Homologous recombination proficiency in ovarian and breast cancer patients

AbstractHomologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi’s. Finally, standard of care treatment and synthetic lethality will be reviewed.

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P14.90 Survival outcomes and prognostic factors in glioblastoma patients treated with radiotherapy plus concomitant and adjuvant temozolomide - real-world study

Neuro-Oncology ◽

10.1093/neuonc/noab180.192 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii55-ii55

Author(s):

M J Sousa ◽

J Magalhães ◽

R Basto ◽

C Costa ◽

A Pego ◽

...

Keyword(s):

Survival Rate ◽

Progression Free Survival ◽

Standard Of Care ◽

Rank Test ◽

Survival Outcomes ◽

Hematologic Toxicity ◽

Current Standard ◽

Adjuvant Temozolomide ◽

Standard Of Care Treatment ◽

Ecog Ps

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour in adults. The current standard of care for newly diagnosed GBM is maximal surgical resection, followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ). This study aimed to evaluate the survival outcomes and identify predictors of survival among these patients. MATERIAL AND METHODS We performed a single-centre retrospective analysis of GBM patients treated with radiotherapy plus concomitant and adjuvant TMZ from 2013 to 2020. The analyses of progression-free survival (PFS) and overall survival (OS), each one evaluated starting from initial diagnosis, were performed. Survival curves were estimated with the Kaplan- Meier method and compared using the log-rank test. RESULTS Fifty-eight patients were identified. The median age was 61 years (range 18- 80), 51 (88%) patients were in ECOG-PS 0–1, 6 (10%) patients had isocitrate dehydrogenase (IDH) mutation and 53 (91%) of patients had undergone debulking surgery. At a median follow-up of 21 months, median OS was 12.8 months (95% confidence interval [CI] 9.7–15.9), whereas median PFS was 9.5 months (95% CI 8.5–10.5). The 1-year survival rate was 42% and the 2-year survival rate was 10%. Grade 3 or 4 hematologic toxicity occurred in 11 (19%) patients. Twenty-five (42%) patients completed at least 6 cycles of TMZ monotherapy with statistically significant differences between this sub-group and those who weren’t able to continue TMZ monotherapy [median OS 19.3 months (95% CI 14.4–24.2) vs 10.6 months (95% CI 7.8–13.4) p<0.001]. ECOG-PS = 0 [median OS 16.7 months (95% CI 13.4–20.0, p=0.001)] and patients under 65 years of age [median OS 15.6 months (95% CI 12.3–18.9, p=0.02) were associated with significantly better median OS. CONCLUSION The current standard of care treatment for GBM remains poor. An important factor predictor of survival is the completion of the 6 maintenance cycles of TMZ. At baseline, ECOG PS and the patient’s age could be used to define patient prognosis.

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RARE-09. CYSTIC GLIOBLASTOMA PRESENTATION AS A BENEFICIAL PROGNOSTIC INDICATOR FOR OVERALL SURVIVAL

Neuro-Oncology ◽

10.1093/neuonc/noz175.932 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi223-vi223

Author(s):

Lee Curtin ◽

Paula Whitmire ◽

Cassandra Rickertsen ◽

Peter D Canoll ◽

Maciej Mrugala ◽

...

Keyword(s):

Overall Survival ◽

Survival Benefit ◽

Standard Of Care ◽

Prognostic Impact ◽

Current Standard ◽

Significant Survival Benefit ◽

Care Treatment ◽

Significant Survival ◽

Cystic Component ◽

Standard Of Care Treatment

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a median overall survival of 15 months with standard-of-care treatment. GBM patients sometimes present with a cystic component, which can be identified through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7–22% of GBM patients and have reported mixed results regarding whether cystic GBM have a survival benefit compared to noncystic GBM. Using our large retrospective cohort of 493 first-diagnosis GBM patients, we aim to elucidate this link between cystic GBM and survival. Within this cohort, 88 patients had a significant cystic component at presentation as identified on MRI. Compared to noncystic GBM (n=405), cystic GBM patients had significantly better overall survival (15 vs 22 months median, log-rank, p=0.001) and were significantly younger at the time of presentation (t-test, p=0.002). However, within patients that received current standard-of-care treatment (n=184), cystic GBM (n=40) was not as beneficial for outcome (22 vs 25 months, log-rank, p=0.3). We also did not observe a significant survival benefit when comparing this standard-of-care cystic cohort to cystic GBM patients diagnosed before the standard was established (n=19, 25 vs 23 months, log-rank, p=0.3), but the analogous result for noncystic GBM patients gives a sizeable benefit, as expected (n=144, n=111, respectively, 22 vs 12 months, log-rank p < 0.0001). Together, these results on current standard-of-care may explain later studies that note no significant survival benefit for cystic GBM patients receiving current standard-of-care. We also report differences in the absolute and relative sizes of imaging abnormalities on MRI and in prognostic impact of cysts based on sex. We discuss current hypotheses for these observed differences, including the possibility that the presence of a cyst could be indicative of a less aggressive tumor.

