Publications by authors named "Mohammed Milhem"

103 Publications

An Open-Label, Randomized, Multi-Center Study Comparing the Sequence of High Dose Aldesleukin (Interleukin-2) and Ipilimumab (Yervoy) in Patients with Metastatic Melanoma.

Oncoimmunology 2021 9;10(1):1984059. Epub 2021 Oct 9.

Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas Md Anderson Cancer Center, Houston, USA.

Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies.
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http://dx.doi.org/10.1080/2162402X.2021.1984059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510610PMC
October 2021

Multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine in patients with post-resection melanoma at high risk of recurrence.

J Immunother Cancer 2021 Oct;9(10)

St. Mary's Hospital and Medical Center, San Francisco, California, USA.

Background: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here.

Methods: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients.

Results: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)).

Conclusions: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas.

Trial Registration Number: NCT01546571.
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http://dx.doi.org/10.1136/jitc-2021-003272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488725PMC
October 2021

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma.

N Engl J Med 2021 09;385(13):1196-1206

From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.).

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells.

Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.

Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported.

Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
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http://dx.doi.org/10.1056/NEJMoa2103485DOI Listing
September 2021

Sustained response to imatinib in patient with extraskeletal myxoid chondrosarcoma and novel mutation.

BMJ Case Rep 2021 Aug 26;14(8). Epub 2021 Aug 26.

Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.

A 55-year-old woman presented with a 3-month history of right groin swelling, discomfort and impaired mobility. On examination, a palpable mass was noted both to the right of midline in the lower abdomen and in the right groin. MRI of the pelvis showed two masses involving the anterior abdominal wall and right groin, as well as lymph node involvement. CT imaging revealed multiple bilateral pulmonary metastases. Pathology demonstrated a myxohayline stroma morphology. Tumour was also notable for gene region rearrangement and mutation in exon 11 at position c.1669 T>G. Based on these findings, she was diagnosed with extraskeletal myxoid chondrosarcoma (EMC). The patient has been on imatinib, a tyrosine kinase inhibitor with activity against KIT, for 3 years with stable disease. Metastatic EMC is generally treated with surgical resection and perioperative radiation therapy with adjuvant chemotherapy and is associated with poor prognosis.
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http://dx.doi.org/10.1136/bcr-2021-242039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395296PMC
August 2021

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 07;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

Overcoming PD-1 Blockade Resistance With CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients With Metastatic Melanoma.

Cancer Discov 2021 Jul 29. Epub 2021 Jul 29.

Clinical Services, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine.

Patients with advanced melanoma that is resistant to programmed death-1 (PD-1) blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong interferon response to induce and attract antitumor T cells. In the dose-escalation part of this phase 1b study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti-PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an interferon-γ gene signature following treatment, as well as increased systemic expression of the interferon-inducible chemokine CXCL10.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0425DOI Listing
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

Current status of intralesional agents in treatment of malignant melanoma.

Ann Transl Med 2021 Jun;9(12):1038

Division of Hematology, Oncology and Blood and Marrow Transplantation and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.

Prognosis of metastatic melanoma has undergone substantial improvement with the discovery of checkpoint inhibitors. Immunotherapies and targeted therapies have improved the median overall survival (OS) of metastatic melanoma from 6 months to more than 3 years. However, still about half of the patients die due to uncontrolled disease. Therefore, multiple strategies are currently being investigated to improve outcomes. One such strategy is intralesional/intratumoral (IT) therapies which can either directly kill the tumor cells or make the tumor more immunogenic to be recognized by the immune system. Talimogene laherparepvec (T-VEC), an oncolytic virus, is the first FDA approved IT therapy. This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.
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http://dx.doi.org/10.21037/atm-21-491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267328PMC
June 2021

Cancer immunotherapy: recent advances and challenges.

Ann Transl Med 2021 Jun;9(12):1032

Clinical Professor, Department of Internal Medicine, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa, Iowa City, IA, USA. (Email:

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http://dx.doi.org/10.21037/atm-21-2325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267257PMC
June 2021

Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma.

