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2022 ◽  
Vol 11 ◽  
Author(s):  
Nervana Hussien ◽  
Rasha S. Hussien ◽  
Darine Helmy Amin Saad ◽  
Mohamed El Kassas ◽  
Walid F. Elkhatib ◽  
...  

BackgroundBorderline Resectable Pancreatic Cancer (BRPC) remains a unique entity that is difficult to categorize due to variance in definitions and the small number of patients. The ultimate goal is to achieve a free resection (R0) after a favorable response to neoadjuvant therapy that is somewhat difficult to assess by current radiological parameters.AimTo evaluate the role of Magnetic Resonance Imaging (MRI) pancreatic protocol, including Diffusion-Weighted Imaging (DWI), in patients with BRPC receiving neoadjuvant therapy, and further compare it to RECIST criteria and outcome.MethodsHistologically confirmed BRPC patients were prospectively included. DWI-MRI was performed pre- and post-therapy. Clinical characteristics with ensuing operability were recorded and correlated to radiological RECIST/apparent diffusion coefficient (ADC) change, preoperative therapy administrated, surgical resection status, and survival.ResultsOut of 30 BRPC cases, only 11 (36.7%) ultimately underwent pancreaticoduodenectomy. Attaining a stationary or stable disease via ADC/RECIST was achieved in the majority of cases (60%/53.3% respectively). Of the 12 patients (40%) who achieved a regression by ADC, 11 underwent surgery with an R0 status. These surgical cases showed variable RECIST responses (PR=5, SD=4, PD=3). Responders by ADC to neoadjuvant therapy were significantly associated to presenting with abdominal pain (p =0.07), a decline in post-therapy CA19-9 (p<0.001), going through surgery (p<0.001), and even achieving better survival (p<0.001 vs. 0.66).ConclusionDWI-MRI ADC picked up patients most likely to undergo a successful operative procedure better than traditional RECIST criteria. An algorithm incorporating novel radiological advances with CA19-9 deserves further assessment in future studies.


2022 ◽  
Vol 8 ◽  
Author(s):  
Gaurav Tripathi ◽  
Sheetalnath Rooge ◽  
Manisha Yadav ◽  
Babu Mathew ◽  
Nupur Sharma ◽  
...  

Introduction: With the advent of direct-acting antiviral (DAA) therapy for HCV, the cure is achieved at similar rates among HIV–HCV coinfected patients as in HCV mono-infected patients. The present study evaluates host plasma metabolites as putative indicators in predicting the treatment response in baseline HIV–HCV patients.Methods: Non-cirrhotic HIV–HCV (N = 43) coinfected patients were treated with sofosbuvir and daclatasvir for 12 weeks. Plasma metabolite profiling of pre- and post-therapy was analyzed in 20/43 patients. Of the 20 selected, 10 (50%) attained the sustained viral response [(SVR) (responders)] as defined by the absence of HCV RNA at 12 weeks after the treatment, and 10 (50%) did not attain the cure for HCV (nonresponders).Results: A total of 563 features were annotated (metabolomic/spectral databases). Before therapy, 39 metabolites differentiated (FC ±1.5, p < 0.05) nonresponders from responders. Of these, 20 upregulated and 19 downregulated were associated with tryptophan metabolism, nicotinamide metabolism, and others. Post therapy, 62 plasma metabolites (12 upregulated and 50 downregulated, FC±1.5, p < 0.05) differentiated nonresponders from responders and highlighted a significant increase in the steroid and histidine metabolism and significant decrease in tryptophan metabolism and ascorbate and pyruvate metabolism in the nonresponders. Based on random forest and multivariate linear regression analysis, the baseline level of N-acetylspermidine (FC > 2, AUC = 0.940, Bfactor = −0.267) and 2-acetolactate (FC > 2, AUC = 0.880, Bfactor = −0.713) significantly differentiated between nonresponders from responders in HIV–HCV coinfected patients and was able to predict the failure of treatment response.Conclusion: Increased baseline levels of N-acetylspermidine and 2-acetolactate levels are associated with the likeliness of failure to attain the cure for HCV in HIV–HCV coinfected patients.


2022 ◽  
Author(s):  
Elizabeth Brooker

In the main research into cognitive anxiety has focused on the conscious mind. The aim of this chapter is to review two psychodynamic psychotherapies, cognitive hypnotherapy (CH) and eye movement desensitisation and reprocessing (EMDR). Both therapies focus on implicit or unconscious processes for the rapid relief of cognitive anxiety. The objective is to give credence to CH and EMDR both in the scientific and medical domains. The philosophy is concerned with changing negative cognitions and dysfunctional feelings through a process of desensitisation and reprocessing, utilising positive imagery. CH and EMDR were investigated in an intervention study with advanced pianists (n = 46). Participants were of mixed gender aged 18–26 and were randomly assigned to a therapy or control group. The therapy groups received two therapies of either CH or EMDR during a two week period between two concerts. Quantitative data were collected through the Spielberger State-Trait Anxiety Inventory. Results showed that both therapy groups (but not the control) experienced a significant reduction in state anxiety post-therapy and trait anxiety decreased significantly below baseline levels in the EMDR group. This chapter further reviews research into CH and EMDR documented through a case study allowing for qualitative assessment of the therapies where two sessions only were required to effect positive change.


