Publications by authors named "Varun Monga"

50 Publications

Intratumoral talimogene laherparepvec injection with concurrent preoperative radiation in patients with locally advanced soft-tissue sarcoma of the trunk and extremities: phase IB/II trial.

J Immunother Cancer 2021 Jul;9(7)

Internal Medicine, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.

Background: Soft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical studies, oncolytic virotherapy in sarcoma has demonstrated antitumor effects via direct intratumoral oncolysis and cytotoxic T-cell-mediated immune responses. Talimogene laherparepvec (TVEC) is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma.

Methods: We explored a novel combination of TVEC with standard-of-care EBRT administered preoperatively in patients with locally advanced STS of the extremities and trunk in a phase IB/II clinical trial. Thirty patients with primary STS >5 cm for which EBRT was indicated to achieve negative margins were enrolled. FDA-approved TVEC doses were used. Immune correlative studies in peripheral blood, biopsy and resected tumor tissues were performed.

Results: No dose-limiting toxicity was observed. Adverse events were similar to those reported in prior studies with TVEC. One patient with myxoid liposarcoma exhibited a partial response. Seven of the 29 (24%) evaluable patients achieved 95% pathological necrosis. None of the patients developed a herpes infection due to the treatment. Eight of the 29 (27%) patients developed postoperative wound complications, which is consistent with previous studies. None of the patients developed local recurrence after surgical resection of the primary sarcoma. 2-year progression-free and overall survival were 57% and 88%, respectively. Caspase-3 demonstrated increased expression of both in TVEC-treated tissue samples as compared with control samples treated with radiation alone.

Conclusion: Preoperative intratumoral TVEC with concurrent EBRT for locally advanced STS is safe and well-tolerated. This combination treatment may enhance immune responses in some cases but did not increase the proposed rate of pathological necrosis. The Caspase-3 biomarker may be associated with a positive effect of TVEC in sarcoma tumor tissue and should be explored in future studies.

Trial Registration Number: NCT02453191.
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http://dx.doi.org/10.1136/jitc-2021-003119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327848PMC
July 2021

An open-label single-arm phase II study of regorafenib for the treatment of angiosarcoma.

Eur J Cancer 2021 Sep 17;154:201-208. Epub 2021 Jul 17.

Siteman Cancer Center, St Louis, MO, USA; Washington University in St. Louis School of Medicine, St Louis MO, USA; St Louis Children's Hospital, Department id Pediatrics, St Louis, MO, 63110, USA.

Purpose: Angiosarcomas represents a diverse group of aggressive high-grade vascular tumours with limited therapeutic options. We sought to determine the safety and efficacy of regorafenib, a small-molecule multikinase inhibitor, in the treatment of metastatic or locally advanced unresectable angiosarcoma.

Patients And Methods: In this single-arm multicentre, open-label phase II clinical trial, 31 patients were enrolled and received regorafenib 160 mg PO daily for 21 days of a 28-day cycle. The primary endpoint for the study was progression-free survival at 4 months. Secondary endpoints included overall survival, response rate, and safety. Patients (≥18 years) with an Eastern Cooperative Oncology Group (ECOG) score of 0-1, a life expectancy of at least 4 months who had progressed on at least one but no more than 4 prior lines of therapy were eligible.

Results: Of the 23 patients evaluable for efficacy, 2 had a complete response (8.7%), and 2 had a partial response (8.7%), for a total overall response rate of 17.4%. Median PFS was 5.5 months, and 12/23 patients (52.2%) had a PFS of greater than 4 months. 10/31 (32.3%) patients evaluable for toxicity had a grade 3 or higher adverse events.

Conclusions: Regorafenib is a safe and active treatment for refractory metastatic and unresectable angiosarcoma. Rates of adverse events were comparable to prior studies of regorafenib for other tumour types. Regorafenib, the single agent, could be considered as therapy for patients with metastatic or unresectable AS.
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http://dx.doi.org/10.1016/j.ejca.2021.06.027DOI Listing
September 2021

Turning 'Cold' tumors 'Hot': immunotherapies in sarcoma.

Ann Transl Med 2021 Jun;9(12):1039

Department of Internal Medicine, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa, Iowa City, IA, USA.

Immunotherapies have an established role in the management of several advanced malignancies. Their responses are largely dependent on the presence of PD-L1, microsatellite instability (MSI), and high tumor mutation burden. Sarcomas are heterogenous tumors which comprise over 100 subtypes. They are broadly considered immunologically inert or "cold". Immunotherapy as monotherapy has shown interesting responses in a certain handful of subtypes, such as undifferentiated pleomorphic sarcoma, dedifferentiated and pleomorphic liposarcoma, and alveolar soft part sarcoma. However, the mechanisms of action of immunotherapy agents in several sarcoma subtypes remains unknown. Several sarcoma types such as leiomyosarcoma have been shown to have an immunosuppressive microenvironment. Early clinical studies suggest the emergence of B cell infiltration in sarcoma tumor tissues as well as the role of PD-1 and PD-L1 as biomarkers of response. Immunotherapy combinations with conventional chemotherapies, radiation therapies, tyrosine kinase inhibitors and oncolytic viruses are showing promise in turning these "cold" tumors "hot". Several novel agents as well as repurposing therapies with the potential to enhance immunotherapy responses are undergoing pre-clinical and clinical studies in other tumor types. Herein we review current clinical studies which have explored the use of immunotherapeutic agents in the management of sarcomas and discuss the challenges and future directions.
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http://dx.doi.org/10.21037/atm-20-6041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267323PMC
June 2021

Radiomic Based Machine Learning Performance for a Three Class Problem in Neuro-Oncology: Time to Test the Waters?

