Comparison of Prognostic Value Between Stimulated and Nonstimulated Thyroglobulins in Differentiated Thyroid Cancer: A Retrospective Study.

Purpose: The growing incidence of differentiated thyroid cancer (DTC) demands dependable prognostic factors to guide follow-up and treatment plans. This study investigated the prognostic value of response to therapy (RTT) assessment using TSH stimulated-thyroglobulin (sti-Tg) and nonstimulated-thyroglobulin (nonsti-Tg) and evaluates whether RTT using nonsti-Tg (nonstiRTT) can replace RTT using sti-Tg (stiRTT) in clinical practice to improve patients' quality of life during assessment. Methods: We enrolled 419 DTC patients who underwent total thyroidectomy, radioactive iodine (RAI) therapy, and Tg assessment. Patients with structural incomplete responses were excluded. Initial RTT assessments based on the 2015 American Thyroid Association guidelines (excellent response; ER, indeterminate response, biochemical incomplete response) were performed 6-24 months after RAI therapy. The second RTT assessments were performed 6-24 months after the first assessment. Statistical analysis for recurrence-free survival (RFS) was done with the log-rank test for stiRTT and nonstiRTT. Results: Although initial stiRTT and nonstiRTT were significant predictors for RFS (p < 0.0001), stiRTT provided better RFS prediction than nonstiRTT. The RFS analysis of the second RTT assessment demonstrated statistical significance only for stiRTT (p < 0.0001). In 116 patients classified as ER on initial stiRTT, there was no RFS difference between patients classified as ER on either second stiRTT or nonstiRTT. Conclusion: The prognostic power of stiRTT surpasses that of nonstiRTT in both the initial and second RTT assessment. Nevertheless, among patients classified as ER on initial stiRTT, a second stiRTT may not be required for those classified as ER on the second nonstiRTT. Supplementary Information: The online version contains supplementary material available at 10.1007/s13139-023-00811-8.

The Preventive Effect of Parotid Gland Massage on Salivary Gland Dysfunction During High-Dose Radioactive Iodine Therapy for Differentiated Thyroid Cancer: A Randomized Clinical Trial.

PURPOSE: To evaluate the preventive effect of parotid gland (PG) massage for PG damage during the I therapy, we prospectively investigated the serum amylase value and salivary gland scintigraphy (SGS) after I therapy. MATERIALS AND METHODS: One hundred patients with thyroidectomized differentiated thyroid cancer who underwent high-dose I therapy were enrolled in the clinical trial and randomized into 2 groups (PG massage group and nonmassage group). The serum amylase value was obtained before and 24 hours after I therapy, and the SGSs were also taken just before and at 8 months after the I therapy. Change in serum amylase value and SGS was compared between PG massage and nonmassage groups. RESULTS: The difference value of serum amylase was significantly lower in PG massage group than in nonmassage group (P = 0.0052). Worsening of PG function on SGS was observed in 43 (45.3%) of the 95 patients. The incidence rate of PG abnormality on F/U SGS was significantly lower in PG massage group than in nonmassage group (odds ratio, 0.3704; P = 0.0195). In the multiple regression analysis, PG massage significantly affected the abnormality on the 8-month F/U SGS (rpartial = -0.2741, P = 0.0090) after adjusting for clinical variables (age, sex, TNM stage, TSH preparation methods for the I therapy, and I dose). CONCLUSIONS: PG gland massage significantly reduced the incidence rates of salivary gland dysfunction on the 8-month F/U SGS and the level of the serological marker of salivary gland destruction after I therapy. Therefore, PG gland massage could alleviate salivary gland damage related to I therapy.

Clinical outcomes of patients with T4 or N1b well-differentiated thyroid cancer after different strategies of adjuvant radioiodine therapy.