Author(s):  
Kelly Patsy Flaminio ◽  
Sherry Cox ◽  
Katherine Haman ◽  
Matthew Allender ◽  
Bethany Groves ◽  
...  

The Northwestern pond turtle ( Actinemys marmorata ) is native to Washington State, USA and has developed a grossly evident form of shell disease affecting a large percentage of the free-ranging population in this state. Emydomyces testavorans is a novel fungus in the order Onygenales that is the presumed causative agent for shell disease in the Northwestern pond turtle. Terbinafine hydrochloride is a lipophilic allylamine broad spectrum antifungal that penetrates keratin and concentrates in the stratum corneum. This study evaluated the drug concentration in the plasma and keratin of 18 Northwestern pond turtles after nebulization with 18 mg terbinafine solution (2 mg/ml) once a day for 28 days. Blood and keratin samples were collected serially during the course of treatment, and for 14 days following the last dose. Plasma and keratin were analyzed by high-performance liquid chromatography. No significant concentrations of terbinafine were found in the plasma of the turtles. Terbinafine in turtle keratin peaked after 16 days of treatment and maintained therapeutic concentrations for 14 days post treatment. Turtle shell lesions also showed signs of clinical improvement post-therapy. Nebulization of terbinafine is recommended for the treatment of shell disease secondary to Emydomyces testavorans , however pulse antifungal therapy is likely needed to prevent disease from reoccurring.


2021 ◽  
Vol 6 (2) ◽  
pp. 223
Author(s):  
Leni Ruslaini ◽  
Asri Arumsari ◽  
Abel Tasman ◽  
Kiki Akhmad Rizki

Background: Mandibular resection will cause mandibular stability disturbance due to loss of some part of the bone. Instability of the mandible can cause aesthetic, physiological, and psychological malfunction. Installment of mandibular reconstruction plat on the remaining mandibular using screws were suggested to restore its stability. However, it is not uncommon that plat exposure occurs following mandibular reconstruction, caused by inaccurate adaptation of the plats to the mandibular bone. The aims of this report are to describe the various complications and managements after jaw resection and reconstruction with plates. Case Report: A 44 years old male patient complained the small defect in the chin, painless, and no fluid emited, accompanied by dermatitis. Intra oral examination showed no abnormalities. About 1 year ago the patient performed segmental resection of the mandible on the indication of ameloblastoma. The radiological x-ray showed all screw detached from the plat and radiolucent images appeared around the plat that attached to the mandible. The diagnosis was fistula at regio mentale, post resection and reconstruction surgery, suspected caused by titanium plate allergies. The provided therapies were fistulectomy, screw removal, and plate reconstruction. Post therapy conditions showed improvement and no patients complaints of pain. Conclusion: Plate exposure is a complication that can occur after the installation of the reconstruction plate, but besides that it can also cause an allergic reaction from the material used. Keywords: Complication, Mandibular Resection, Plate Reconstruction, Titanium Plate Allergies


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 840-840
Author(s):  
Xu Ji ◽  
Xin Hu ◽  
Joseph Lipscomb ◽  
Ann Mertens ◽  
Sharon M. Castellino