Cancers (Basel) 2021 May 24;13(11). Epub 2021 May 24.

Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.

Prior radiomics studies have focused on two-class brain tumor classification, which limits generalizability. The performance of radiomics in differentiating the three most common malignant brain tumors (glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastatic disease) is assessed; factors affecting the model performance and usefulness of a single sequence versus multiparametric MRI (MP-MRI) remain largely unaddressed. This retrospective study included 253 patients (120 metastatic (lung and brain), 40 PCNSL, and 93 GBM). Radiomic features were extracted for whole a tumor mask (enhancing plus necrotic) and an edema mask (first pipeline), as well as for separate enhancing and necrotic and edema masks (second pipeline). Model performance was evaluated using MP-MRI, individual sequences, and the T1 contrast enhanced (T1-CE) sequence without the edema mask across 45 model/feature selection combinations. The second pipeline showed significantly high performance across all combinations (Brier score: 0.311-0.325). GBRM fit using the full feature set from the T1-CE sequence was the best model. The majority of the top models were built using a full feature set and inbuilt feature selection. No significant difference was seen between the top-performing models for MP-MRI (AUC 0.910) and T1-CE sequence with (AUC 0.908) and without edema masks (AUC 0.894). T1-CE is the single best sequence with comparable performance to that of multiparametric MRI (MP-MRI). Model performance varies based on tumor subregion and the combination of model/feature selection methods.
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http://dx.doi.org/10.3390/cancers13112568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197204PMC
May 2021

Phase II study of pazopanib with oral topotecan in patients with metastatic and non-resectable soft tissue and bone sarcomas.

Br J Cancer 2021 Aug 28;125(4):528-533. Epub 2021 May 28.

Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma.

Methods: This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort.

Results: 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients.

Conclusions: In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.
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http://dx.doi.org/10.1038/s41416-021-01448-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368095PMC
August 2021

Machine learning based differentiation of glioblastoma from brain metastasis using MRI derived radiomics.

Sci Rep 2021 May 18;11(1):10478. Epub 2021 May 18.

Department of Radiology, University of Iowa Hospital and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA.

Few studies have addressed radiomics based differentiation of Glioblastoma (GBM) and intracranial metastatic disease (IMD). However, the effect of different tumor masks, comparison of single versus multiparametric MRI (mp-MRI) or select combination of sequences remains undefined. We cross-compared multiple radiomics based machine learning (ML) models using mp-MRI to determine optimized configurations. Our retrospective study included 60 GBM and 60 IMD patients. Forty-five combinations of ML models and feature reduction strategies were assessed for features extracted from whole tumor and edema masks using mp-MRI [T1W, T2W, T1-contrast enhanced (T1-CE), ADC, FLAIR], individual MRI sequences and combined T1-CE and FLAIR sequences. Model performance was assessed using receiver operating characteristic curve. For mp-MRI, the best model was LASSO model fit using full feature set (AUC 0.953). FLAIR was the best individual sequence (LASSO-full feature set, AUC 0.951). For combined T1-CE/FLAIR sequence, adaBoost-full feature set was the best performer (AUC 0.951). No significant difference was seen between top models across all scenarios, including models using FLAIR only, mp-MRI and combined T1-CE/FLAIR sequence. Top features were extracted from both the whole tumor and edema masks. Shape sphericity is an important discriminating feature.
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http://dx.doi.org/10.1038/s41598-021-90032-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131619PMC
May 2021

Radiomics-based differentiation between glioblastoma and primary central nervous system lymphoma: a comparison of diagnostic performance across different MRI sequences and machine learning techniques.

Eur Radiol 2021 Apr 23. Epub 2021 Apr 23.

College of Engineering, University of Iowa, Iowa City, IA, USA.

Objectives: Despite the robust diagnostic performance of MRI-based radiomic features for differentiating between glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL) reported on prior studies, the best sequence or a combination of sequences and model performance across various machine learning pipelines remain undefined. Herein, we compare the diagnostic performance of multiple radiomics-based models to differentiate GBM from PCNSL.

Methods: Our retrospective study included 94 patients (34 with PCNSL and 60 with GBM). Model performance was assessed using various MRI sequences across 45 possible model and feature selection combinations for nine different sequence permutations. Predictive performance was assessed using fivefold repeated cross-validation with five repeats. The best and worst performing models were compared to assess differences in performance.

Results: The predictive performance, both using individual and a combination of sequences, was fairly robust across multiple top performing models (AUC: 0.961-0.977) but did show considerable variation between the best and worst performing models. The top performing individual sequences had comparable performance to multiparametric models. The best prediction model in our study used a combination of ADC, FLAIR, and T1-CE achieving the highest AUC of 0.977, while the second ranked model used T1-CE and ADC, achieving a cross-validated AUC of 0.975.

Conclusion: Radiomics-based predictive accuracy can vary considerably, based on the model and feature selection methods as well as the combination of sequences used. Also, models derived from limited sequences show performance comparable to those derived from all five sequences.

