Thyroid-Stimulating Hormone, Age, and Tumor Size are Risk Factors for Progression During Active Surveillance of Low-Risk Papillary Thyroid Microcarcinoma in Adults.

BACKGROUND: Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and is gradually spreading worldwide. We assessed the effect of thyroid-stimulating hormone (TSH) levels on PTMC enlargement in patients on AS. METHODS: We enrolled 2705 patients with cytologically diagnosed PTMC who had undergone AS between January 2005 and July 2019. Patients with Graves disease were excluded. The median AS period was 5.5 years (range 1.0-15.7 years). Tumor enlargement was defined as a size increase ≥3 mm. Chi-square test, Kaplan-Meier method, log-rank test, Cox proportional hazard, and logistic regression were used to compare variables. RESULTS: Ninety-two patients (3.4%) experienced tumor enlargement; the 5-, 10-, and 15-year enlargement rates were 3.0%, 5.5%, and 6.2%, respectively. Young age (<40 years, p < 0.001), large tumor size (≥9 mm, p = 0.017), and high detailed TSH score (≥3, higher than the lower normal limit, p = 0.011) were significant factors relating to tumor enlargement in the multivariate analysis. In a subset of patients aged <40 years, a low detailed TSH score (<3) was an independent factor against tumor enlargement (p = 0.039). Only 22 patients (0.8%) experienced novel lymph node metastasis; the 5-, 10-, and 15-year node metastasis rates were very low, at 0.9%, 1.1%, and 1.1%, respectively. CONCLUSIONS: Young patients with PTMC are more likely to experience tumor growth. Mild TSH suppression to achieve a low normal range may prevent carcinoma enlargement; however, prospective studies are needed to draw more reliable conclusions.

Active surveillance is an excellent management technique for identifying patients with progressive low-risk papillary thyroid microcarcinoma requiring surgical treatment.

Although the outcomes of active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) are generally excellent, some patients undergo conversion surgery for various reasons, including disease progression. We studied the outcomes of PTMC patients who underwent AS, who underwent conversion surgery after AS, and who underwent immediate surgery. Between 2005 and 2019, 4,635 patients were diagnosed with low-risk cT1aN0M0 PTMC at Kuma Hospital: 2,896 opted for AS (AS group) and 1,739 underwent immediate surgery (Surgery group). In the AS group, 242 patients underwent conversion surgery (Conversion group): 72 owing to disease progression (Conversion-prog group) and 170 for other reasons (Conversion-non-prog group). Of the 1,739 patients in the Surgery group, 1,625 had no high-risk features (Surgery-low-risk group). Locoregional recurrence (LRR) occurred in 9, 1, 1, and 0 patient in the Surgery-low-risk group, the Conversion-prog group, the AS group, and the Conversion-non-prog group, respectively. The LRR rate of the AS group was significantly lower than that of the Surgery-low-risk group (0.1% vs. 0.7% at 10 years, p = 0.006). Additionally, the LRR rate of the Conversion group (0.6% at 10 years, p = 0.741) and that of the Conversion-prog group (3.3% at 10 years, p = 0.103) did not significantly differ from the LRR of the Surgery-low-risk group. As the postoperative prognosis of patients with progressive PTMC who underwent conversion surgery did not significantly differ from that of patients who underwent immediate surgery, we think that AS may have resulted in efficient identification of the small proportion of patients with progressive PTMC that require surgical treatment.

Observational management of papillary microcarcinoma appearing in the remnant thyroid after hemithyroidectomy.

Active surveillance for papillary thyroid microcarcinomas (PTMCs) initiated in Japan is becoming adopted worldwide as a management option. However, it remains unclear how to manage newly appearing PTMCs in the remnant thyroid after hemithyroidectomy. We investigated the outcomes of similar observational management (OM) for PTMCs appearing in the remnant thyroid after hemithyroidectomy for papillary thyroid carcinoma (PTC) and benign thyroid nodules. Eighty-three patients were newly diagnosed with PTMC in the remnant thyroid between January 1998 and March 2017. Of these, 42 patients underwent OM with >3 times ultrasound examinations. Their initial diagnoses were PTC (initially malignant group) in 37 patients and benign nodule (initially benign group) in 5 patients. We calculated the tumor volume doubling rate (TV-DR) during OM for each PTMC. The TV-DR (/year) was <-0.1, -0.1-0.1, 0.1-0.5, and >0.5 in 12, 19, 5, and 6 patients, respectively. The TV-DRs in both groups did not statistically differ, but six patients (16%) in the initially malignant group showed moderate growth (TV-DR >0.5/year). They underwent conversion surgery and none of them had further recurrence. The remaining 36 patients retained OM without disease progression. The TV-DR in the initially malignant group was not significantly associated with patients' backgrounds or their initial clinicopathological features. None of the patients in this study showed distant metastases/recurrences or died of thyroid carcinoma. Although a portion of PTMCs appearing after hemithyroidectomy for thyroid malignancy are moderately progressive, OM may be acceptable as a management option for PTMCs appearing in the remnant thyroid after hemithyroidectomy.