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Abstract WP32: Introducing STAR: A Multicenter International Collaborative Registry of Real-World Outcomes After Mechanical Thrombectomy for Ischemic Stroke

Stroke ◽

10.1161/str.51.suppl_1.wp32 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Ali M Alawieh ◽

Shakeel Chowdhry ◽

Italo Linfante ◽

Jonathan Grossberg ◽

Benjamin Gory ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Real World ◽

Mechanical Thrombectomy ◽

Standard Of Care ◽

Outcome Data ◽

Treatment Level ◽

Current Standard ◽

Anterior Circulation ◽

Standard Of Care Treatment

Introduction: Mechanical thrombectomy (MT) for acute stroke is the current standard of care treatment. Level 1 evidence for efficacy of thrombectomy has been established in multiple randomized controlled trials on selective patient populations; however, the high effect size of MT had led multiple centers in the US and globally to expand their patient selection to include populations that were not studied in major trials. To provide ongoing data on MT outcomes in different patient populations from the real-world, we have initiated an international multicenter initiative, STAR (Stroke Thrombectomy and Aneurysm Registry). Methods: STAR is a multicenter and international platform to curate patient outcome data after MT for acute ischemic stroke at comprehensive stroke centers. STAR includes all patients who underwent MT for acute ischemic stroke irrespective of age, time from onset, ASPECT score, and NIHSS. Patients were curated from 01/2015 to date and is prospectively maintained. Patient charts are reviewed for demographics, baseline functioning, and admission deficits. Procedure notes are reviewed for technical variables and technical outcomes. Clinical outcomes were collected at 90-day follow-up by stroke neurologist. Results: A total of 24 centers globally have enrolled in STAR. By December 2018, the total number of enrolled and verified patients in STAR was 3,850 (mean age 69±14, 51% females). Anterior circulation strokes were treated in 89% of cases, average NIHSS on admission was 15.5±7, and 73% had pre-stroke mRS below 2. Around 51% of patients received IV-tPA. Mechanical thrombectomy was performed using aspiration (45%), stent retriever (28%), primary combined approach (24%) or intracranial stenting (3%). Successful recanalization was achieved in 84% of cases, the rate of favorable outcome (mRS 0-2) was 41%, and mortality was 25%. Complication rate was 6% and rate of symptomatic post-procedural hemorrhage was 6%. Conclusions: STAR represent a large real-world international registry for outcomes after MT, and constitutes a statistically robust platform to study real-world practice outcome in patient sub-populations that are under-represented in randomized trials. Link: https://medicine.musc.edu/departments/neurosurgery/star

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Updates on clinical trials evaluating the regenerative potential of allogenic mesenchymal stem cells in COVID-19

npj Regenerative Medicine ◽

10.1038/s41536-021-00147-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Dhavan Sharma ◽

Feng Zhao

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Mesenchymal Stem Cells ◽

Therapeutic Potential ◽

Adaptive Immune Response ◽

Standard Of Care ◽

Multiple Organ ◽

Current Standard ◽

Number Of Patients ◽

Standard Of Care Treatment

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected nearly 118 million people and caused ~2.6 million deaths worldwide by early 2021, during the coronavirus disease 2019 (COVID-19) pandemic. Although the majority of infected patients show mild-to-moderate symptoms, a small fraction of patients develops severe symptoms. Uncontrolled cytokine production and the lack of substantive adaptive immune response result in hypoxia, acute respiratory distress syndrome (ARDS), or multiple organ failure in severe COVID-19 patients. Since the current standard of care treatment is insufficient to alleviate severe COVID-19 symptoms, many clinics have been prompted to perform clinical trials involving the infusion of mesenchymal stem cells (MSCs) due to their immunomodulatory and therapeutic properties. Several phases I/II clinical trials involving the infusion of allogenic MSCs have been performed last year. The focus of this review is to critically evaluate the safety and efficacy outcomes of the most recent, placebo-controlled phase I/II clinical studies that enrolled a larger number of patients, in order to provide a statistically relevant and comprehensive understanding of MSC’s therapeutic potential in severe COVID-19 patients. Clinical outcomes obtained from these studies clearly indicate that: (i) allogenic MSC infusion in COVID-19 patients with ARDS is safe and effective enough to decreases a set of inflammatory cytokines that may drive COVID-19 associated cytokine storm, and (ii) MSC infusion efficiently improves COVID-19 patient survival and reduces recovery time. These findings strongly support further investigation into MSC-infusion in larger clinical trials for COVID-19 patients with ARDS, who currently have a nearly 50% of mortality rate.