Key Points: • Radiomics-based diagnostic performance of various machine learning models for differentiating glioblastoma and PCNSL varies considerably. • ML models using limited or multiple MRI sequences can provide comparable performance, based on the chosen model. • Embedded feature selection models perform better than models using a priori feature reduction.
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http://dx.doi.org/10.1007/s00330-021-07845-6DOI Listing
April 2021

Glioblastoma and primary central nervous system lymphoma: differentiation using MRI derived first-order texture analysis - a machine learning study.

Neuroradiol J 2021 Aug 3;34(4):320-328. Epub 2021 Mar 3.

Department of Radiology, University of Iowa Hospitals and Clinics, USA.

Objectives: To evaluate the diagnostic performance of multiple machine learning classifier models derived from first-order histogram texture parameters extracted from T1-weighted contrast-enhanced images in differentiating glioblastoma and primary central nervous system lymphoma.

Methods: Retrospective study with 97 glioblastoma and 46 primary central nervous system lymphoma patients. Thirty-six different combinations of classifier models and feature selection techniques were evaluated. Five-fold nested cross-validation was performed. Model performance was assessed for whole tumour and largest single slice using receiver operating characteristic curve.

Results: The cross-validated model performance was relatively similar for the top performing models for both whole tumour and largest single slice (area under the curve 0.909-0.924). However, there was a considerable difference between the worst performing model (logistic regression with full feature set, area under the curve 0.737) and the highest performing model for whole tumour (least absolute shrinkage and selection operator model with correlation filter, area under the curve 0.924). For single slice, the multilayer perceptron model with correlation filter had the highest performance (area under the curve 0.914). No significant difference was seen between the diagnostic performance of the top performing model for both whole tumour and largest single slice.

Conclusions: T1 contrast-enhanced derived first-order texture analysis can differentiate between glioblastoma and primary central nervous system lymphoma with good diagnostic performance. The machine learning performance can vary significantly depending on the model and feature selection methods. Largest single slice and whole tumour analysis show comparable diagnostic performance.
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http://dx.doi.org/10.1177/1971400921998979DOI Listing
August 2021

Testosterone deficiency in men receiving immunotherapy for malignant melanoma.

Oncotarget 2021 Feb 2;12(3):199-208. Epub 2021 Feb 2.

Department of Medicine, University of Iowa, Iowa City, IA, 52242, USA.

Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.
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http://dx.doi.org/10.18632/oncotarget.27876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869578PMC
February 2021

Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas.

Cancers (Basel) 2021 Feb 8;13(4). Epub 2021 Feb 8.

Division of Hematology, Oncology, and Blood & Marrow Transplant, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.

Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation therapy, or, less commonly, chemotherapy, depending on tumor subtype. Verteporfin has the potential to be incorporated into this standard of care due to its unique molecular properties: inhibition of the upregulated Hippo pathway that frequently drives soft tissue sarcoma and photodynamic therapy-mediated necrosis due to oxidative damage. The initial anti-proliferative effect of verteporfin is mediated via binding and dissociation of YAP/TEAD proteins from the nucleus, ultimately leading to decreased cell proliferation as demonstrated in multiple in vitro studies. This effect has the potential to be compounded with use of photodynamic therapy to directly induce cellular necrosis with use of a clinical laser. Photodynamic therapy has been incorporated into multiple malignancies and has the potential to be incorporated into sarcoma treatment.
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http://dx.doi.org/10.3390/cancers13040675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915813PMC
February 2021

Survival prediction in glioblastoma on post-contrast magnetic resonance imaging using filtration based first-order texture analysis: Comparison of multiple machine learning models.

Neuroradiol J 2021 Aug 3;34(4):355-362. Epub 2021 Feb 3.

Department of Radiology, University of Iowa Hospitals and Clinics, USA.

Objective: Magnetic resonance texture analysis (MRTA) is a relatively new technique that can be a valuable addition to clinical and imaging parameters in predicting prognosis. In the present study, we investigated the efficacy of MRTA for glioblastoma survival using T1 contrast-enhanced (CE) images for texture analysis.

Methods: We evaluated the diagnostic performance of multiple machine learning models based on first-order histogram statistical parameters derived from T1-weighted CE images in the survival stratification of glioblastoma multiforme (GBM). Retrospective evaluation of 85 patients with GBM was performed. Thirty-six first-order texture parameters at six spatial scale filters (SSF) were extracted on the T1 CE axial images for the whole tumor using commercially available research software. Several machine learning classification models (in four broad categories: linear, penalized linear, non-linear, and ensemble classifiers) were evaluated to assess the survival prediction performance using optimal features. Principal component analysis was used prior to fitting the linear classifiers in order to reduce the dimensionality of the feature inputs. Fivefold cross-validation was used to partition the data iteratively into training and testing sets. The area under the receiver operating characteristic curve (AUC) was used to assess the diagnostic performance.

Results: The neural network model was the highest performing model with the highest observed AUC (0.811) and cross-validated AUC (0.71). The most important variable was the age at diagnosis, with mean and mean of positive pixels (MPP) for SSF = 0 being the second and third most important, followed by skewness for SSF = 0 and SSF = 4.