We aimed to determine whether recombinant human thyrotropin (rhTSH) plus 3.7 GBq could replace thyroid hormone withdrawal (THW) plus 5.55 GBq for adjuvant radioactive iodine (RAI) therapy in differentiated thyroid cancer (DTC) patients with T4 or N1b disease. This study was a retrospective study comparing ablation success rate, response to initial therapy, and recurrence-free survival (RFS) of patients with rhTSH plus 3.7 GBq versus those with THW plus 5.55 GBq in 253 DTC patients with T4 or N1b disease. There were no differences in the TSH-stimulated thyroglobulin level, rate of incomplete response after initial treatment, or the RFS between the two treatment strategies. However, thyroid bed uptake on follow-up diagnostic RAI whole-body scanning (WBS) was more frequently observed in the group treated with rhTSH plus 3.7 GBq than in the group with THW plus 5.55 GBq. Adjuvant RAI therapy with rhTSH plus 3.7 GBq had comparable results in the absence of persistent tumor, compared with that with THW plus 5.55 GBq. Although thyroid bed uptake was more frequently observed, rhTSH plus 3.7 GBq may be used instead of THW plus 5.55 GBq for adjuvant RAI therapy in patients with T4 or N1b disease.

Clinical outcomes of low-dose and high-dose postoperative radioiodine therapy in patients with intermediate-risk differentiated thyroid cancer.

PURPOSE: Recent studies have suggested that a low dose (LD) of radioiodine (RAI) is sufficient to treat differentiated thyroid cancer (DTC) even in patients with intermediate risk. However, these studies evaluated the efficacy of RAI therapy, irrespective of the results of the whole-body scan (WBS). The aim of the present study was to evaluate the response to LD and high-dose (HD) RAI therapy using two different criteria (with and without WBS results) and the reclassification system according to the revised 2015 guidelines of the American Thyroid Association in Korean intermediate-risk DTC patients. In addition, we evaluated the long-term clinical outcomes of treatment with LD and HD RAI. MATERIALS AND METHODS: In total, 204 intermediate-risk DTC patients who underwent postoperative RAI therapy at two tertiary referral hospitals from 2003 to 2004 were enrolled in the present retrospective study. One hundred and twenty-four patients were treated with 3.7 and 5.55 GBq (HD) of RAI in one center and 80 patients were treated with 1.11 GBq (LD) in the other center. The success rate of RAI therapy was assessed with or without the inclusion of WBS results in the analysis. In addition, the response to therapy during the first 2 years of follow-up after the initial RAI therapy was categorized according to the reclassification system of 2015 American Thyroid Association guidelines as excellent response, indeterminate response, biochemical incomplete response, or structural incomplete response. Recurrence was defined as a newly detected cytologically or pathologically confirmed lesion. RESULTS: There were no significant differences between the success rates of the HD and LD groups irrespective of the inclusion of WBS results in the analysis (with WBS: 54.84 vs. 45.0%, P=0.23; without WBS: 60.48 vs. 62.5%, P=0.77). The response to HD and LD RAI therapy was excellent in 54.84 and 45.0% of the patients, respectively; indeterminate in 34.68 and 30.0% of the patients, respectively; biochemical incomplete in 4.03 and 13.75% of the patients, respectively; and structural incomplete in 6.45% and in 11.25% of the patients, respectively (P=0.04). In particular, the biochemical or structural incomplete response rate was lower in patients treated with HD than in patients treated with LD (HD, 10.48%; LD, 25.0%, P=0.01). At the last follow-up (HD, median 11 years; LD, median 10 years), patients who achieved an excellent response showed no evidence of disease. After the initial RAI therapy, eight patients in the HD group and 18 patients in the LD group who achieved either indeterminate response or biochemical incomplete response received additional RAI therapy. Seven patients (indeterminate response in five patients; biochemical incomplete response in two patients) in the HD group and seven patients (indeterminate response in five patients; biochemical incomplete response in two patients) in the LD group showed recurrences. CONCLUSION: LD RAI therapy after thyroidectomy appears to be insufficient in Korean DTC patients with intermediate risk. The patients in the LD group predominantly showed biochemical or structural incomplete response to initial RAI therapy and additional RAI therapy was required.

Brazilin Isolated from Caesalpinia sappan suppresses nuclear envelope reassembly by inhibiting barrier-to-autointegration factor phosphorylation.