J Immunother Cancer 2021 06;9(6)

University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa, USA.

Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.

Methods: Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.

Results: Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator's choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).

Conclusion: In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.
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http://dx.doi.org/10.1136/jitc-2020-002057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202104PMC
June 2021

Ultraviolet camera-aided sunscreen application in children: Demonstration of efficacy and receptivity.

J Am Acad Dermatol 2021 May 29. Epub 2021 May 29.

Department of Dermatology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.

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http://dx.doi.org/10.1016/j.jaad.2021.05.044DOI Listing
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

Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.

Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2-4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45-0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32-0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma.
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http://dx.doi.org/10.3390/cancers13071489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037963PMC
March 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

Status of the Clinician Investigator in America: An Essential Healthcare Provider Driving Advances in Cancer Care.

J Natl Compr Canc Netw 2021 02 2;19(2):122-125. Epub 2021 Feb 2.

10University of Mississippi Medical Center Cancer Institute, Jackson, Mississippi.

Background: Translation of basic discoveries to clinical care for patients with cancer is a difficult process greatly enabled by physician-trained researchers. Three categories of physicians, with responsibilities spanning from laboratory and preclinical research to direct patient care, are involved in the translational research continuum: physician-scientist (PS), clinician investigator (CI), and academic clinician (AC).

Methods: To define how protected time for research efforts is supported, the Association of American Cancer Institutes (AACI) conducted a survey of their member institutions, obtaining 56 responses documenting time spent in research and clinical activities across multiple cancer disciplines, and providing information about funding streams for the different categories of cancer physicians.

Results: Responses showed that PSs and ACs are minimally involved in clinical research activities; the driver or clinical research in academic cancer centers is the CI. A significant concern was a lack of stable funding streams for nonbillable clinical research activities, putting the sustainability of the CI in jeopardy. Limited funding was derived from hospital sources, with most support derived from cancer center sources.

Conclusions: This study highlights the importance of the CI in translational cancer medicine and represents a call to action for institutions and research funding agencies to develop new programs targeted toward CI support to ensure continued progress against cancer.
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http://dx.doi.org/10.6004/jnccn.2020.7685DOI Listing
February 2021

Morphea following treatment with pembrolizumab for melanoma with metastatic lymph nodes: case report and review of literature.

Melanoma Res 2021 02;31(1):98-100

Department of Dermatology, University of Iowa Hospitals and Clinics.

Pembrolizumab is a humanized IgG4 isotype mAb that the targets and blocks the programmed cell death protein 1 receptor on lymphocytes. Its use in treating metastatic melanoma is associated with increased overall survival compared to other older immunotherapies. Several adverse effects have been noted including both systemic and cutaneous manifestations. As a relatively novel treatment option, many new cutaneous manifestations are still being observed, occurring at various times after initiation of therapy. Previously noted cutaneous adverse effects include sarcoid-like reactions, rash, and changes in preexisting lesions or scars. Here we present a case in which biopsy-proven morphea developed after completion of pembrolizumab therapy.
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http://dx.doi.org/10.1097/CMR.0000000000000713DOI Listing
February 2021

Role of Natural Killer Cells in Uveal Melanoma.

Cancers (Basel) 2020 Dec 9;12(12). Epub 2020 Dec 9.

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

Uveal melanoma has a high mortality rate following metastasis to the liver. Despite advances in systemic immune therapy, treatment of metastatic uveal melanoma (MUM) has failed to achieve long term durable responses. Barriers to success with immune therapy include the immune regulatory nature of uveal melanoma as well as the immune tolerant environment of the liver. To adequately harness the anti-tumor potential of the immune system, non-T cell-based approaches need to be explored. Natural Killer (NK) cells possess potent ability to target tumor cells via innate and adaptive responses. In this review, we discuss evidence that highlights the role of NK cell surveillance and targeting of uveal melanoma. We also discuss the repertoire of intra-hepatic NK cells. The human liver has a vast and diverse lymphoid population and NK cells comprise 50% of the hepatic lymphocytes. Hepatic NK cells share a common niche with uveal melanoma micro-metastasis within the liver sinusoids. It is, therefore, crucial to understand and investigate the role of intra-hepatic NK cells in the control or progression of MUM.
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http://dx.doi.org/10.3390/cancers12123694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764114PMC
December 2020