Conclusions: First-order texture features, when combined with age at presentation, show good accuracy in predicting GBM survival.
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http://dx.doi.org/10.1177/1971400921990766DOI Listing
August 2021

Combination therapies for MPNSTs targeting RABL6A-RB1 signaling.

Oncotarget 2021 Jan 5;12(1):10-14. Epub 2021 Jan 5.

Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa, USA.

Precision medicine relies on a detailed molecular understanding of disease pathogenesis. Here, we consider urgently needed therapeutic options for malignant peripheral nerve sheath tumors (MPNSTs) based on emerging insights into druggable pathway alterations found to drive this deadly cancer. Recent observations demonstrate an essential role for an oncogenic GTPase, RABL6A, in promoting MPNST progression through hyperactivation of cyclin-dependent kinases (CDKs) and inactivation of the retinoblastoma (RB1) tumor suppressor. Monotherapies with CDK4/6 inhibitors have shown limited efficacy and durability in pre-clinical studies of MPNSTs and in clinical studies of other tumors. Therefore, we discuss the rationale and clinical benefits of inhibiting multiple RABL6A effectors, particularly CDK4/6 and MEK kinases, in targeted combination therapies suitable for MPNSTs and other Ras-driven malignancies.
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http://dx.doi.org/10.18632/oncotarget.27862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800773PMC
January 2021

Magnetic resonance imaging (MRI) of pharmacological ascorbate-induced iron redox state as a biomarker in subjects undergoing radio-chemotherapy.

Redox Biol 2021 01 19;38:101804. Epub 2020 Nov 19.

Department of Radiology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA. Electronic address:

Pharmacological ascorbate (P-AscH) combined with standard of care (SOC) radiation and temozolomide is being evaluated in a phase 2 clinical trial (NCT02344355) in the treatment of glioblastoma (GBM). Previously published data demonstrated that paramagnetic iron (Fe) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe). Because paramagnetic Fe may influence relaxation times observed in MR imaging, quantitative MR imaging of P-AscH-induced changes in redox-active Fe was assessed as a biomarker for therapy response. Gel phantoms containing either Fe or Fe were imaged with T2* and quantitative susceptibility mapping (QSM). Fifteen subjects receiving P-AscH plus SOC underwent T2* and QSM imaging four weeks into treatment. Subjects were scanned: pre-P-AscH infusion, post-P-AscH infusion, and post-radiation (3-4 h between scans). Changes in T2* and QSM relaxation times in tumor and normal tissue were calculated and compared to changes in Fe and Fe gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool. Phantoms containing Fe demonstrated detectable changes in T2* and QSM relaxation times relative to Fe phantoms. Compared to pre-P-AscH, GBM T2* and QSM imaging were significantly changed post-P-AscH infusion consistent with conversion of Fe to Fe. No significant changes in T2* or QSM were observed in normal brain tissue. There was moderate concordance between T2* and QSM changes in both progression free survival and overall survival. The GBM mouse model showed similar results with P-AscH inducing greater changes in tumor labile iron pools compared to the normal tissue. CONCLUSIONS: T2* and QSM MR-imaging responses are consistent with P-AscH reducing Fe to Fe, selectively in GBM tumor volumes and represent a potential biomarker of response. This study is the first application using MR imaging in humans to measure P-AscH-induced changes in redox-active iron.
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http://dx.doi.org/10.1016/j.redox.2020.101804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708874PMC
January 2021

Radioresistance in Glioblastoma and the Development of Radiosensitizers.

Cancers (Basel) 2020 Sep 3;12(9). Epub 2020 Sep 3.

Free Radical & Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.

Ionizing radiation is a common and effective therapeutic option for the treatment of glioblastoma (GBM). Unfortunately, some GBMs are relatively radioresistant and patients have worse outcomes after radiation treatment. The mechanisms underlying intrinsic radioresistance in GBM has been rigorously investigated over the past several years, but the complex interaction of the cellular molecules and signaling pathways involved in radioresistance remains incompletely defined. A clinically effective radiosensitizer that overcomes radioresistance has yet to be identified. In this review, we discuss the current status of radiation treatment in GBM, including advances in imaging techniques that have facilitated more accurate diagnosis, and the identified mechanisms of GBM radioresistance. In addition, we provide a summary of the candidate GBM radiosensitizers being investigated, including an update of subjects enrolled in clinical trials. Overall, this review highlights the importance of understanding the mechanisms of GBM radioresistance to facilitate the development of effective radiosensitizers.
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http://dx.doi.org/10.3390/cancers12092511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564557PMC
September 2020

The Effect of Concurrent Stereotactic Body Radiation and Anti-PD-1 Therapy for Recurrent Metastatic Sarcoma.

Radiat Res 2020 08;194(2):124-132

Department of Radiation Oncology.