To date, many anticancer drugs have been developed by directly or indirectly targeting microtubules, which are involved in cell division. Although this approach has yielded many anticancer drugs, these drugs produce undesirable side effects. An alternative strategy is needed, and targeting mitotic exit may be one alternative approach. Localization of phosphorylated barrier-to-autointegration factor (BAF) to the chromosomal core region is essential for nuclear envelope compartment relocalization. In this study, we isolated brazilin from Caesalpinia sappan Leguminosae and demonstrated that it inhibited BAF phosphorylation in vitro and in vivo. Moreover, we demonstrated direct binding between brazilin and BAF. The inhibition of BAF phosphorylation induced abnormal nuclear envelope reassembly and cell death, indicating that perturbation of nuclear envelope reassembly could be a novel approach to anticancer therapy. We propose that brazilin isolated from C. sappan may be a new anticancer drug candidate that induces cell death by inhibiting vaccinia-related kinase 1-mediated BAF phosphorylation.

Emptying effect of massage on parotid gland radioiodine content.

BACKGROUND: To prevent salivary dysfunction in thyroid cancer patients who have undergone radioiodine ablation, massaging the parotid gland (PG) is presumed to be helpful for the removal of radioiodine. The purpose of this study was to evaluate the effect of PG massage in the removal of radioiodine from the PG. METHODS: Forty-four patients (female, 38; 49.1 ± 11.0 years) who underwent total thyroidectomy followed by I-131 ablation were included in this prospective study. Three serial salivary gland scans were performed 2 h after administration of I-123 in thyroid hormone withdrawal status. The patients were divided into two groups. There was a 1-min (or 2-min) interval between the first and second scans for control, followed by the performance of PG massage for 1 min (or 2 min) between the second and third scans. Changes in uptakes were calculated between the first and second scans (control) and between the second and third scans (massage). RESULTS: The mean change in uptake at the 1-min massage was 0.97 ± 11.27%, whereas that at the 1-min control was 11.54 ± 5.59% (P<0.001). The mean change in uptake at the 2-min massage was also significantly lower than that at the 2-min control (11.11 ± 6.97 vs. -0.85 ± 9.78%, P<0.001). However, no statistical difference was observed between the mean changes in uptake after 1- and 2-min massages (P=0.573). CONCLUSION: PG massage reduced the radioiodine uptake in the PG, and the effect of PG massage for 1 min was comparable with that of PG massage for 2 min. PG massage can be applied to thyroid cancer patients who receive radioiodine therapy to reduce PG dysfunction.

Scoparone exerts anti-tumor activity against DU145 prostate cancer cells via inhibition of STAT3 activity.

Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3) contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2) or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C) was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.

Curcumin in various cancers.

Curcumin (diferuloylmethane), an active constituent of turmeric, is a well-described phytochemical, which has been used since ancient times for the treatment of various diseases. The dysregulation of cell signaling pathways by the gradual alteration of regulatory proteins is the root cause of cancers. Curcumin modulates regulatory proteins through various molecular mechanisms. Several research studies have provided in-depth analysis of multiple targets through which curcumin induces protective effects against cancers including gastrointestinal, genitourinary, gynecological, hematological, pulmonary, thymic, brain, breast, and bone. The molecular mechanisms of action of curcumin in treating different types of cancers remain under investigation. The multifaceted role of this dietary agent is mediated through its inhibition of several cell signaling pathways at multiple levels. Curcumin has the ability to inhibit carcinogenicity through the modulation of the cell cycle by binding directly and indirectly to molecular targets including transcription factors (NF-kB, STAT3, ß-catenin, and AP-1), growth factors (EGF, PDGF, and VEGF), enzymes (COX-2, iNOS, and MMPs), kinases (cyclin D1, CDKs, Akt, PKC, and AMPK), inflammatory cytokines (TNF, MCP, IL-1, and IL-6), upregulation of proapoptotic (Bax, Bad, and Bak) and downregulation of antiapoptotic proteins (Bcl(2) and Bcl-xL). A variety of animal models and human studies have proven that curcumin is safe and well tolerated even at very high doses. This study elaborates the current understanding of the chemopreventive effects of curcumin through its multiple molecular pathways and highlights its therapeutic value in the treatment and prevention of a wide range of cancers.

Effect of parotid gland massage on parotid gland Tc-99m pertechnetate uptake.

