Oncology precision medicine for hepatobiliary and pancreatic cancer: An institutional review.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14626-e14626
Author(s):  
Geoffrey Bellini ◽  
Jennifer Jo Godden ◽  
James L. Weese ◽  
Aaron Chevinsky ◽  
Wesley Allan Papenfuss ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Genetic Alterations ◽  
Molecular Testing ◽  
Cancer Type ◽  
Extrahepatic Cholangiocarcinoma ◽  
Term Outcome ◽  
Primary Tumors ◽  
Long Term Outcome ◽  
Molecular Alterations ◽  
Number Of Patients

e14626 Background: Hepatobiliary cancers - hepatocellular carcinoma (HCC), intra or extrahepatic cholangiocarcinoma (I/EC), and gallbladder carcinoma (GB) - and pancreatic adenocarcinoma (PC) remain a leading cause of death with little improvement in long-term outcome. Recent studies have suggested that these cancers harbor actionable mutations to varying degrees. The aim of our study was to examine the number of patients (Pts) with these primary tumors who underwent molecular testing in a large vertically integrated health system. Subsequently, we analyzed the percentage of that population who may be candidates for oncology precision medicine (OPM) directed therapy. Methods: We identified Pts with HCC, IC, EC, GB in an IRB reviewed OPM database of our system over a one year period. Pts who underwent molecular panel testing were selected out, and their molecular alterations were identified and stratified by cancer type. Results: 304 total Pts were identified. 61 (20%) underwent molecular testing broken down as follows: 17/132 (13%) I/EC and HCC, 3/11 (27%) GB, and 41/161 (25%) PC. Quantity not sufficient for testing was in 10/61 (16%), of which 5/10 (50%) were resubmitted and tested successfully. 6/61 (10%) were cancelled or deemed not appropriate. Test recommended potential actionability was 8/17 (47%) of I/EC and HCC, 2/3 (67%) of GB, and 25/41 (61%) of PC. Conclusions: OPM is a dynamic area of increasing testing and learning. We found 13-27% of hepatobiliary and pancreatic Pts had molecular testing, which suggests the potential to increase molecular screening for this difficult group of tumors. Total genetic alterations (TGA) and clinically relevant genomic alterations (CRGA) per patient are similar to Ross et al. ( http://ow.ly/k52a30nBMnU ) for GB. Final interpretation regarding pragmatic actionability (patient on drug) and clinical outcomes are still under investigation.[Table: see text]

Oncology precision medicine for hepatobiliary and pancreatic cancer: Insights and updates upon an institutional review.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 570-570
Author(s):  
Geoffrey Bellini ◽  
Nicholas Sich ◽  
Jennifer Jo Godden ◽  
James L. Weese ◽  
Wesley Allan Papenfuss ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Precision Medicine ◽  
Braf Mutation ◽  
Brca Mutation ◽  
Progression Free Survival ◽  
Systematic Evaluation ◽  
Molecular Testing ◽  
Cancer Type ◽  
Extrahepatic Cholangiocarcinoma ◽  
Free Survival

570 Background: Hepatobiliary cancers - hepatocellular carcinoma (HCC), intra or extrahepatic cholangiocarcinoma (I/EC), and gallbladder carcinoma (GB) - and pancreatic adenocarcinoma (PC) do have actionable alterations (AA). The importance of testing early in a patient’s (pts) course to identify oncology precision medicine (OPM) options could be paramount for progression free survival (PFS). Methods: We identified pts with HCC, IC, EC, GB or PC in our OPM database since the centralization of our system. Pts who underwent molecular panel testing had AA’s identified and stratified by cancer type. Treatment course was analyzed using swimmers plots. Results: 456pts were diagnosed with HCC, IC, EC, GB or PC. 104/456pts (23%) were ordered for molecular testing and 88/456pts (19.3%) completed testing: 18/88pts (20.4%) I/EC, 2/88pts (2.3%) HCC, 5/88pts (5.7%) GB, and 63/88pts (71.6%) PC. Of the PC pts, 3/63 (4.8%) had a BRCA mutation. These pts did not receive targeted therapy. Overall, 5/88pts (5.7%) had a BRAF mutation (2 PC, 2 I/EC, 1GB). Thus, 8/88 (9.1%) of tested pts became eligible for some form of targeted therapy over their treatment course. Of those with a BRAF mutation, only 2/5 pts had OPM testing sent with initial diagnostic workup, and 2/5 eventually began targeted therapy. One had a progression free survival (PFS) of 2.5months while the other discontinued secondary to toxicity. Conclusions: Our data showed that we are testing a minority of pts with pancreas and hepatobiliary cancers. Of those tested, it may have occurred too late in the course of illness to improve outcomes. Given the potential utility of uncovering potential germline alterations like BRCA1/2 as well as pragmatic AAs including somatic BRCA and BRAF, we are moving to a more systematic evaluation of pts to capture and respond to these issues. [Table: see text]