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A Primer on the Current State-of-the-Science Neoadjuvant and Adjuvant Therapy for Patients with Locally Advanced Rectal Adenocarcinomas

International Journal of Surgical Oncology ◽

10.1155/2012/863034 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Jeffrey T. Yorio ◽

Nishin A. Bhadkamkar ◽

Bryan K. Kee ◽

Christopher R. Garrett

Keyword(s):

Adjuvant Therapy ◽

Locally Advanced ◽

Standard Of Care ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Current Standard ◽

Colon Cancers ◽

Standard Of Care Treatment ◽

Rectal Cancers ◽

State Of The Science

Patients with rectal cancers, due to the unique location of the tumor, have a recurrence pattern distinct from colon cancers. Advances in adjuvant therapy over the last three decades have played an important role in improving patient outcomes. This article serves to review the clinical studies that lay the basis for our current standard-of-care treatment of patients with locally advanced rectal cancer, as well as touch upon future ongoing experimental clinical trials of adjuvant chemoradiation therapy.

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Bevacizumab and etoposide combination chemotherapy in patients with recurrent malignant gliomas who failed bevacizumab

Drugs and Therapy Studies ◽

10.4081/dts.2012.e6 ◽

2012 ◽

Vol 2 (1) ◽

pp. 6

Author(s):

Beverly D. Fu ◽

Mark E. Linskey ◽

Daniela Annenelie Bota

Keyword(s):

Malignant Glioma ◽

Tumor Progression ◽

Malignant Gliomas ◽

Retrospective Chart Review ◽

Progression Free Survival ◽

Standard Of Care ◽

Current Standard ◽

Institutional Review ◽

Standard Of Care Treatment ◽

The University

Bevacizumab is the current standard of care treatment for recurring malignant glioma patients. However, most of the tumors become resistant to bevacizumab, and there is no standardized, effective chemotherapy for the malignant glioma patients after bevacizumab failure. Retrospective chart review was performed in order to identify the malignant glioma patients treated with oral, metronomic etoposide in combination with bevacizumab after being diagnosed with progressive disease while on bevacizumab. This review was approved by the Institutional Review Board (IRB) of the University of California, Irvine. Six malignant gliomas patients met the inclusion criteria. The median progression-free survival (PFS) for the anaplastic astrocytoma (AA) patients was eight months, and the overall survival was 28 months. The two Glioblastoma Multiforme (GBM) patients showed tumor progression after four to eight weeks of treatment with bevacizumab and etoposide, and died within four months of beginning the etoposide/bevacizumab regimen. In this limited study, patients with AA demonstrated prolonged control on combination treatment with bevacizumab and oral etoposide, despite initial tumor progression on bevacizumab. These results may warrant further investigation on a prospective clinical trial of this combination in AA patients who developed resistance to bevacizumab.

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Long Non-Coding RNA ANRIL as a Potential Biomarker of Chemosensitivity and Clinical Outcomes in Osteosarcoma

International Journal of Molecular Sciences ◽

10.3390/ijms222011168 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11168

Author(s):

Adam M. Lee ◽

Asmaa Ferdjallah ◽

Elise Moore ◽

Daniel C. Kim ◽

Aritro Nath ◽

...

Keyword(s):