Patients diagnosed with metastatic sarcoma have limited options for achieving both local and distant tumor control. While SBRT can achieve local control, distant response rates remain low. There is limited evidence demonstrating the safety and efficacy for combining SBRT with concurrent PD-1 checkpoint blockade in metastatic sarcoma. In this prospective case-series, we examined five patients with metastatic sarcoma on pembrolizumab treated concurrently with SBRT from July 1, 2016-October 30, 2018. Acute and chronic toxicity were recorded using Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). SBRT-treated tumor control was assessed using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). With median follow-up of 14.9 months, three patients with undifferentiated pleomorphic sarcoma, one with intimal, and one with chondroblastic osteosarcoma received SBRT with concurrent pembrolizumab to 10 sites of metastatic disease. No grade 5 toxicities were observed. There was a single incidence of transient grade 4 lymphopenia which resolved without intervention. Grade 3 toxicities included anemia, thrombocytopenia, lymphopenia and colitis. One tumor demonstrated local progression after SBRT, and all others remained stable or with response. In conclusion, combining SBRT with PD-1 inhibition appeared to be safe in this patient population. Expected high rates of treated-tumor local control after SBRT were observed. Two of five patients demonstrated either enhanced local tumor regression, or possible abscopal effect.
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http://dx.doi.org/10.1667/RADE-20-00017DOI Listing
August 2020

Neoadjuvant Radiotherapy-Related Wound Morbidity in Soft Tissue Sarcoma: Perspectives for Radioprotective Agents.

Cancers (Basel) 2020 Aug 12;12(8). Epub 2020 Aug 12.

Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52422, USA.

Historically, patients with localized soft tissue sarcomas (STS) of the extremities would undergo limb amputation. It was subsequently determined that the addition of radiation therapy (RT) delivered prior to (neoadjuvant) or after (adjuvant) a limb-sparing surgical resection yielded equivalent survival outcomes to amputation in appropriate patients. Generally, neoadjuvant radiation offers decreased volume and dose of high-intensity radiation to normal tissue and increased chance of achieving negative surgical margins-but also increases wound healing complications when compared to adjuvant radiotherapy. This review elaborates on the current neoadjuvant/adjuvant RT approaches, wound healing complications in STS, and the potential application of novel radioprotective agents to minimize radiation-induced normal tissue toxicity.
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http://dx.doi.org/10.3390/cancers12082258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465163PMC
August 2020

A phase II study of pazopanib as front-line therapy in patients with non-resectable or metastatic soft-tissue sarcomas who are not candidates for chemotherapy.

Eur J Cancer 2020 09 23;137:1-9. Epub 2020 Jul 23.

Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, USA; Siteman Cancer Center, Washington University School of Medicine, USA. Electronic address:

Background: Cytotoxic chemotherapy remains the standard of care first-line treatment for advanced and metastatic soft-tissue sarcomas (STSs). Certain patients may not be chemotherapy candidates based upon age or co-morbidities, leaving limited treatment options. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA-approved for metastatic STS after the first line. We proposed a phase II study evaluating pazopanib as a first-line agent in patients with advanced disease who are deemed not to be candidates for chemotherapy.

Methods: Eligible patients were at least 18 years old, not candidates for chemotherapyand were treatment naive. Pazopanib was titrated from 200 mg twice daily to a goal of 800 mg daily. The primary end point was the clinical benefit rate (CBR) (CBR = completed response + partial response + stable disease per Response Evaluation Criteria in Solid Tumours [RECIST 1.1]) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesised CBR of ≥35% against an unfavourable CBR of ≤20%. If ≥ 17 patients achieved benefit, the null CBR of 20% would be rejected at a nominal 5% alpha level. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life and serum biomarkers.

Findings: Fifty-six patients were enrolled from May 2015 to February 2019 and are included in the intention-to-treat analysis. Median PFS was 3.67 (2.62-7.25) months. Median OS was 14.16 (95% confidence interval [CI]: 8.4-NR) months, CBR = 39.29% (22/56) (CI = 0.265-0.533, p = 0.0007). No new or unexpected adverse events were seen. The most common grade I-II events were diarrhoea, nausea and fatigue. The most common grade III-IV events were hypertension and liver function test abnormalities.

Interpretation: These data suggest that there is a benefit to front-line pazopanib in patients with STS who are not candidates for cytotoxic chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2020.06.016DOI Listing
September 2020

Non-Conventional Treatments for Conventional Chondrosarcoma.

Cancers (Basel) 2020 Jul 19;12(7). Epub 2020 Jul 19.

Division of Oncology, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.

Chondrosarcomas are the most common malignant tumors of the cartilage, are seen predominantly in adults, and have varied clinical behavior. The majority of them affect the medullary canal of long bones and pelvic bones. The prognosis of chondrosarcoma is closely related to histological grading; however, the grading is subject to interobserver variability. Conventional chondrosarcomas are overall considered to be chemotherapy- and radiation-resistant, resulting in limited treatment options. The majority of advanced conventional chondrosarcomas are treated with chemotherapy without any survival benefit. Recent studies have evaluated molecular genetic findings which have improved the understanding of chondrosarcoma biology. Newer therapeutic targets are desperately needed. In this review article, we explore ongoing clinical trials evaluating novel ways of treating advanced conventional chondrosarcoma.
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http://dx.doi.org/10.3390/cancers12071962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409290PMC
July 2020

A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas.

Cancers (Basel) 2020 Jul 11;12(7). Epub 2020 Jul 11.

Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients-72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS.
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http://dx.doi.org/10.3390/cancers12071873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408640PMC
July 2020

CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets.

Int J Mol Sci 2020 Apr 24;21(8). Epub 2020 Apr 24.

Molecular Medicine Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.

Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy.
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http://dx.doi.org/10.3390/ijms21083018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215455PMC
April 2020

A Retrospective Analysis of Clinical Trial Accrual of Patients Presented in a Multidisciplinary Tumor Board at a Tertiary Health Care Center and Associated Barriers.