Evaluation of the diagnostic utility of the aminotransferase/lactate dehydrogenase ratio for the suspension of tissue specimens during thyroid surgery for the identification of parathyroid tissue.

Identification of the parathyroid glands during surgery is crucial for preventing postoperative hypoparathyroidism. Kikumori et al. reported that the aspartate aminotransferase (AST)/lactate dehydrogenase (LDH) ratio for the saline suspension of a suspicious tissue can differentiate parathyroid tissue from other tissues. The aim of this study was to evaluate the utility of this method and investigate the appropriate time for measurement. We obtained 465 tissue specimens during thyroidectomy of 102 patients with papillary thyroid carcinoma (PTC), and 422 specimens (129 parathyroid, 92 PTC, and 201 other tissues) with measurable AST and LDH were analyzed. Small pieces of the tissues were immersed in saline and sent for measurement of AST and LDH. The assay was performed immediately after thyroidectomy for 245 specimens (the same-day group) and during the next morning for the remaining 177 specimens (the next-day group). The accuracy of diagnosing parathyroid tissue was significantly better in the same-day group than in the next-day group. A cut-off value of 0.18 gave the best diagnostic precision, with an area under the receiver operating characteristic curve of 0.95 and 88.7% sensitivity and specificity in the same-day group. When the cut-off value was set to 0.20, the specificity for excluding carcinomatous tissues was 100%. When measured on the day of the surgery, the AST/LDH ratio for the saline suspension of the surgical specimens is useful for discriminating parathyroid tissues from other tissues. This method can be utilized at most hospitals where intraoperative frozen sections or rapid parathyroid hormone assays are not available.

The Impact of Ovariectomy on Olfactory Neuron Regeneration in Mice.

Estrogen has been shown to affect differentiation and proliferation as a mitogen in various neural systems. Olfactory receptor cells are unique within the nervous system, and have the ability to regenerate even after an individual has reached maturity. Olfactory receptor cells also regenerate after experimentally induced degeneration. The purpose of this study is to observe the influence of estrogen depletion induced by ovariectomy on olfactory nerve regeneration. Female mice underwent bilateral ovariectomy at 8 weeks of age and received intraperitoneal administration of methimazole 1 week later. At 2, 4, and 6 weeks after methimazole administration, the olfactory mucosa was analyzed histochemically to determine olfactory epithelium (OE) thickness, olfactory marker protein distribution, and Ki-67 immunoreactivity. Furthermore, 2 weeks after ovariectomy, trkA protein distribution in the OE and nerve growth factor (NGF) levels in the olfactory bulb were determined by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. Our results showed that in ovariectomized mice OMP, Ki-67, and trkA-immunopositive cells expression decreased at 2 weeks after methimazole injection, a time point at which regeneration is underway. At this same time point, although NGF production in the olfactory bulb had increased before methimazole administration, no differences were observed between the ovx and control groups. These results suggest that estrogen depletion induces a suppressive effect on regeneration of olfactory neurons, and that estrogen may have a potential use in the treatment of sensorineural olfactory dysfunction.

Effects of Tokishakuyakusan on Regeneration of Murine Olfactory Neurons In Vivo and In Vitro.

Post-upper respiratory tract infection related olfactory dysfunction typically occurs due to neural damage after an upper respiratory tract infection associated with a common cold or influenza. At present, Tokishakuyakusan, a Japanese traditional Kampo medicine, has been found to be effective for post-viral olfactory dysfunction. However, the pharmacodynamics of Tokishakuyakusan in the treatment of post-viral olfactory dysfunction remains unresolved. We investigated the effects of Tokishakuyakusan on the regeneration of olfactory neurons and expression of nerve growth factor (NGF) in neural systems, using in vivo murine studies and in vitro cell culture studies. Eight-week-old BALB/C female mice were fed a pellet diet with or without Tokishakuyakusan. Degeneration of cells in olfactory epithelium was induced by intraperitoneal methimazole injection. Regeneration of olfactory neurons was observed by histological and immunohistochemical procedures. NGF expression in the olfactory bulb was measured by enzyme-linked immunosorbent assay. NGF gene and protein expression were measured using rat primary cultured astrocytes by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. We found that olfactory marker protein, Ki-67, and NGF were more highly expressed in the olfactory epithelium during the regeneration period in mice receiving Tokishakuyakusan. In cultured astrocytes, Tokishakuyakusan as well as its individual components, Atractylodes lancea rhizome and Japanese angelica root, increased NGF expression. Screening assays revealed that NGF production was increased by atractylodin and levistolide A, which are ingredients in Atractylodes lancea rhizome and Japanese angelica root, respectively. These results suggest that Tokishakuyakusan promotes regeneration of olfactory neurons by increasing NGF expression in the olfactory bulb.