A randomized, open-label, phase 2, multicenter trial of gemcitabine with pazopanib or gemcitabine with docetaxel in patients with advanced soft-tissue sarcoma.

Cancer 2021 03 24;127(6):894-904. Epub 2020 Nov 24.

Department of Internal Medicine, University of Arizona Cancer Center, Tucson, Arizona.

Background: Therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS.

Methods: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline-based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m on days 1 and 8 and docetaxel at a dose of 100 mg/m on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression-free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent-to-treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events).

Results: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P = .3, log-rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively).

Conclusions: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS.
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http://dx.doi.org/10.1002/cncr.33216DOI Listing
March 2021

Multivariable Analysis of 169 Cases of Advanced Cutaneous Melanoma to Evaluate Antibiotic Exposure as Predictor of Survival to Anti-PD-1 Based Immunotherapies.

Antibiotics (Basel) 2020 Oct 27;9(11). Epub 2020 Oct 27.

Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.

Recently antibiotic exposure has been associated with worse outcomes in patients undergoing treatment with antibodies directed against programmed cell death protein-1 (PD-1). We reviewed data of 1264 patients enrolled at Melanoma Skin and Ocular Tissue Repositories at University of Iowa Hospitals and Clinic. Reviewed data included patient demographics, prior medical history, baseline hematologic and disease parameters and outcomes including progression-free survival (PFS) and overall survival (OS). Cox regression models were used to determine predictive markers. Overall, 169 patients with advanced cutaneous melanoma received anti-PD-1 based therapies. Median follow up was 18.46 (range 0.89 to 62.52) months. On multivariable analysis brain metastasis, higher absolute neutrophil count (ANC) and lower absolute lymphocyte count were associated with poorer PFS while brain and liver metastasis and lower albumin were associated with poorer OS. Prior antibiotics, radiation as well as age, gender, basal metabolic index (BMI), smoking status, mutation, line of therapy (first or latter), prior treatments (ipilimumab or BRAF inhibitors), hemoglobin, neutrophil-to-lymphocyte ratio, white blood cell, platelet and eosinophil counts were not associated with PFS or OS in multivariable analysis. Contrary to some prior studies BMI, radiation, and antibiotics were not associated with PFS or OS.
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http://dx.doi.org/10.3390/antibiotics9110740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692514PMC
October 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

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

Results of a Randomized, Double-Blinded, Placebo-Controlled, Phase 2.5 Study of Saracatinib (AZD0530), in Patients with Recurrent Osteosarcoma Localized to the Lung.

Sarcoma 2020 30;2020:7935475. Epub 2020 Apr 30.

Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California Children's Hospital Los Angeles, 4650 Sunset Blvd Mail Stop 57, Los Angeles, CA 90027, USA.

Purpose: Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. . Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles.

Results: Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (=0.47). Median OS was not reached in either arm.

Conclusions: Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.
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http://dx.doi.org/10.1155/2020/7935475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211262PMC
April 2020

Functional Genomic Screening Independently Identifies CUL3 as a Mediator of Vemurafenib Resistance via Src-Rac1 Signaling Axis.

Front Oncol 2020 3;10:442. Epub 2020 Apr 3.

Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, United States.