scholarly journals Bayesian adaptive design of early-phase clinical trials for precision medicine based on cancer biomarkers

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shinjo Yada
Keyword(s):  
Neural Network ◽  
Clinical Trials ◽  
Precision Medicine ◽  
Early Phase ◽  
Patient Specific ◽  
Specific Gene ◽  
Cancer Type ◽  
Background Characteristics ◽  
Number Of Patients ◽  
Early Phase Clinical Trials

Abstract Cancer tissue samples obtained via biopsy or surgery were examined for specific gene mutations by genetic testing to inform treatment. Precision medicine, which considers not only the cancer type and location, but also the genetic information, environment, and lifestyle of each patient, can be applied for disease prevention and treatment in individual patients. The number of patient-specific characteristics, including biomarkers, has been increasing with time; these characteristics are highly correlated with outcomes. The number of patients at the beginning of early-phase clinical trials is often limited. Moreover, it is challenging to estimate parameters of models that include baseline characteristics as covariates such as biomarkers. To overcome these issues and promote personalized medicine, we propose a dose-finding method that considers patient background characteristics, including biomarkers, using a model for phase I/II oncology trials. We built a Bayesian neural network with input variables of dose, biomarkers, and interactions between dose and biomarkers and output variables of efficacy outcomes for each patient. We trained the neural network to select the optimal dose based on all background characteristics of a patient. Simulation analysis showed that the probability of selecting the desirable dose was higher using the proposed method than that using the naïve method.

scholarly journals Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma

2021 ◽  
Vol 28 (5) ◽  
pp. 337-351
Author(s):  
Adam Stenman ◽  
Samuel Backman ◽  
Klara Johansson ◽  
Johan O Paulsson ◽  
Peter Stålberg ◽  
...  
Keyword(s):  
High Risk ◽  
Single Case ◽  
Papillary Thyroid ◽  
Fusion Event ◽  
Term Outcome ◽  
Primary Tumors ◽  
Long Term Outcome ◽  
Regulatory Pathways ◽  
Genomic Landscape ◽  
Gene Fusion Event

Pediatric papillary thyroid carcinomas (pPTCs) are often indolent tumors with excellent long-term outcome, although subsets of cases are clinically troublesome and recur. Although it is generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and -transcriptome sequencing. Primary tumors and their metastatic components displayed an exceedingly low number of coding somatic mutations and gross chromosomal alterations overall, with surprisingly few shared mutational events. Two cases exhibited one established gene fusion event each (SQSTM1-NTRK3 and NCOA4-RET) in both primary and metastatic tissues, and one case each was positive for a BRAF V600E mutation and a germline truncating CHEK2 mutation, respectively. One single case was without apparent driver events and was considered as a genetic orphan. Non-coding mutations in cancer-associated regions were generally not present. By expressional analyses, fusion-driven primary and metastatic pPTC clustered separately from the mutation-driven cases and the sole genetic orphan. We conclude that pPTCs are genetically indolent tumors with exceedingly stable genomes. Several mutations found exclusively in the metastatic samples which may represent novel genetic events that drive the metastatic behavior, and the differences in mutational compositions suggest early clonal divergence between primary tumors and metastases. Moreover, an overrepresentation of mutational and expressional dysregulation of immune regulatory pathways was noted among fusion-positive pPTC metastases, suggesting that these tumors might facilitate spread through immune evasive mechanisms.

