Oncocyte Membrane-Camouflaged Multi-Stimuli-Responsive Nanohybrids for Synergistic Amplification of Tumor Oxidative Stresses and Photothermal Enhanced Cancer Therapy.

The combination of various therapeutic modalities has received considerable attention for improving antitumor performance. Herein, an innovative nanohybrid, namely CaO2@FePt-DOX@PDA@CM (CFDPM), was developed for synergistic chemotherapy/chemodynamic therapy/Ca2+ overloading-mediated amplification of tumor oxidative stress and photothermal enhanced cancer therapy. Camouflage of the 4T1 cell membrane enabled CFDPM to escape the immune surveillance and accumulate in the tumor tissue. Ca2+, released from CaO2, could lead to mitochondrial dysfunction and facilitate the production of reactive oxygen species to amplify intracellular oxidative stress. Meanwhile, the increase of H2O2 concentration could enhance the efficiency of the chemodynamic therapy (CDT). Moreover, the hypoxic condition could be alleviated remarkably, which is attributed to the sufficient O2 supply by CaO2, resulting in the suppression of drug resistance and promotion of the chemotherapeutic effect. The nanohybrids involving Ca2+ overloading/CDT/chemotherapy could synergistically amplify the tumor oxidative stresses and remarkably aggravate the death of cancer cells. Significantly, the excellent photothermal conversion performance of CFDPM could further promote the tumoricidal effect. The in vitro and in vivo studies revealed that CFDPM could effectively advance the therapeutic efficiency via the cooperation of various therapeutic modalities to optimize their individual virtue, which would open a valuable avenue for effective cancer treatment.

Clinical impact of follicular oncocytic (Hürthle cell) carcinoma in comparison with corresponding classical follicular thyroid carcinoma.

PURPOSE: There are controversial debates if patients with Hürthle cell carcinoma, also known as oxyphilic or oncocytic cell follicular thyroid carcinoma, have a poorer outcome. In this study, we systematically evaluated the clinical outcome in a large patient cohort following thyroidectomy and initial I-131 radioactive iodine therapy (RIT). METHODS: We retrospectively evaluated a total of 378 patients with diagnosed oncocytic follicular Hürthle cell carcinoma (OFTC) (N = 126) or with classical follicular thyroid carcinoma (FTC) (N = 252). Patients received thyroidectomy and complementary I-131 RIT. Clinical data regarding basic demographic characteristics, tumor grade, persistent disease and recurrence during follow-up, and disease-free, disease-specific, and overall survival were collected during follow-up of 6.9 years (interquartile range 3.7; 11.7 years). Univariate and multivariate analyses were used to identify factors associated with disease-related and overall survival. RESULTS: Before and after matching for risk factors, recurrence was significantly more frequently diagnosed in OFTC patients during follow-up (17% vs. 8%; p value 0.037). Likewise, OFTC patients presented with a reduced mean disease-free survival of 17.9 years (95% CI 16.0-19.8) vs. 20.1 years (95% CI 19.0-21.1) in FTC patients (p value 0.027). Multivariate analysis revealed OFTC (HR 0.502; 95% CI 0.309-0.816) as the only independent prognostic factor for disease-free survival. Distant metastases of OFTC patients were significantly less iodine-avid (p value 0.014). Mean disease-specific and overall survival did not differ significantly (p value 0.671 and 0.687) during follow-up of median 6.9 years (3.7; 11.7 years). CONCLUSIONS: Our study suggests that recurrence is more often seen in OFTC patients. OFTC patients have a poorer prognosis for disease-free survival. Thus, OFTC and FTC behave differently and should be categorized separately. However, patients suffering from OFTC present with the same overall and disease-specific survival at the end of follow-up indifferent to FTC patients after initial RIT.

Clinicopathological features and outcomes after radioactive iodine treatment of oncocytic well-differentiated thyroid carcinomas.

OBJECTIVE: The aim of this study was to compare the clinicopathological features of Hürthle cell carcinomas (HCC) and oncocytic papillary thyroid carcinomas (OPTC) and to evaluate their response to radioactive iodine (RAI) treatment. METHODS: We retrospectively reviewed the charts of patients with histopathologically verified OPTC (group 1) and HCC (group 2), during a 17-year period. All patients underwent total thyroidectomy and received RAI adjuvant therapy. Clinicopathological characteristics of the two groups were compared. Response to initial therapy was assessed 6 to 24 months after RAI ablation according to the American Thyroid Association dynamic risk reclassification. Clinical outcomes were evaluated. RESULTS: A total of 28 patients (8 OPTC and 20 HCC) were included. There was no significant difference in clinicopathological features including sex, age, tumour size and vascular invasion. Distant metastases were absent in both groups. OPTC, however, presented more features of local invasion (50% vs. 10%, P = 0.03), extrathyroidal extension (25% vs. 0%, P = 0.07) and lymph node involvement (37.5% vs. 0%, P = 0.01). Median cumulative RAI activity administered to both groups was 200 mCi (range: 100-300 mCi). Response to RAI therapy was excellent in all HCC and 87.5% of OPTC (P = 0.28). One patient with OPTC (12.5%) presented an indeterminate response. Clinical outcomes were favourable after a median follow-up of 87.5 and 49 months, respectively. CONCLUSION: Although OPTC presented more locoregional invasion, clinicopathological characteristics of OPTC and HCC were comparable. Both OPTC and HCC were iodine responsive. We suggest that adjuvant RAI therapy after total thyroidectomy is beneficial for OPTC and HCC and may improve disease-free survival.