Patients with malignant melanoma have a 5-year survival rate of only 15-20% once the tumor has metastasized to distant tissues. While MAP kinase pathway inhibitors (MAPKi) are initially effective for the majority of patients with melanoma harboring BRAF mutation, over 90% of patients relapse within 2 years. Thus, there is a critical need for understanding MAPKi resistance mechanisms. In this manuscript, we performed a forward genetic screen using a whole genome shRNA library to identify negative regulators of vemurafenib resistance. We identified loss of NF1 and CUL3 as drivers of vemurafenib resistance. NF1 is a known driver of vemurafenib resistance in melanoma through its action as a negative regulator of RAS. However, the mechanism by which CUL3, a key protein in E3 ubiquitin ligase complexes, is involved in vemurafenib resistance was unknown. We found that loss of CUL3 was associated with an increase in RAC1 activity and MEK phosphorylation. However, the addition of the Src family inhibitor saracatinib prevented resistance to vemurafenib in CUL3 cells and reversed RAC1 activation. This finding suggests that inhibition of the Src family suppresses MAPKi resistance in CUL3 cells by inactivation of RAC1. Our results also indicated that the loss of CUL3 does not promote the activation of RAC1 through stabilization, suggesting that CUL3 is involved in the stability of upstream regulators of RAC1. Collectively, our study identifies the loss of CUL3 as a driver of MAPKi resistance through activation of RAC1 and demonstrates that inhibition of the Src family can suppress the MAPKi resistance phenotype in CUL3 cells by inactivating RAC1 protein.
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http://dx.doi.org/10.3389/fonc.2020.00442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169429PMC
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

Cancer Cells Resist Mechanical Destruction in Circulation via RhoA/Actomyosin-Dependent Mechano-Adaptation.

Cell Rep 2020 03;30(11):3864-3874.e6

Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Cancer Biology Program, Biomedical Sciences, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA; Departments of Pathology, Urology and Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address:

During metastasis, cancer cells are exposed to potentially destructive hemodynamic forces including fluid shear stress (FSS) while en route to distant sites. However, prior work indicates that cancer cells are more resistant to brief pulses of high-level FSS in vitro relative to non-transformed epithelial cells. Herein, we identify a mechano-adaptive mechanism of FSS resistance in cancer cells. Our findings demonstrate that cancer cells activate RhoA in response to FSS, which protects them from FSS-induced plasma membrane damage. We show that cancer cells freshly isolated from mouse and human tumors are resistant to FSS, that formin and myosin II activity protects circulating tumor cells (CTCs) from destruction, and that short-term inhibition of myosin II delays metastasis in mouse models. Collectively, our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought.
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http://dx.doi.org/10.1016/j.celrep.2020.02.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219793PMC
March 2020

Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer.

Cancer Chemother Pharmacol 2020 03 8;85(3):621-626. Epub 2020 Feb 8.

Mayo Clinic, Phoenix, AZ, USA.

Purpose: CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure to malignant cells and maximize clinical activity. CC-486 300 mg daily, administered for 14 or 21 days of 28-day treatment cycles, is currently under investigation in two ongoing phase III trials. The 300-mg daily dose in these studies is administered as two 150-mg tablets (Formulation A).

Methods: We evaluated the bioequivalence of one 300-mg CC-486 tablet (Formulation B) with Formulation A and food effect on Formulation B, in adult patients with cancer in a 2-stage crossover design study.

Results: The ratios of the geometric means of the maximum azacitidine plasma concentration (C) and of the area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC) were 101.5% and 105.7%, demonstrating the bioequivalence of Formulations A and B. Formulation B was rapidly absorbed under fasted and fed conditions. The geometric mean of C was significantly decreased by ~ 21% in the fed state. Median T was reached at 2 h and 1 h post-dose in fed and fasted states, respectively (P < 0.001). Nevertheless, systemic drug exposure (AUC) in fed and fasted states was within the 80-125% boundaries of bioequivalence and differences in C and T are not expected to have a clinical impact.

Conclusion: The single 300-mg CC-486 tablet was bioequivalent to two 150-mg tablets, which have shown to be efficacious and generally well-tolerated in clinical trials, and can be taken with or without food.
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http://dx.doi.org/10.1007/s00280-020-04037-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036073PMC
March 2020
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