Publications by authors named "R Michael Tuttle"

602 Publications

Primary High Grade Non-Anaplastic Thyroid Carcinoma: A Retrospective Study of 364 Cases.

Histopathology 2021 Aug 27. Epub 2021 Aug 27.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: High grade non-anaplastic thyroid carcinomas (HGTC) are carcinomas of follicular cells with prognosis intermediate between well-differentiated and anaplastic carcinoma.

Methods: This study includes 364 HGTC patients: 200 patients (54.9%) were diagnosed as poorly differentiated thyroid carcinoma based on Turin consensus (HGTC-PDTC) and 164 with high grade features that did not meet Turin criteria (HGTC-nonPDTC).

Results: HGTC are aggressive: 3-year, 5-year, 10-year, and 20-year disease specific survival (DSS) were 89%, 76%, 60% and 35% respectively. Although DSS was similar between HGTC-PDTC and HGTC-nonPDTC, HGTC-PDTC was associated with higher rate of RAI avidity, higher frequency of RAS mutations, lower rate of BRAF V600E mutations, and higher propensity for distant metastasis (DM) compared with HGTC-nonPDTC. Independent clinicopathologic markers of worse outcome were older age, male sex, extensive necrosis, lack of encapsulation for DSS; older age, male sex, vascular invasion for DM free survival; older age, necrosis, positive margin, lymph node metastasis for locoregional recurrence free survival. The frequency of BRAF, RAS, TERT, TP53, and PTEN alterations was 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN, and TERT were independent molecular markers associated with unfavorable outcome independent of clinicopathologic parameters. Coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM.

Conclusions: The above data supports the classification of high grade non-anaplastic thyroid carcinoma as a single group with two distinct subtypes based on tumor differentiation: HGTC-PDTC and HGTC-nonPDTC.
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http://dx.doi.org/10.1111/his.14550DOI Listing
August 2021

Blood-Based Multi-Cancer Detection Using a Novel Variant Calling Assay (DEEPGEN): Early Clinical Results.

Cancers (Basel) 2021 Aug 15;13(16). Epub 2021 Aug 15.

Division of Visceral Surgery, Department of Surgery, University Hospital Geneva and Medical School, 1211 Geneva, Switzerland.

This is an early clinical analysis of the DEEPGENTM platform for cancer detection. Newly diagnosed cancer patients and individuals with no known malignancy were included in a prospective open-label case-controlled study (NCT03517332). Plasma cfDNA that was extracted from peripheral blood was sequenced and data were processed using machine-learning algorithms to derive cancer prediction scores. A total of 260 cancer patients and 415 controls were included in the study. Overall, sensitivity for all cancers was 57% (95% CI: 52, 64) at 95% specificity, and 43% (95% CI: 37, 49) at 99% specificity. With 51% sensitivity and 95% specificity for all stage 1 cancers, the stage-specific sensitivities trended to improve with higher stages. Early results from this preliminary clinical, prospective evaluation of the DEEPGENTM liquid biopsy platform suggests the platform offers a clinically relevant ability to differentiate individuals with and without known cancer, even at early stages of cancer.
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http://dx.doi.org/10.3390/cancers13164104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392437PMC
August 2021

Pulmonary injury and oxidative stress in rats induced by inhaled sulfur mustard is ameliorated by anti-tumor necrosis factor-α antibody.

Toxicol Appl Pharmacol 2021 Oct 11;428:115677. Epub 2021 Aug 11.

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. Electronic address:

Sulfur mustard (SM) is a bifunctional alkylating agent that causes severe injury to the respiratory tract. This is accompanied by an accumulation of macrophages in the lung and the release of the proinflammatory cytokine, tumor necrosis factor (TNF)α. In these studies, we analyzed the effects of blocking TNFα on lung injury, inflammation and oxidative stress induced by inhaled SM. Rats were treated with SM vapor (0.4 mg/kg) or air control by intratracheal inhalation. This was followed 15-30 min later by anti-TNFα antibody (15mg/kg, i.v.) or PBS control. Animals were euthanized 3 days later. Anti-TNFα antibody was found to blunt SM-induced peribronchial edema, perivascular inflammation and alveolar plasma protein and inflammatory cell accumulation in the lung; this was associated with reduced expression of PCNA in histologic sections and decreases in BAL levels of fibrinogen. SM-induced increases in inflammatory proteins including soluble receptor for glycation end products, its ligand, high mobility group box-1, and matrix metalloproteinase-9 were also reduced by anti-TNFα antibody administration, along with increases in numbers of lung macrophages expressing TNFα, cyclooxygenase-2 and inducible nitric oxide synthase. This was correlated with reduced oxidative stress as measured by expression of heme oxygenase-1 and Ym-1. Together, these data suggest that inhibiting TNFα may represent an efficacious approach to mitigating acute lung injury, inflammatory macrophage activation, and oxidative stress induced by inhaled sulfur mustard.
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http://dx.doi.org/10.1016/j.taap.2021.115677DOI Listing
October 2021

Intensity-modulated radiation therapy and doxorubicin in thyroid cancer: A prospective phase 2 trial.

Cancer 2021 Jul 22. Epub 2021 Jul 22.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: The use of external-beam radiotherapy for locally advanced nonanaplastic thyroid cancer remains controversial. This prospective study evaluated the efficacy and tolerability of intensity-modulated radiation therapy (IMRT) with or without concurrent chemotherapy in patients with locally advanced thyroid cancer.

Methods: The authors conducted a nonrandomized phase 2 trial of IMRT with or without concurrent doxorubicin in patients with gross residual or unresectable nonanaplastic thyroid carcinoma (ClinicalTrials.gov identifier NCT01882816). The primary end point was 2-year locoregional progression-free survival (PFS). Secondary end points included overall survival (OS), safety, patient-reported outcomes, and functional outcomes.

Results: Twenty-seven patients were enrolled: 12 (44.4%) with unresectable disease and 15 (55.6%) with gross residual disease. The median follow-up was 45.6 months (interquartile range, 42.0-51.6 months); the 2-year cumulative incidences of locoregional PFS and OS were 79.7% and 77.3%, respectively. The rate of grade 3 or higher acute and late toxicities was 33.4%. There were no significant functional differences 12 months after treatment (assessed objectively by the modified barium swallow study). Patient-reported quality of life in the experimental group was initially lower but returned to the baseline after 6 months and improved thereafter. In a post hoc analysis, concurrent chemotherapy with intensity-modulated radiation therapy (CC-IMRT) resulted in significantly less locoregional failure at 2 years (no failure vs 50%; P = .001), with higher rates of grade 2 or higher acute dermatitis, mucositis, and dysphagia but no difference in long-term toxicity, functionality, or patient-reported quality of life.

Conclusions: In light of the excellent locoregional control rates achieved with CC-IMRT and its acceptable toxicity profile as confirmed by functional assessments and patient-reported outcomes, CC-IMRT may be preferred over IMRT alone.
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http://dx.doi.org/10.1002/cncr.33804DOI Listing
July 2021

Monitoring a MOF Catalyzed Reaction Directly in Blood Plasma.

ACS Appl Mater Interfaces 2021 Jul 19. Epub 2021 Jul 19.

Herein, we establish a method to quantitatively monitor a metal-organic framework (MOF)-catalyzed, biomedically relevant reaction directly in blood plasma, specifically, the generation of nitric oxide (NO) from the endogenous substrate -nitrosoglutathione (GSNO) catalyzed by H[(CuCl)-(BTTri)] (CuBTTri). The reaction monitoring method uses UV-vis and H NMR spectroscopies along with a nitric oxide analyzer (NOA) to yield the reaction stoichiometry and catalytic rate for GSNO to NO conversion catalyzed by CuBTTri in blood plasma. The results show 100% loss of GSNO within 16 h and production of 1 equiv. of glutathione disulfide (GSSG) per 2 equiv. of GSNO. Only 78 ± 10% recovery of NO(g) was observed, indicating that blood plasma can scavenge the generated NO before it can escape the reaction vessel. Significantly, to best apply and understand reaction systems with biomedical importance, such as NO release catalyzed by CuBTTri, methods to study the reaction directly in biological solvents must be developed.
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http://dx.doi.org/10.1021/acsami.1c08917DOI Listing
July 2021
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