scholarly journals Progress in Rectal Cancer Treatment

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Wim P. Ceelen
Keyword(s):  
Rectal Cancer ◽  
Neoadjuvant Therapy ◽  
Imaging Techniques ◽  
Dramatic Improvement ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Number Of Patients ◽  
Systemic Relapse ◽  
Selection Of Patients ◽  
Selection Of

The dramatic improvement in local control of rectal cancer observed during the last decades is to be attributed to attention to surgical technique and to the introduction of neoadjuvant therapy regimens. Nevertheless, systemic relapse remains frequent and is currently insufficiently addressed. Intensification of neoadjuvant therapy by incorporating chemotherapy with or without targeted agents before the start of (chemo)radiation or during the waiting period to surgery may present an opportunity to improve overall survival. An increasing number of patients can nowadays undergo sphincter preserving surgery. In selected patients, local excision or even a “wait and see” approach may be feasible following active neoadjuvant therapy. Molecular and genetic biomarkers as well as innovative imaging techniques may in the future allow better selection of patients for this treatment option. Controversy persists concerning the selection of patients for adjuvant chemotherapy and/or targeted therapy after neoadjuvant regimens. The currently available evidence suggests that in complete pathological responders long-term outcome is excellent and adjuvant therapy may be omitted. The results of ongoing trials will help to establish the ideal tailored approach in resectable rectal cancer.

scholarly journals Long-Term Outcome Following Decompressive Craniectomy in Pediatric Penetrating Blast Brain Injury; a Prospective Study

2021 ◽  
Vol 8 (4) ◽  
Author(s):  
Seyed Amir Hossein Javadi ◽  
Parisa Balu ◽  
Fereshteh Naderi Behdani ◽  
Amir Hossein Orandi ◽  
Ehsan Ahmadipour ◽  
...  
Keyword(s):  
Brain Injury ◽  
Decompressive Craniectomy ◽  
Early Death ◽  
Motor Deficits ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Number Of Patients ◽  
Secondary Injuries ◽  
A Prospective Study

Background: Brain penetrating blast injury is a leading cause of early death due to excessively elevated intracranial pressure (ICP), culminating in trans-tentorial herniation. The role of craniectomy to decrease ICP and secondary injuries has been controversial particularly in pediatric patients. Three cases of pediatric penetrating blast injuries undergoing decompressive craniectomy are reported in Methods: The current study was a prospective series, including fifteen cases of pediatric blast-related brain injury referred to the emergency ward during a period of two years. Three survived patients had a Glasgow Coma Scale (GCS) of four along with anisocoric pupillary light reflex (PLR). Decompressive craniectomy and ventriculostomy (EVD) were performed. The patients underwent ICP monitoring for two weeks. Results: Early postoperative GCS (5 days) was 7/15 in all three patients. Two weeks and one month’s GCS were 9 and 14, respectively. After three months, cranioplasty was performed. Long-term follow-up detected no major motor deficits after one year and was associated with excellent school performance. Neuroplasticity resulted in contralateral dominancy and handedness in one case. Conclusions: Survivors of pediatric blast brain injury had a favorable outcome after decompressive craniectomy in the current paper. However, there was a limited number of patients, and the results could not be generalized. Further research in this regard with larger sample size is recommended.

Next-generation sequencing (NGS) in metastatic gastrointestinal cancer (mGIC) patients: Translation from sequence data into clinical practice.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 72-72 ◽  
Author(s):  
Raphael Brandao Moreira ◽  
Matheus Bongers Alessandretti ◽  
Carina Mina Abrahao ◽  
Aline Da Rocha Lino ◽  
Tarcia Tarciane Soares de Sousa ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Gastrointestinal Cancer ◽  
Sequence Data ◽  
Performance Status ◽  
Objective Response ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Primary Tumors ◽  
Mutational Profiling ◽  
Number Of Patients

