K-RAS Acts as a Critical Regulator of CD44 to Promote the Invasiveness and Stemness of GBM in Response to Ionizing Radiation

Radiation therapy is a current standard-of-care treatment and is used widely for GBM patients. However, radiation therapy still remains a significant barrier to getting a successful outcome due to the therapeutic resistance and tumor recurrence. Understanding the underlying mechanisms of this resistance and recurrence would provide an efficient approach for improving the therapy for GBM treatment. Here, we identified a regulatory mechanism of CD44 which induces infiltration and mesenchymal shift of GBM. Ionizing radiation (IR)-induced K-RAS/ERK signaling activation elevates CD44 expression through downregulation of miR-202 and miR-185 expression. High expression of CD44 promotes SRC activation to induce cancer stemness and EMT features of GBM cells. In this study, we demonstrate that the K-RAS/ERK/CD44 axis is a key mechanism in regulating mesenchymal shift of GBM cells after irradiation. These findings suggest that blocking the K-RAS activation or CD44 expression could provide an efficient way for GBM treatment.

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De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus

Cancers ◽

10.3390/cancers13092099 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2099

Author(s):

Eric Miller ◽

Jose Bazan

Keyword(s):

Squamous Cell Carcinoma ◽

Radiation Therapy ◽

Cell Carcinoma ◽

Squamous Cell ◽

Early Stage ◽

Intensity Modulated Radiation Therapy ◽

Late Toxicity ◽

Standard Of Care ◽

The Elderly ◽

Current Standard

The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly in the elderly, with increased mortality in this age group. While the current standard of care for localized SCCA remains chemoradiation (CRT), completion of this treatment can be challenging with risks for severe acute and late toxicity. It remains unclear if full course CRT is required for the management of early-stage SCCA or if de-escalation of treatment is possible without compromising patient outcomes. Alternative therapies include radiation therapy alone or local excision for appropriate patients. Modifying standard CRT may also reduce toxicity including the routine use of intensity-modulated radiation therapy for treatment delivery, modification of treatment volumes, and selection and dosing of concurrent systemic therapy agents. Finally, we provide an overview of currently accruing prospective trials focused on defining the role of de-escalation of therapy in patients with early-stage SCCA.

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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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Preoperative Serum IL-12p40 Is a Potential Predictor of Kasai Portoenterostomy Outcome in Infants with Biliary Atresia

Gastroenterology Research and Practice ◽

10.1155/2017/9089068 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Shaimaa Samy Goda ◽

Mohamed Ahmed Khedr ◽

Soha Zaki Elshenawy ◽

Tarek Mohamed Ibrahim ◽

Hanaa Ahmed El-Araby ◽

...

Keyword(s):

Biliary Atresia ◽

Surgical Outcomes ◽

Standard Of Care ◽

Successful Outcome ◽

Kasai Portoenterostomy ◽

Successful Operation ◽

Potential Predictor ◽

Preoperative Serum ◽

Standard Of Care Treatment ◽

And Control

The standard-of-care treatment for biliary atresia (BA) is surgical restoration of bile flow by Kasai portoenterostomy. We aimed to study serum interleukin- (IL-) 12p40, a natural antagonist for the proinflammatory IL-12p70, and its relation to surgical outcomes of BA. The study included 75 infants with neonatal cholestasis: BA group (n=25), non-BA cholestasis group (n=30), and neglected BA group (n=20), in addition to thirty healthy neonates serving as controls. IL-12p40 was measured by ELISA in all individuals and a second assessment was performed 3 months postoperatively in the BA group. The surgical outcomes were classified as successful (bilirubin ≤ 2 mg/dl) or failed (bilirubin > 2 mg/dl). IL-12p40 was higher in BA compared to that in the non-BA and control groups (P values were 0.036 and <0.0001, resp.) but comparable to that in the neglected BA group. Preoperative IL-12p40 levels in BA patients were significantly higher in successful Kasai compared with failed Kasai and a cutoff level of 547.47 pg/ml could predict the successful outcome with 87.5% sensitivity and 82.4% specificity. Three-month postoperative IL-12p40 tended to decrease in both the successful and failed groups. In conclusion, preoperative serum IL-12p40 is a potential predictor of Kasai outcome. Serial postoperative measurements may anticipate the failure of an initially successful operation, hence the need for liver transplantation.