Oncol Res Treat 2020 27;43(5):196-203. Epub 2020 Mar 27.

Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA,

Introduction: Cancer clinical trial accruals have been historically low and are affected by several factors. Multidisciplinary Tumor Board Meetings (MTBM) are conducted regularly and immensely help to devise a comprehensive care plan including discussions about clinical trial availability and eligibility.

Objectives: To evaluate whether patient discussion at MTBM was associated with a higher consent rate for clinical trials at a single tertiary care center.

Methods: Institutional electronic medical records (EMR) and clinical trials management system (OnCore) were queried to identify all new patient visits in oncology clinics, consents to clinical trials, and MTBM notes between January 1, 2011 and December 31, 2015. The association between MTBM discussion and subsequent clinical trial enrollment within 16 weeks of the new patient visit was evaluated using a χ2 test.

Results: Between January 1, 2011 and December 31, 2015, 11,794 new patients were seen in oncology clinics, and 2,225 patients (18.9%) were discussed at MTBMs. MTBM discussion conferred a higher rate of subsequent clinical trial consent within 16 weeks following the patient's first consultation in an oncology clinic: 4.1% for those who were discussed at a MTBM compared to 2.8% for those not discussed (p < 0.01).

Conclusions: This study provides evidence that MTBMs may be effective in identifying patients eligible for available clinical trials by reviewing eligibility criteria during MTBM discussions. We recommend discussion of all new patients in MTBM to improve the quality of care provided to those with cancer and enhanced clinical trial accrual.
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http://dx.doi.org/10.1159/000506840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188843PMC
September 2020

Survival after reoperation for recurrent glioblastoma.

J Clin Neurosci 2020 Mar 24;73:118-124. Epub 2020 Jan 24.

Department of Neurosurgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Determining which patients will benefit from reoperation for recurrent glioblastoma remains difficult and the impact of the volume of FLAIR signal hyperintensity is not well known. The primary purpose of this study is to analyze the impact of preoperative volume of FLAIR hyperintensity on prognosis. 37 patients who underwent a reoperation for recurrent glioblastoma after initial gross total resection followed by standard chemoradiation were retrospectively reviewed. Volumetric analysis of preoperative MR images from the initial and second surgery was performed and correlated with clinical data. Survival probabilities were estimated using the Kaplan-Meier method and Cox regression to assess the effect of risk factors on time to reoperation (TTR), progression-free survival (PFS) after reoperation, and overall survival (OS). The volumes of FLAIR signal hyperintensity prior to the initial surgery and reoperation were not associated with prognosis. TTR and OS were significantly affected by the preoperative enhancement volume at the initial surgery, with increasing volumes yielding poorer prognosis. Patients with tumor in critical/eloquent areas were found to have a worse prognosis. Median TTR was 11 months, median PFS after reoperation was 3 months, and OS in patients undergoing a reoperation was 21 months. The results suggest FLAIR signal change seen in patients with glioblastoma does not influence time to reoperation, progression-free survival, or overall survival. These findings suggest the amount of FLAIR signal change should not greatly influence a surgeon's decision to perform a second surgical resection compare to other factors, and when appropriate, aggressive surgical intervention should be considered.
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http://dx.doi.org/10.1016/j.jocn.2020.01.009DOI Listing
March 2020

Dermatofibrosarcoma protuberans - the use of neoadjuvant imatinib for treatment of an uncommon breast malignancy: a case report.

J Med Case Rep 2019 Dec 19;13(1):374. Epub 2019 Dec 19.

University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA.

Background: Dermatofibrosarcoma protuberans is a rare soft tissue malignancy that, if left untreated, can be locally destructive and life-threatening. Dermatofibrosarcoma protuberans is uncommon in the breast, and the similarity of its morphologic features with other spindle cell malignancies can make correct identification difficult. Immunohistochemistry and molecular testing can aid in the correct diagnosis when there is diagnostic uncertainty. Imatinib, a selective tyrosine kinase inhibitor, has been used for adjuvant treatment of dermatofibrosarcoma protuberans following surgical resection. When used as a neoadjuvant treatment, imatinib offers the opportunity to decrease tumor size prior to surgery to lessen the chance for disfigurement.

Case Presentation: We present the case of a Caucasian woman who was 46-year-old when she first noted a mass in her right breast in 2015; she was initially diagnosed as having metaplastic breast carcinoma. Mastectomy and systemic chemotherapy were planned; however, after review of pathology at a referral center, the diagnosis was changed to dermatofibrosarcoma protuberans. She was treated with 4 months of neoadjuvant imatinib with adequate tumor shrinkage to perform breast conservation.

Conclusion: This patient's case stresses the importance of correctly diagnosing this rare breast tumor through the histopathologic appearance of dermatofibrosarcoma protuberans, molecular pathogenesis, and immunohistochemistry. These techniques can help differentiate dermatofibrosarcoma protuberans from metaplastic breast carcinoma and other spindle cell lesions of the breast. This is critical, as the treatment options for metaplastic breast carcinoma significantly differ from treatment options for dermatofibrosarcoma protuberans. This case describes the use of imatinib as a neoadjuvant option to reduce preoperative tumor size and improve surgical outcomes.
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http://dx.doi.org/10.1186/s13256-019-2316-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921555PMC
December 2019

Factors Impacting Fertility Preservation in Adolescents and Young Adults with Cancer: A Retrospective Study.