Cell Lines ◽

Cancer Metastasis ◽

Treatment Resistance ◽

Standard Of Care ◽

Osteosarcoma Cell ◽

Current Standard ◽

Over Expression ◽

Non Coding Rna ◽

Potential Biomarker ◽

Standard Of Care Treatment

Osteosarcoma has a poor prognosis due to chemo-resistance and/or metastases. Increasing evidence shows that long non-coding RNAs (lncRNAs) can play an important role in drug sensitivity and cancer metastasis. Using osteosarcoma cell lines, we identified a positive correlation between the expression of a lncRNA and ANRIL, and resistance to two of the three standard-of-care agents for treating osteosarcoma—cisplatin and doxorubicin. To confirm the potential role of ANRIL in chemosensitivity, we independently inhibited and over-expressed ANRIL in osteosarcoma cell lines followed by treatment with either cisplatin or doxorubicin. Knocking-down ANRIL in SAOS2 resulted in a significant increase in cellular sensitivity to both cisplatin and doxorubicin, while the over-expression of ANRIL in both HOS and U2OS cells led to an increased resistance to both agents. To investigate the clinical significance of ANRIL in osteosarcoma, we assessed ANRIL expression in relation to clinical phenotypes using the osteosarcoma data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset. Higher ANRIL expression was significantly associated with increased rates of metastases at diagnosis and death and was a significant predictor of reduced overall survival rate. Collectively, our results suggest that the lncRNA ANRIL can be a chemosensitivity and prognosis biomarker in osteosarcoma. Furthermore, reducing ANRIL expression may be a therapeutic strategy to overcome current standard-of-care treatment resistance.

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The Role of PI3K Inhibition in the Treatment of Breast Cancer, Alone or Combined With Immune Checkpoint Inhibitors

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.648663 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zhizhu Zhang ◽

Ann Richmond

Keyword(s):

Breast Cancer ◽

Checkpoint Inhibitors ◽

Metastatic Breast ◽

Standard Of Care ◽

Pi3k Pathway ◽

Breast Cancer Patients ◽

Current Standard ◽

Development Of Resistance ◽

Pi3k Inhibition

Dysregulation of phosphoinositide 3-kinase (PI3K) signaling is highly implicated in tumorigenesis, disease progression, and the development of resistance to the current standard of care treatments in breast cancer patients. This review discusses the role of PI3K pathway in breast cancer and evaluates the clinical development of PI3K inhibitors in both early and metastatic breast cancer settings. Further, this review examines the evidence for the potential synergistic benefit for the combination treatment of PI3K inhibition and immunotherapy in breast cancer treatment.

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Endocrine Treatment for Breast Cancer Patients Revisited—History, Standard of Care, and Possibilities of Improvement

Cancers ◽

10.3390/cancers13225643 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5643

Author(s):

Naiba Nabieva ◽

Peter A. Fasching

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Hormone Receptor ◽

Standard Of Care ◽

Resistance Mechanisms ◽

Endocrine Treatment ◽

Breast Cancer Patients ◽

Current Standard ◽

Hormone Receptor Positive ◽

Positive Breast Cancer

Purpose of review: Due to the findings of current studies and the approval of novel substances for the therapy of hormone-receptor-positive breast cancer patients, the established standards of endocrine treatment are changing. The purpose of this review is to give an overview of the history of endocrine treatment, to clarify its role in the present standard of care, and to discuss the possibilities of improvement. Recent findings: Tamoxifen, aromatase inhibitors, and fulvestrant are the main drugs that have been used for decades in the therapy of hormone-receptor-positive breast cancer patients. However, since a relevant number of women suffer at some point from disease recurrence or progression, several novel substances are being investigated to overcome resistance mechanisms by interfering with certain signaling pathways, such as the PI3K/AKT/mTOR or the CDK4/6 pathways. mTOR and CDK4/6 inhibitors were the first drugs approved for this purpose and many more are in development. Summary: Endocrine treatment is one of the best tolerable cancer therapies available. Continuous investigation serves to improve patients’ outcomes and modernize the current standard of care. Considering the resistance mechanisms and substances analyzed against these, endocrine treatment of hormone-receptor-positive breast cancer is on the brink of a new era.

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The neuropathic pain: An overview of the current treatment and future therapeutic approaches

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738419838383 ◽

2019 ◽

Vol 33 ◽

pp. 205873841983838 ◽

Cited By ~ 21

Author(s):

Eugenio Cavalli ◽

Santa Mammana ◽

Ferdinando Nicoletti ◽

Placido Bramanti ◽

Emanuela Mazzon

Keyword(s):

Neuropathic Pain ◽

Viral Infections ◽

Standard Of Care ◽

Current Treatment ◽

Phase Iii ◽

Therapeutic Approaches ◽

Current Standard ◽

Phase Iii Clinical Trials ◽

Nociceptive Responses ◽

Standard Of Care Treatment

Neuropathic pain is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). The conditions and the pathophysiological states that determine the onset of neuropathic pain are heterogeneous, such as metabolic disorders, neuropathy caused by viral infections, and autoimmune diseases affecting the central nervous system (CNS). Neuropathic pain in the general population is estimated to have a prevalence ranging between 3% and 17%. Most of the available treatments for neuropathic pain have moderate efficacy and present side effects that limit their use; therefore, other therapeutic approaches are needed for patients. In this article, the current standard of care treatment, the emerging pharmacological approaches from the completed phase III clinical trials, and the preclinical studies on novel promising therapeutic options will be reviewed.

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