BACKGROUND: Salivary dysfunction is the most common side effect associated with (131)I therapy in patients with differentiated thyroid cancer. The purpose of this study was to evaluate the effect of parotid gland (PG) massage on radioisotope accumulation in the salivary gland. METHODS: Sixty patients were included in this study. Using Tc-99m pertechnetate, two salivary scans were performed in all patients. In 30 patients, PG massage was performed between the two salivary gland scans, whereas in the other 30 patients no massage was performed between the two scans. Total counts of both PGs and accumulation ratios were calculated. RESULTS: In the patients who received massage, no difference was observed between the mean PG counts of first and second images (8556.9±3333.4 count vs. 8598.3±3341.3 count, p=0.39). In the patients who did not receive massage, the mean PG count on second images was significantly higher than that on first images (8581.2±3618.0 count vs. 9096.4±3654.0 count, p<0.01). Mean accumulation ratio in the patients who received massage was significantly lower than in the patients who did not receive massage (0.5%±3.3% vs. 6.8%±3.8%, p<0.01). Further, among the patients who received massage there was a higher percentage of patients with a negative accumulation ratio than among the patients who did not receive massage (43.3% vs. 0%, p<0.01). CONCLUSIONS: PG massage can reduce Tc-99m pertechnetate accumulation in the PG, and thus, should be helpful to prevent salivary damage associated with (131)I therapy.

Prognostic implications of microscopic involvement of surgical resection margin in patients with differentiated papillary thyroid cancer after high-dose radioactive iodine ablation.

OBJECTIVE: To evaluate the relationship between microscopic cancerous involvement of surgical margin and recurrence in patients with differentiated papillary thyroid cancer (PTC) who underwent total thyroidectomy followed by high-dose radioactive iodine ablation (HDRIA). METHODS: Consecutive 197 PTC patients (184 women; mean age 44.9 years) who underwent total thyroidectomy without gross residual tumor followed by HDRIA were retrospectively reviewed. Resection margin involvement was evaluated and recurrence of the disease was assessed with clinicopathologically. Recurrence detected within 12 months after HDRIA were defined as early recurrence, detected after 12 months were defined as late recurrence. RESULTS: The mean follow-up was 85.9 ± 16.6 months. Twelve patients (6.1%) had microscopic cancerous involvement of surgical margin [margin (+) group], and 185 patients had negative surgical resection margins [margin (-) group]. Three patients (25.0%) in the margin (+) group and 11 patients (5.9%) in the margin (-) group had early recurrence. Margin (+) group showed higher incidence of early recurrence and lower incidence of disease free compared to margin (-) group (25.0 vs. 5.9%, p < 0.01; 66.7 vs. 81.1%, p < 0.01, respectively); however, there was no difference in incidence of late recurrence between the two groups (p = 1.00). There were no significant differences in the disease-free survival between the margin (+) and margin (-) groups after exclusion of early recurrence (p = 0.78). CONCLUSIONS: After high-dose radioactive iodine ablation, PTC patients with microscopic cancerous surgical margin involvement had a higher incidence of early recurrence and no different late recurrence rate compared to patients without microscopic cancerous surgical margin involvement.

Pulmonary aspergilloma mimicking metastasis from papillary thyroid cancer.

BACKGROUND: Whole-body scans (WBSs) based on diagnostic or therapeutic doses of I-131 can visualize metastatic lesions in thyroid cancer patients who have undergone total thyroidectomy. However, a variety of unusual lesions may cause false-positive results, and therefore, careful evaluation of abnormal scans is imperative to avoid unnecessary surgical removal or high-dose radioiodine treatment. Here, we report a patient with pulmonary aspergilloma mimicking metastasis of thyroid cancer on WBS. SUMMARY: A 53-year-old woman with papillary thyroid cancer stage III (T1N1aM0) who had undergone total thyroidectomy and 150 mCi of radioiodine treatment for remnant ablation was found to have focal intense radioiodine accumulation in the left lung field by WBS, suggestive of pulmonary metastasis, at 5 days after I-131 administration. Whole-body F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and Tc-99m methoxyisobutyl isonitrile scans showed no remarkable tracer accumulation at the pulmonary nodule. An enhanced chest CT scan demonstrated a nonenhancing pulmonary nodule with an air-crescent sign suggestive of pulmonary fungus ball. A subsequent blood test for precipitating antibodies to Aspergillus antigens produced a result of 29.9 U/mL (reference range: 0-8 U/mL). The patient was clinically diagnosed as having pulmonary aspergilloma based on serologic test and radiologic imaging results. CONCLUSION: Extreme caution should be exercised when interpreting abnormal radioiodine WBS findings when the serum thyroglobulin is normal and imaging characteristics indicate a benign condition. Pulmonary aspergilloma is a cause of a false-positive lesion when radioiodine WBSs are performed.