Rectal adenocarcinoma with oncocytic features: possible relationship with preoperative chemoradiotherapy.

BACKGROUND: The introduction of preoperative chemoradiation into the treatment protocol of rectal adenocarcinomas has affected the microscopical morphology in subsequent resection specimens. The constellation of histopathological changes is varied and well documented. AIM: To describe oncocytic change in rectal cancers that have been treated with chemoradiation before surgery. METHODS: 7 of 54 patients with rectal cancer were identified with a history of chemoradiation, specifically directed to the rectal tumours in fractions of 4500-5000 cGy of radiation and 5-fluorouracil. The rectal tumours in five of these seven patients were composed of oncocytes that constituted 30-80% of the cancers. The patients were three men and two women aged 65-73 years, all with T3 N0 tumours. The intervals between chemoradiation and resection varied from 3 to 12 weeks. RESULTS: The tumour cells conformed to oncocytes morphologically (large size with abundant, granular eosinophilic cytoplasm, vesicular nuclei and prominent acidophilic nucleoli), immunohistochemically (positive for carcinoembryonic antigen, cytokeratin 20 and caudal type homeo box transcription factor 2, but negative for both chromogranin and synaptophysin) and ultrastructurally (large cells showing tight junctions, cytoplasmic engorgement by mitochondria and absence of neurosecretory granules). CONCLUSIONS: The changes in these cells differ from those described previously in endocrine cells encountered in pretreated rectal cancers. Oncocytic change in this particular clinical context occurs as a reflection of cytotoxic damage or cellular hypoxia induced by chemoradiation resulting in degeneration of the cell and the oncocytic phenotype. Oncocytic change may be an under-recognised histopathological change in rectal cancers receiving preoperative chemoradiation.

Oncocytic modifications in rectal adenocarcinomas after radio and chemotherapy.

The purpose of the study is to highlight oncocytic modifications in rectal adenocarcinomas and evaluate a possible correlation with preoperative radiochemotherapy (RCT). Twenty-eight cases of advanced rectal carcinoma, treated preoperatively by 5-fluorouracil (200-225 mg/m(2)) and 44-46 Gy in 22-23 fractions, were studied. All patients underwent biopsy before RCT. Surgery was performed within 6 weeks after RCT. In all cases oncocytic modifications were searched for on hematoxylin and eosin (H&E) and at immunohistochemistry using an antimitochondrial antibody. In addition, in two cases, both pre- and post-RCT tissues were examined at electron microscopy. All tumors were adenocarcinomas. In pre-RCT biopsies, oncocytic changes were difficult to find on H&E, while the antimitochondrial antibody strongly stained numerous neoplastic cells (mean 48.4%). In post-RCT surgical specimens, oncocytic changes were detected in 24 out of 28 cases on H&E and the antimitochondrial antibody stained most of the residual neoplastic cells (mean 76.7%). Ultrastructural examination revealed large and bizarre mitochondria inside tumor cells both in pre- and post-RCT tissues. In conclusion, the present data suggest that rectal adenocarcinomas are "mitochondrion-rich" tumors. After preoperative RCT, residual neoplastic cells acquire a definite oncocytic phenotype.

Hürthle cell carcinoma.

Patients with Hürthle cell carcinoma (HCC) of the thyroid often have aggressive tumors and generally have a worse prognosis than those with papillary or follicular thyroid carcinomas. A total thyroidectomy with ipsilateral central neck lymphadenectomy and a modified radical neck dissection, if central or lateral nodes are positive, are indicated for HCC. The completeness of this procedure should be assessed by radioiodine scan 3 to 4 months after surgery. Any thyroid remnant should be ablated with radiolabeled iodine 131 to eliminate all tissue at risk and to facilitate the use of serum thyroglobulin in surveillance for tumor recurrence. Fewer than 10% of these cancers take up radioiodine. Recurrent disease is treated surgically with good palliation and appreciable prolongation of life. Local excision and neck dissection for recurrent neck disease or pulmonary wedge resection for lung metastasis has been shown to be effective. All patients with HCC should be given thyroid hormone because most of these tumors have thyrotropin receptors. External beam radiation may be considered for patients with unresectable disease, but this is considered palliative.