J Adolesc Young Adult Oncol 2020 04 25;9(2):208-221. Epub 2019 Oct 25.

Department of Pediatrics, Hematology Oncology, University of Iowa Hospitals and Clinics, Stead Family Children's Hospital, Iowa City, Iowa.

Fertility preservation before therapy is underutilized for those diagnosed with cancer as an adolescent or young adult (AYA). The purpose of this study was to describe factors impacting utilization of fertility preservation consultations and procedures among AYAs at the University of Iowa Health Care (UIHC). Patients were identified by the oncology registry at UIHC. Disease site, histology, date of diagnosis, sex, race, ethnicity, insurance, and zip code data were gathered by the registrars. UIHC's electronic medical record was queried for fertility preservation consultation. The Reproductive Endocrinology and Infertility clinical database captured information about patients who underwent fertility preservation. Rural-urban commuting area codes measured rurality. Descriptive statistics and multivariate linear probability models were used to predict the probability of fertility preservation consultation and procedure. From 2008 to 2017, 2932 AYAs were treated for an invasive malignancy at UIHC. Of the 440 (15%) who received a fertility preservation consultation, 156 (5%) underwent a fertility preservation procedure. Multivariate analyses showed that AYAs with public insurance coverage, those diagnosed with central nervous system (CNS) disease or melanoma, and those >30 years old at diagnosis had a significant decrease in the percentage point probability of having a consultation. The percentage point probability of undergoing a procedure was decreased for female patients, those with melanoma or carcinoma, those seen by a pediatric-based provider, and those diagnosed after 25 years of age. This study has important implications for practice and policy, particularly regarding insurance coverage and patient and provider characteristics leading to fertility preservation consultations and procedures for AYAs with cancer.
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http://dx.doi.org/10.1089/jayao.2019.0100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360112PMC
April 2020

Durable Clinical Benefit in Patients with Advanced Cutaneous Melanoma after Discontinuation of Anti-PD-1 Therapies Due to Immune-Related Adverse Events.

J Oncol 2019 25;2019:1856594. Epub 2019 Jul 25.

Division of Hematology, Oncology and Blood & Marrow Transplantation, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52242, USA.

Introduction: Anti-PD-1 therapies, pembrolizumab and nivolumab, are currently the standard of care for treatment of patients with metastatic melanoma. Treatment is usually continued until toxicity or disease progression. Though these therapies are well tolerated, some patients discontinue them due to immune-related adverse events (irAE). Discontinuation of therapy brings challenges to their management due to limited treatment options and lack of long-term prognostic information for these patients. Herein, we reviewed patients at our institution to analyze their clinical outcomes.

Materials And Methods: Charts of 1264 consecutive patients enrolled between 8/1/2012 and 7/31/2017 at Melanoma Skin & Ocular Tissue Repositories at Holden Comprehensive Cancer Center at the University of Iowa Hospitals and Clinic were reviewed. Eligible patients were those who received single-agent anti-PD-1 therapy and subsequently discontinued it due to irAE. Reviewed data included patient demographics, prior medical history, baseline disease parameters, and outcomes. Kaplan-Meier survival analysis was done to determine progression-free survival (PFS) and overall survival (OS).

Results: Overall 169 patients with advanced, unresectable, or metastatic cutaneous melanoma received anti-PD-1 therapy of which 16 (9.5%) white, non-Hispanic patients with median age of 64.5 (range 35 to 81 years) discontinued treatment due to irAE. Fifteen patients received pembrolizumab and one received nivolumab. The median duration of treatment was 4.7 (range 0.7 to 11.5) months. Median follow-up was 30.3 (range 4.6 to 49.4) months. Median PFS was 24.6 months and median OS was not reached. Durable clinical benefit (time to progression or next treatment of more than 6 months from last treatment) was observed in 13 (81.2%) patients. At the time of analysis, 8 patients had progressed and 4 patients died (all-cause).

Discussion: Our results suggest that advanced melanoma patients discontinuing anti-PD-1 therapy due to irAE usually experience durable clinical benefit. However, caution is needed with these agents in patients with underlying autoimmune diseases.
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http://dx.doi.org/10.1155/2019/1856594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683789PMC
July 2019

First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.

Clin Cancer Res 2019 11 19;25(22):6590-6597. Epub 2019 Aug 19.

Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, Iowa.

Purpose: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH to standard RT/TMZ therapy.

Patients And Methods: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH phase). Eight P-AscH dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03).

Results: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable promoter methylation (), median PFS was 10 months and median OS was 23 months.

Conclusions: P-AscH/RT/TMZ is safe with promising clinical outcomes warranting further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858950PMC
November 2019

Timing of surgery following neoadjuvant chemoradiation in rectal cancer: a retrospective analysis from an academic medical center.

J Gastrointest Oncol 2019 Aug;10(4):597-604

Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa, University of Iowa, Iowa City, IA, USA.

Background: Neoadjuvant chemoradiotherapy (nCRT) has been shown to achieve decreased local recurrence (LR) with lower toxicity in rectal cancer patients, but data confirming the optimal timing of surgery following this therapy is less robust.