72 Background: A considerable number of patients with mGIC progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with the use of a NGS platform in refractory mGIC and its clinical utility. Methods: We retrospectively reviewed demographics, NGS results, and the suggested therapies received by patients undergoing NGS (Foundation Medicine, Cambridge, MA, USA): exonic sequencing of 236 genes and selective intronic sequencing from 19 genes for refractory mGIC. Co-primary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage of them who received genotype-directed therapy. Results: Samples from 32 patients were tested. Primary tumors consisted of colorectal adenocarcinoma (37,5%), pancreatic adenocarcinoma (31,2%), gastric adenocarcinoma (12,5%), cholangiocarcinoma (12,5%) and hepatocellular carcinoma (6%). Most patients (87,5%) were found to harbor potentially actionable genetic alterations involving mitogen-activated protein kinase (93,7%), phosphatidylinositol 3-kinase-AKT (18,7%), p53 (50%) and cell-cycle regulation (9%) pathways. Of the 6 patients who received the suggested targeted therapy, 4 achieved an objective response. Conclusions: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in the majority of advanced gastrointestinal cancer patients. The assay provided clinical benefit in 12% of the patients.

Clinical utility of molecular testing to select therapy in relapsed/refractory non-Hodgkin lymphoma: Mayo Clinic Center for Individualized Medicine experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11571-11571
Author(s):  
Nabila Nora Bennani ◽  
Stephen Maxted Ansell ◽  
Thomas E. Witzig ◽  
Andew L. Feldman ◽  
Tammy M McAllister ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Targeted Therapy ◽  
Precision Medicine ◽  
Mayo Clinic ◽  
Individualized Medicine ◽  
Tumor Board ◽  
Current Therapy ◽  
Molecular Profile ◽  
Molecular Testing ◽  
Molecular Alterations

11571 Background: Relapsed/refractory (R/R) non-Hodgkin lymphomas (NHL) have a poor prognosis with limited treatment options. Our expanding knowledge of molecular alterations seen in R/R NHL allows identification of patients that potentially may benefit from a precision medicine approach. However, experience in routine clinical implementation of precision medicine has been limited. Here, we summarize our clinical experience in molecular characterization of RR NHL targeted therapy (TT) using next-generation sequencing (NGS), and selection of targeted therapy (TT) based on molecular profile. Methods: We conducted a prospective study in RR NHL through the Center for Individualized Medicine at Mayo Clinic. Consenting patients underwent NGS using FoundationOne Heme panel from biopsies done at time of relapse. Results of NGS were discussed at the Genomic Tumor Board and recommendations for TT were given based on matching specific molecular alteration(s) with potential agent(s) predicted to be active based on NGS. The agents could include FDA-approved, off-label use and clinical trial therapies. Results: 28 cases were enrolled: 18 aggressive NHL, 10 follicular lymphoma (FL). Molecular alterations were present in all cases. In aggressive B-cell NHL, CDKN2A/B gene cluster alterations were seen in 73% (8/11), while seen in only 1/7 T-cell lymphomas (TCL), and 1/10 FL. TP53 deletions were second most common genomic alterations in DLBCL (57%) and seen in 40% FL. JAK-STAT and ERBB pathways were altered in TCL (2/7 each). IGH-BCl-2 gene rearrangement were common in FL (70%), followed by MLL gene alterations (50%). Targetable mutations were present in 86% (24/28) of cases. A TT was recommended in all 24 cases, but received by 2 patients only. Remaining patients did not due to benefit from current therapy (10/24), ineligibility or lack of clinical trial (7/24) or interim clinical deterioration (5/24). Conclusions: Targetable mutations were identified in most cases of RR NHL with TT recommended for all cases. However, access to TT limits potential clinical benefit of molecular-based matching strategy. More studies are needed to assess impact on clinical outcomes.

scholarly journals Long term outcome for onabotulinumtoxinA (Botox) therapy in chronic migraine: A 2-year prospective follow-up audit of patients attending the Hull (UK) migraine clinic

