MATERIAL AND METHODS: The group of breast cancer patients who underwent SLNB from March 2012 to May 2013. As well as the standard procedure of the preoperative diagnostics model, in each patient the USS of axillary lymph nodes was performed additionally. The results were compared with the data from postoperative pathological reports. We attempted to define the factors influencing the possibility of obtaining false positive and false negative USS results. RESULTS: The analysis comprised 172 patients. In 14.4% of cases with normal USS result the pathological result was different from the expected one (pN1). In 42.3% of patients with suspicious axillary lymph nodes the result of the pathological report was positive. The sensitivity of the USS testing was 89.3%, and the specificity was 34.4%, PPV - 85.6%, NPV - 42.3%. CONCLUSIONS: Ultrasonographic assessment of axillary lymph nodes in breast cancer patients qualified for SLNB is a test with high sensitivity and high predictive value of the positive test result. The possibility of a result contrary to the actual nodal status may result primarily from the technical limitations of USS testing.

Diagnostic value of preoperative axillary lymph node ultrasound assessment in patients with breast cancer qualified for sentinel lymph node biopsy.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) is a standard procedure in the therapeutic management of patients with non-advanced breast cancer. AIM: To analyse the utility of ultrasound scan (USS) examination in the process of patient qualification for SLNB and to estimate the optimal time to perform USS in the clinical preoperational assessment of axillary lymph nodes. MATERIAL AND METHODS: A prospective analysis of 702 patients with invasive breast cancer treated with SLNB between 7.03.2012 and 27.05.2013 was performed. The patients were divided into three groups: I (USS < 8 weeks before SLNB), II (USS > 8 weeks before SLNB and another one on the day before SLNB) and III (USS > 8 weeks before SLNB without perioperative USS). In these patients the percentage of metastases in the sentinel lymph node and the clinical factors influencing the diagnostic value of preoperative ultrasound scan were assessed. RESULTS: Metastatic lesions in sentinel lymph nodes were found in 154 (21.9%) patients. The highest percentage of metastases was noted in patients operated on in the second and third month from the beginning of preoperative diagnostics. None of the factors tested (size of the original tumour, histological malignancy grading, kind of preoperative diagnostics, Ki-67 value, biological type of the tumour, age) had a statistically significant influence on the diagnostic value of perioperative USS examination in the analysed time span. CONCLUSIONS: The lowest percentage of metastases in the sentinel lymph node was noted in the patients qualified for SLNB who had the ultrasound performed directly before the surgical procedure (not more than 4 weeks before the surgery).

Penetration of cotrimoxazole components into skin after a single oral dose. Theoretical versus experimental approach.

Concentrations of trimethoprim and sulfamethoxazole in plasma, cantharidin-induced skin blister fluid and theoretical peripheral compartment were determined in twelve male subjects suffering from bacterial skin diseases after a single oral dose of 0.32 g of trimethoprim and 1.6 g of sulfamethoxazole. Maximum trimethoprim concentrations of 8.5 +/- 1.1 micromol/l in plasma, 5.6 +/- 0.8 micromol/l in blister fluid and 5.8 +/- 2.2 micromol/l in theoretical peripheral compartment were found after 3 +/- 1, 7 +/- 2 and 9 +/- 6 h, respectively. Degree of penetration into blister fluid and theoretical peripheral compartment was 0.94 +/- 0.23 and 1.05 +/- 0.09, respectively. The differences between respective pharmacokinetic parameters of trimethoprim in blister fluid and theoretical peripheral compartment were statistically insignificant. Maximum sulfamethoxazole concentrations of 295 +/- 47 micromol/l in plasma, 182 +/- 46 micromol/l in blister fluid and 239 +/- 58 micromol/l in theoretical peripheral compartment were found after 3 +/- 1, 8 +/- 2 and 7 +/- 4 h, respectively. Degree of penetration into blister fluid and theoretical peripheral compartment was 0.82 +/- 0.20 and 1.04 +/- 0.02, respectively. In contrast to trimethoprim, the differences between respective pharmacokinetic parameters of sulfamethoxazole in blister fluid and theoretical peripheral compartment, except time to maximum concentration, were statistically significant. Cantharidin-induced skin blister fluid method can be used to estimate drug penetration into skin. Due to differences between the respective pharmacokinetic parameters in experimental and theoretical peripheral compartment, in some cases evaluation of drug penetration into skin should not be replaced by the theoretical peripheral compartment calculation.