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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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Characterizing Cell Stress and GRP78 in Glioma to Enhance Tumor Treatment

Frontiers in Oncology ◽

10.3389/fonc.2020.608911 ◽

2020 ◽

Vol 10 ◽

Author(s):

Kristie Liu ◽

Kathleen Tsung ◽

Frank J. Attenello

Keyword(s):

Radiation Therapy ◽

Patient Outcomes ◽

Cellular Proliferation ◽

Standard Of Care ◽

Tumor Grade ◽

Primary Brain Tumor ◽

Current Standard ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Glioblastoma (GBM) is the most common primary brain tumor, carrying a very poor prognosis, with median overall survival at about 12 to 15 months despite surgical resection, chemotherapy with temozolomide (TMZ), and radiation therapy. GBM recurs in the vast majority of patients, with recurrent tumors commonly displaying increase in resistance to standard of care chemotherapy, TMZ, as well as radiotherapy. One of the most commonly cited mechanisms of chemotherapeutic and radio-resistance occurs via the glucose-regulated protein 78 (GRP78), a well-studied mediator of the unfolded protein response (UPR), that has also demonstrated potential as a biomarker in GBM. Overexpression of GRP78 has been directly correlated with malignant tumor characteristics, including higher tumor grade, cellular proliferation, migration, invasion, poorer responses to TMZ and radiation therapy, and poorer patient outcomes. GRP78 expression is also higher in GBM tumor cells upon recurrence. Meanwhile, knockdown or suppression of GRP78 has been shown to sensitize cells to TMZ and radiation therapy. In light of these findings, various novel developing therapies are targeting GRP78 as monotherapies, combination therapies that enhance the effects of TMZ and radiation therapy, and as treatment delivery modalities. In this review, we delineate the mechanisms by which GRP78 has been noted to specifically modulate glioblastoma behavior and discuss current developing therapies involving GRP78 in GBM. While further research is necessary to translate these developing therapies into clinical settings, GRP78-based therapies hold promise in improving current standard-of-care GBM therapy and may ultimately lead to improved patient outcomes.

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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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Hematological Changes Following Low Dose Radiation Therapy and Comparison to Current Standard of Care Cancer Treatments

Dose-Response ◽

10.1177/15593258211056196 ◽

2021 ◽

Vol 19 (4) ◽

pp. 155932582110561

Author(s):

Alexandra Jameus ◽

Allison E. Kennedy ◽

Christopher Thome

Keyword(s):

Radiation Therapy ◽

Low Dose ◽

Standard Of Care ◽

Limiting Factors ◽

High Dose ◽

Hematologic Toxicity ◽

Low Dose Radiation ◽

Current Standard ◽

Hematological Changes ◽

Dose Radiation

Cancer is the second leading cause of mortality worldwide accounting for almost 10 million deaths in 2020. Current standard of care treatment varies depending on the type and stage of disease, but commonly includes surgery, chemotherapy, and/or radiation therapy. There is evidence that whole- and half-body exposure to low dose ionizing radiation can also be an effective therapeutic due to its stimulation of anti-cancer immunity. One of the limiting factors for past clinical trials using low dose radiation therapy has been adverse hematological events. However, similar hematological changes are also frequently reported following standard of care treatments in oncology. This review summarizes the effects of various cancer therapies on hematologic toxicity through the evaluation of complete blood count reports. The reviewed literature elucidates hematological trends in patients undergoing chemotherapy, and both high and low dose radiation therapy. In general, high dose radiation and chemotherapy can result in widespread changes in blood counts, with the most severe effects related to leukopenia. Overall, compared to standard of care treatments, low dose radiation results in similar, yet more mild hematological changes. Taken together, hematological toxicities should not be a limiting factor in the applicability of low dose radiation as a cancer therapeutic.

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Homologous recombination proficiency in ovarian and breast cancer patients

BMC Cancer ◽

10.1186/s12885-021-08863-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Justin Fortune Creeden ◽

Nisha S. Nanavaty ◽

Katelyn R. Einloth ◽

Cassidy E. Gillman ◽

Laura Stanbery ◽

...

Keyword(s):

Homologous Recombination ◽

Synthetic Lethality ◽

Standard Of Care ◽

Breast Cancer Patients ◽

Genome Maintenance ◽

Testing Methods ◽

Breast And Ovarian Cancer ◽

Current Standard ◽

Standard Testing ◽

Standard Of Care Treatment

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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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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