Methods: The University of Iowa Cancer Registry was queried to identify all patients with stages II-III rectal cancer who received nCRT and surgery from 2000 through 2012. Primary endpoints were time interval to surgery (TI), and overall survival (OS). Secondary endpoints included pathologic outcomes, perioperative morbidities and postoperative complications. Patient characteristics and treatment regimens were compared. Univariate Cox proportional hazard models were used to study the association between TI and OS. Associations of TI with secondary endpoints were tested using Chi-square tests of association.

Results: Eighty-seven patients presented with stages II-III rectal cancer. Mean TI was 9.92 weeks. There was no significant association between TI and OS when comparing <8 to ≥8 weeks (P=0.23) or when considering the interval as a continuous variable (P=0.85). Increased LOS [median 7.00 days, P=0.05, HR 1.03 (1.00-1.06)] did correlate with worse survival outcomes. Delaying surgery beyond 8 weeks was associated with increased risk for wound infection (P=0.05).

Conclusions: OS was not influenced by longer intervals between nCRT and surgery. Delaying surgery beyond 8 weeks was associated with increased risk for wound infection.
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http://dx.doi.org/10.21037/jgo.2019.02.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657321PMC
August 2019

Exceptional responses with sequential metronomic temozolomide after pembrolizumab failure in patients with metastatic melanoma.

Melanoma Res 2019 12;29(6):643-647

Departments of Hematology, Oncology, and Blood and Marrow Transplantation.

Pembrolizumab is an effective therapy for patients with metastatic melanoma. However, not all patients derive benefit. It is postulated that an increase in regulatory T cells in melanoma patients can impair the response to immunotherapies. Continuous low-dose temozolomide has shown to cause immunomodulatory effects resulting in CD4 + lymphopenia due to which Treg population can also decrease significantly. Herein, we present a case series of three patients with metastatic melanoma who after progression on pembrolizumab showed a radiological response after just one cycle of metronomic temozolomide (75 mg/m daily for 6 weeks on 8-week cycle). This suggests that temozolomide may be a useful alternative for patients with metastatic melanoma after disease progression on pembrolizumab. Further studies with biomarkers are warranted to elucidate which patients will derive benefit from this strategy.
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http://dx.doi.org/10.1097/CMR.0000000000000592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717692PMC
December 2019

Discrepancy between treatment goals documentation by oncologists and their understanding among cancer patients under active treatment with chemotherapy.

Eur J Cancer Care (Engl) 2019 Mar 3;28(2):e12973. Epub 2018 Dec 3.

Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Carver College of Medicine, Iowa City, Iowa.

Objective/background: Discussion of treatment goals between oncologists and patients is challenging. Patients frequently misunderstand goals of therapy. There are several methods to document goals of chemotherapy, however, and are frequently not incorporated into patient charts.

Methods/design: Cancer patients receiving their first cycle of chemotherapy were interviewed. Patients' recall of discussions with their oncologist regarding therapy intent was assessed and compared to documentation. An adjusted McNemar's test was utilised. A one-sample proportion test was used to evaluate whether the overall observed rate of discordance was significantly different from the proposed 33% rate; a rate posited as a threshold too high in the clinical sense.

Results: Two hundred and seven eligible patients were interviewed. Oncologist identified treatment goals were not documented in 24.6% of cases and had to be excluded. There was not a significant difference in the directionality of discordance present. Inter-rater agreement between patient and oncologist was found to be adequate (κ = 0.64). The overall rate of discordance (17.29%) was found to be significantly less than the proposed acceptable level of 33% (p < 0.01). Upon univariable analysis, age, gender, marital and employment status were not found to be associated with discordance.

Conclusions: Discordance between treatment goals documentation and their understanding exists, indicating continued miscommunication between the patient and oncologist.
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http://dx.doi.org/10.1111/ecc.12973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416062PMC
March 2019

Biallelic TP53 gain of function mutations in rapidly progressing solid tumors.

Cancer Genet 2018 04 24;222-223:20-24. Epub 2018 Feb 24.

Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City 52241, IA, USA . Electronic address:

Recent studies are discovering TP53 mutations with gain of function (GOF) properties that promote tumorigenesis via a variety of mechanisms. To our knowledge, all reported compound mutations are allelic. We identified two patients with biallelic GOF TP53 mutations in their tumors and a third with allelic compound variants. The correlation with p53 expression was also examined. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and mutational analysis was performed using Ion AmpliSeq™Cancer HotSpot Panel V2. Biallelic GOF mutations (p.R273H and p.R273C) were identified in a 19-year-old male with glioblastoma (allele frequencies 94% and 48%) and a 54-year-old with pT3 penile squamous cell carcinoma (allele frequencies 19% and 27%). Immunohistochemistry showed nuclear accumulation of p53. The third patient, a 62-year-old female with metastatic lung adenocarcinoma, had allelic p.P278S (GOF) and p.R283L (non-GOF) variants at frequencies of 61% but with null staining for p53. Germline testing for Patient 1 confirmed wildtype TP53. No other variants were discovered among the genes tested in these cases. All patients succumbed within two years of diagnosis despite aggressive treatment. In conclusion, implementation of TP53 mutation analysis in clinical practice may predict patient outcome, and inhibition of GOF p53 could represent an attractive target for therapy.
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http://dx.doi.org/10.1016/j.cancergen.2018.02.001DOI Listing
April 2018
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