Abstract Background: The Children's Oncology Group Long-Term Follow-up Guidelines recommend surveillance for late effects in pediatric cancer survivors based on therapeutic exposures. In particular, the Guidelines recommend an echocardiogram, or comparable imaging, every 2 to 5 years to evaluate cardiac function in survivors exposed to anthracycline chemotherapy. However, little is known about the real-world utilization of cardiac surveillance tests following the completion of cancer therapy. Objective: This study fills this gap by describing the proportion of anthracycline-treated survivors of pediatric cancer who received surveillance for cardiac function following the completion of their cancer therapy. Method : We developed an algorithm to identify a cohort of pediatric cancer survivors using the IBM MarketScan ® Commercial Claims and Encounters Database (a nationwide private insurance enrollment and claims database). The cohort for inclusion was enrollees who (1) received anthracycline for blood cancer (leukemia or lymphoma); (2) aged ≤21 years at cancer diagnosis; (3) completed all cancer therapy between 2009 and 2018; and (4) remained continuously insured for at least one year post-therapy. Outcomes assessed included the receipt of: (1) echocardiogram, (2) cardiac magnetic resonance imaging (MRI), (3) multiple gate acquisition (MUGA) scan, and (4) any of the aforementioned cardiac surveillance tests over the 5-year period after the completion of all cancer therapy. The Kaplan-Meier (K-M) method was used to estimate the cumulative incidence of an event post-therapy, where the event was defined as the initial healthcare claim for a cardiac surveillance test. Individuals were censored if they had not received a test by study termination or were lost to follow-up at any time during the 5 years post-therapy. Multivariate Cox proportional hazard models were estimated to identify the demographic and cancer-related factors strongly associated with the initial test receipt. Results : Among 1,914 eligible blood cancer survivors, 259 (13.5%) survivors received a hematopoietic stem cell transplantation (HSCT; Table 1). The K-M estimated probability of receiving a cardiac surveillance test by 5 years post-therapy was 61.0% (95% Confidence Interval [CI]: 57.2% to 64.7%), with the median time to the initial test being 2.6 years (95% CI: 2.2 to 3.1 years) from therapy completion. The vast majority of cardiac surveillance test users underwent an echocardiogram (n=850; versus only 10 who had a cardiac MRI, and 14 who had a MUGA scan) by the end of their follow-up period. The proportion of survivors who had an initial cardiac test increased over time but varied by age at cancer therapy completion and the receipt of HSCT. The K-M estimated probability of receiving an initial test by 5 years post-therapy was: 86.0% (95% CI: 77.3% to 91.6%) for children (ages ≤11 years), 85.0% (95% CI: 75.4% to 91.1%) for adolescents (ages 12-17 years), and 36.8% (95% CI: 32.6% to 41.0%) for young adults (ages 18-28 years; Figure 1). Multivariate Cox models showed that compared with children, adolescents were more likely to receive an initial cardiac test (Hazard Ratio [HR] = 1.3; 95% CI: 1.1 to 1.5), while young adults were less likely to receive a test (HR = 0.4; 95% CI: 0.3 to 0.5). In addition, survivors who received a HSCT were more likely than those who did not to complete an initial cardiac test (HR=1.8; 95% CI: 1.5 to 2.2). Conclusions: This nationwide, claims data-based study showed that a substantial proportion of anthracycline-exposed survivors of blood cancers had not completed a cardiac surveillance test within 5 years post-therapy. Within this high-risk population, young adults were significantly less likely to receive surveillance testing for the prevention and early detection of cardiac dysfunction. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi217-vi217
Author(s):  
David James ◽  
Craig Horbinski ◽  
Roger Stupp ◽  
Atique Ahmed

Abstract PURPOSE Post-therapy recurrent glioblastoma (GBM) patient-derived xenografts (PDX), developed from corresponding treatment-naïve PDX, could serve as useful resources for identifying therapeutics with activity against recurrent GBM. The goal of this study was to determine whether treatment-naïve intracranial GBM PDX, in mice receiving radiotherapy (RT) and/or temozolomide (TMZ), acquire the same mutations that occur in post-RT+TMZ GBMs from patients. METHODS Luciferase-modified, treatment-naïve GBM PDX were engrafted in the brains of athymic nude mice, followed by treatment with RT only (2 Gy/day x 5), TMZ only (10 mg/kg/day x 5), or RT+TMZ. Bioluminescence imaging was used to monitor intracranial tumor growth, response to treatment, and recurrence from treatment. Some mice with recurrent tumors received additional TMZ treatment. When mice became symptomatic, intracranial tumors were resected and engrafted subcutaneously in a new mouse host, then sequentially propagated subcutaneously into additional host mice. After the third passage, whole-exome sequencing (WES) was done, comparing post-therapy with treatment-naïve PDX sequence variants. RESULTS Analysis of PDX WES showed the following: 1) TMZ consistently caused more genes to incur coding sequence mutations than RT, as much as 13x more; 2) TMZ-treated tumor mutations were mostly G-C to A-T transitions (71-92%), consistent with the known mutagenic effect of TMZ; and 3) post-therapy PDX acquire similar mutations as do recurrent GBMs in patients, for example involving DNA mismatch repair gene MSH6. One of the derivative PDX with MSH6 mutation has been retested for response to RT and TMZ, with results showing its having become TMZ, but not RT resistant. CONCLUSIONS The mutation profiles of RT+TMZ-treated PDX are similar to those reported for GBMs that recur after RT+TMZ in patients. The new PDX resources described here may prove useful for identifying effective treatments against recurrent GBM.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi72-vi72
Author(s):  
Helen Shih ◽  
Shervin Tabrizi ◽  
Brian Kabat ◽  
Erin Twohy ◽  
Susan Geyer ◽  
...  