RETRACTED ARTICLE: Radiation sialadenitis induced by high-dose radioactive iodine therapy.

Radioactive iodine ((131)I) is accumulated in the thyroid tissue and plays an important role in the treatment of differentiated papillary and follicular cancers after thyroidectomy. Simultaneously, (131)I is concentrated in the salivary glands and secreted into the saliva. Dose-related damage to the salivary parenchyma results from the (131)I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of (131)I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, candidiasis, and neoplasia. Prevention of (131)I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration. Recently interventional sialoendoscopy has been introduced an effective tool for the management of patients with (131)I-induced sialadenitis that is unresponsive to medical treatment.

In vitro antiproliferative characteristics of flavonoids and diazepam on SNU-C4 colorectal adenocarcinoma cells.

The need for beneficial use of sedatives in oncologic patients is increasing. Therefore, in this study, antiproliferative characteristics of herbal and synthetic sedatives were examined in vitro in SNU-C4 human colorectal adenocarcinoma cells. Apigenin (50% inhibition concentration, IC(50) = 1.8 +/- 0.5 microM) and diazepam (IC(50) = 7.0 +/- 0.5 microM) showed concentration-dependent inhibition of SNU-C4 cancer cell survival. Efficacy of cancer cell survival inhibition by apigenin and diazepam was much lower than that of 5-fluorouracil (5-FU), a known chemotherapeutic drug. However, 10(-6) M concentration of apigenin and diazepam potentiated 5-FU-induced cytotoxicity. In SNU-C4 cells, 10(-6) M concentrations of diazepam, flumazenil (Ro15-1788), Ro5-4864, or PK11195, all ligands for central- or peripheral-type benzodiazepine (BZD) receptors, inhibited cell survival like the flavonoid apigenin (4',5,7-trihydroxyflavone) and fisetin (3,7,3',4'-tetrahydroxyflavone). Also like the plant flavonoids, treatment with 10(-6) M concentration of diazepam for 3 days hardly affect the peripheral-type BZD receptor (PBR) messenger RNA (mRNA) expression and inhibited glucose utilization of SNU-C4 cells. Treatment with flavonoids or diazepam for 6 days upregulated PBR mRNA expression and cell cytotoxicity of SNU-C4 cells. Furthermore, treatment with 10(-6) M concentration of apigenin, a natural sedative material originating from traditional herbs, positively modulated BZD-induced antiproliferative cytotoxicity in SNU-C4 cells. Overall, the in vitro antiproliferative activity on SNU-C4 cancer cells of herbal sedatives, such as apigenin, plus additive enhancement of synthetic BZD- and 5-FU-induced antiproliferative activities, were shown. In conclusion, this study provides experimental basis for advanced trial in the future.

Upregulation of PBR mRNA expression in human neuroblastoma cells by flavonoids.

To investigate the putative mediation of peripheral benzodiazepine receptor (PBR) in the cytotoxicity of flavonoids, in this study, modulatory effects of several flavonoids on the lipid peroxide (LPO) production and PBR mRNA expression of human neuroblastoma cells were observed. Elevated levels of peroxidated products in cancer cells may activate pro-apoptotic and anti-proliferative signaling pathways. Treatment of 10(-6) M 4'-chlorodiazepam and PK 11195 ligands of the PBR for 6 days enhanced the generation of LPO of the human neuroblastoma cells. Several flavonoids, well-known cytotoxic substances, potentiated the enhancement of LPO production by PBR ligands. Treatment of 10(-6) M flavonoids for 6 days elevated the expression of PBR mRNA in cells. These findings indicate that the potential of flavonoids to induce apoptosis in cancer cells is strongly associated with their PBR-inducing properties, thereby providing a new mechanism by which polyphenolic compounds may exert their cancer-preventive and anti-neoplastic effects.