2021 ◽  
Vol 4 ◽  
pp. 251581632098544
Author(s):  
Fayyaz Ahmed ◽  
Alina Buture ◽  
Taukir Tanvir ◽  
Modar Khalil
Keyword(s):  
Chronic Migraine ◽  
Real World ◽  
Episodic Migraine ◽  
Sustained Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Large Patient ◽  
Number Of Patients

Objective: The objective of this prospective audit was to determine the long term outcome of patients diagnosed with chronic migraine who were treated with onabotulinumtoxinA for the prevention of chronic migraine. Background: While long term and real-world studies have confirmed the safety and efficacy of onabotulinumtoxinA in CM, there remains limited information from large patient numbers on the number of cycles and duration of onabotulinumtoxinA needed to successfully convert chronic migraine to episodic migraine, development of resistance to treatment and sustainability of response after stopping treatment. Methods: A total of 655 adult patients diagnosed with chronic migraine who received onabotulinumtoxinA at the Hull Migraine Clinic were followed up prospectively for a minimum of 2 years. OnabotulinumtoxinA was delivered as per the PREEMPT study protocol and patients were asked to keep a headache diary for at least 30 days prior to and continuously after receiving onabotulinumtoxinA. The primary outcome assessed in this prospective real-world audit was either the number of patients who achieved a ≥50% reduction in headache days or migraine days or an increment in crystal clear days twice that of baseline in a 30-day period. Patients were also assessed for analgesic medication overuse. Results: Treatment data were available for 655 patients who commenced treatment between July 2010 and October 2016 and followed for at least 2 years (24–70 months), with the last follow-up taking place in September 2018. Of the 655 patients, 380 patients responded to treatment after two cycles and went on to receive the third cycle. Of these, 152 patients were still on active treatment at 2 years. A further 61 patients had relapsed and were on treatment at 2 years. Of the 228 patients who stopped treatment, 112 were successfully converted to episodic migraine and showed a sustained response, 28 reverted to chronic migraine after the initial response despite continuing treatment (developed resistance), 14 were lost to follow up and 61 patients after achieving remission relapsed after a mean of 9 months (range 4–24 months) and recommenced treatment with onabotulinumtoxinA. Conclusion: After a minimum of 2 years, 29.4% of patients with chronic migraine who initially responded to treatment were successfully converted to episodic migraine and maintained a sustained response. Forty percent of the initial cohort of responders continued therapy with onabotulinumtoxinA to manage their chronic migraine.

scholarly journals Long-Term Outcome of Screening for Polyoma Bk Virus Infection in Kidney Transplant Recipients

2013 ◽  
Vol 67 (1) ◽  
pp. 47-51
Author(s):  
Ieva Ziediņa ◽  
Svetlana Čapenko ◽  
Modra Murovska
Keyword(s):  
Serum Creatinine ◽  
Graft Function ◽  
Bk Virus ◽  
Kidney Transplant Recipients ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Qualitative Polymerase Chain Reaction ◽  
Group 4 ◽  
Number Of Patients ◽  
Group 2

BK virus (BKV) infection was studied prospectively in 50 unselected consecutive patients who had undergone kidney transplantation. Infection was monitored for one year after transplantation. Viral DNA in urine (viruria) and plasma (viremia) samples was detected by nested, qualitative polymerase chain reaction. BKV screening data was available for 92% (n = 46) of patients enrolled in the study. Four groups of patients were distinguished: uninfected patients (group 1, n = 30), patients with viruria (group 2, n = 3), patients with viremia (group 3, n = 6) and patients with developed BKV nephropathy (group 4, n = 7). Infection was observed starting form the first month, and the maximum number of patients with active BKV infection occurred at six months after transplantation. Five-year graft survival was 69% for patients with any evidence of BKV infection, compared with 80.0% (P = NS) for patients without BKV infection. The best graft function was observed in group one patient (mean serum creatinine 130 mkmol/l and glomerular filtration rate (GFR) 60.9 ml/min) and the worst in group 4 (mean serum creatinine 180 mkmol/l and GFR 52.31 ml/min) at five years after transplantation. Five-year patient survival was 82.6% and was not affected by presence of BKV infection.

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