Abstract PURPOSE Standard of care for craniopharyngiomas is surgery with or without radiotherapy (RT). Cohort A of Alliance A071601 evaluated the efficacy of BRAF/MEK inhibition with vemurafenib/cobimetinib in patients with previously untreated papillary craniopharyngiomas (PCP), which carry the BRAF V600E mutation. Cohort B is currently enrolling patients with recurrence after RT. In a correlative analysis, we examined changes in RT volumes after BRAF/MEK therapy in Cohort A. METHODS Previously unirradiated patients with BRAF-mutated PCP were treated with vemurafenib/cobimetinib. Sixteen patients had scans available before starting vemurafenib/cobimetinib (“pre-therapy”) and after completing therapy (“post-therapy”). Two patients went off study treatment after 8 and 9 days due to side-effects and were excluded for this analysis. Gross target volumes (GTV) were contoured on pre-therapy and post-therapy scans. On post-therapy scans, an additional target comprising gross disease and at-risk regions for microscopic residual disease (GTV-micro) was defined and considered the treatment volume. Clinical target volume (CTV) was a 5-mm uniform expansion on pre-therapy GTV and post-therapy GTV-micro. Volumes were independently reviewed by two radiation oncologists. Changes in volumes from pre- versus post-therapy were compared using the Wilcoxon signed rank test. RESULTS In 14 patients evaluated, 57% were female and median age at enrollment was 49.5 years (range 33-83). Median time on treatment was 8.9 months (range 4.0-18.0). Median GTV pre-therapy was 3.8 mL (range 0.2-23.4) versus 0.3 mL (range 0.0-3.2) post-therapy (p=0.0001) and 1.7 mL (range 0.1-8.0) post-therapy GTV-micro (p=0.0001). Median CTV pre-therapy was 13.7 mL (range 2.8-51.8) versus 9.1 mL (range 2.2-27.5) post-therapy (p=0.0001). All tumors abutted the optic chiasm pre-therapy, only 6 did post-therapy. CONCLUSIONS Vemurafenib/cobimetinib resulted in smaller RT volumes. BRAF/MEK inhibitors could reduce RT volumes and spare dose to surrounding normal structures. Enrollment to Cohort B of Alliance A071601 should be considered for patients with recurrent tumors after RT. SUPPORT https://acknowledgments.alliancefound.org


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi81-vi82
Author(s):  
Ella Perrault ◽  
Jack Shireman ◽  
Peiyu Lin ◽  
Eunus Ali ◽  
Andrew Zolp ◽  
...  

Abstract Glioblastoma (GBM) remains one of the most resistant and fatal forms of cancer. Previous studies examine pre- and post-tumor recurrence; however, it is incredibly difficult to study tumor evolution during therapy where resistance develops. To investigate this, our lab performed a single-cell RNA-sequencing screen before, during, and after temozolomide-based (TMZ) chemotherapy in a patient-derived xenograft (PDX) model in vivo. Our analysis found 149 genes uniquely expressed during TMZ-therapy compared to pre- and post-therapy (p< 0.0001). Of these, the ribonucleotide reductase (RNR) gene family stood out due to the preferential switch to Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) during therapy. Classically, RRM2, or its isoform RRM2B, forms a complex with RRM1 to create an RNR, mediating deoxynucleoside triphosphate (dNTP) production. Our single-cell data revealed that GBM cells rely on RRM1-RRM2 interaction during therapy, but switch to RRM1-RRM2B in post-therapy recurrent GBM. In vitro, RRM2-knockdown cells increased TMZ susceptibility, whereas RRM1- and RRM2B-knockdowns were more resistant to TMZ (p< 0.001). Immunocytochemistry found elevated yH2AX fluorescence in RRM2-knockdowns after TMZ treatment, signifying reduced DNA repair capacity compared to the control (p< 0.001). To understand the mechanism of RRM2-mediated chemoresistance, targeted metabolomics was applied to quantify dNTP signatures during TMZ-therapy. In response to TMZ, dCTP and dGTP production in GBM cells increased 100-fold and 80-fold respectively (p< 0.001). RRM2-knockdowns produced significantly less dCTP and dGTP (p< 0.0001). By supplementing RRM2-knockdowns with dCTP and dGTP, TMZ-susceptibility was rescued, suggesting that RRM2 drives chemoresistance by promoting production of these two nucleotides. In vivo, following intracranial injection of GBM cells, mice treated with the RRM2 inhibitor Triapine with TMZ survived longer than those treated with TMZ alone, indicating promising clinical opportunities in targeting RRM2 (p< 0.0001). Overall, our data present a novel understanding of how RRM2 activity is altered during therapeutic stress to counteract TMZ-induced DNA damage.


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