Reduced nasal transport of insulin-like growth factor-1 to the mouse cerebrum with olfactory bulb resection.

Although the olfactory nerve is involved in nasal transport of insulin-like growth factor-1 (IGF-1) to the brain, to our knowledge there have been no direct assessments of the effects of olfactory nerve damage on this transport. To determine whether olfactory bulb resection resulted in reduced transport of nasally administered human recombinant IGF-1 (hIGF-1) to the cerebrum, we measured the uptake of nasally administered iodine-125 hIGF-1 ((125)I-hIGF-1) in the cerebrum as a percentage of that in the blood in male ICR mice subjected to left olfactory bulb resection (model mice) and in sham-operated male ICR mice (control mice). Phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204)/(Thr185/Tyr187) as a percentage of total ERK 1/2 in the left cerebrum was also assessed by using enzyme-linked immunosorbent assay after nasal administration of hIGF-1. Uptake of nasally administered (125)I-hIGF-1 in the cerebrum as a percentage of that in the blood was significantly lower in the model group than in the control group 30min after nasal administration of hIGF-1. Unilateral olfactory bulb resection prevented nasally administered hIGF-1 from increasing the phosphorylation of ERK 1/2 in the mouse cerebrum in vivo. These findings suggest that olfactory bulb damage reduces nasal transport of hIGF-1 to the brain in vivo.

CLPTM1L expression predicts recurrence of patients with intermediate­ and high­risk stage IB­IIB cervical cancer undergoing radical hysterectomy followed by TP as adjuvant chemotherapy.

According to the National Comprehensive Cancer Network clinical practice guidelines of cervical cancer, concurrent chemoradiotherapy or radiotherapy is suggested for patients who receive radical hysterectomy and have intermediate- and high-risk cervical cancer. However, adjuvant chemotherapy has been increasingly chosen given the adverse events associated with chemoradiotherapy or radiotherapy and the increase in evidence regarding the efficacy of adjuvant chemotherapy. Given that adjuvant chemotherapy is not a standard treatment at present, if recurrence after adjuvant chemotherapy could be predicted, it would assist the decision of gynecological oncologists selecting which adjuvant therapy (chemotherapy or radiation therapy) to use. Cleft lip and palate transmembrane protein 1-like protein (CLPTM1L; also known as cisplatin resistance-related protein 9) is associated with apoptotic mechanisms and is related to the proliferation of the tumor cells and resistance against chemotherapy. In the present study, the association between CLPTM1L expression and recurrence of intermediate- and high-risk stage IB-IIB cervical cancer in patients undergoing radical hysterectomy followed by treatment with cisplatin and paclitaxel (TP) as adjuvant chemotherapy was determined. Patients were divided into two groups: Recurrence group and no-recurrence group. CLPTM1L expression was examined using immunohistochemistry in paraffin-embedded sections using weighted scores. Regarding the characteristics of the patients, a histology of non-squamous cell carcinoma, lymph node metastasis and parametrium invasion were more common in the recurrence group compared with the non-recurrence group. In the recurrence group, CLPTM1L expression was significantly higher than that in the no-recurrence group. Next, patients were divided into low and high-expression groups based on the weighted score with a cut-off value of 6. In the high expression group, patients exhibited a higher rate of recurrence (37.5 vs. 5.1%) and had worse overall survival. Multivariate analysis revealed that high CLPTM1L expression was independently related to recurrence. In in vitro analysis, small interfering RNA-mediated knockdown of CLPTM1L enhanced the sensitivity of cervical cancer cells to cisplatin. In conclusion, the present study revealed that CLPTM1L expression may be a predictive biomarker of recurrence of intermediate- and high-risk stage IB-IIB cervical cancer in patients undergoing radical hysterectomy followed by TP as adjuvant chemotherapy.

Comparison of Postoperative Unfavorable Events in Patients with Low-Risk Papillary Thyroid Carcinoma: Immediate Surgery Versus Conversion Surgery Following Active Surveillance.

Background: Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and has gradually spread worldwide. We previously demonstrated that AS is associated with a much lower incidence of unfavorable events than immediate surgery (IS). However, conversion surgery (CS) raises concerns about increased surgical complications due to advanced disease. In this study, we conducted a comparative analysis of unfavorable events after IS and CS. Methods: Between 2005 and 2019, 4635 patients clinically diagnosed with low-risk PTMC at Kuma Hospital were enrolled. Of these, 2896 underwent AS (AS group), and the remaining 1739 underwent IS (IS group). To date, 242 patients (0.8%) in the AS group have undergone CS for various reasons (CS group). Results: The incidence of unfavorable events, such as levothyroxine administration after surgery, postoperative hematoma, transient/persistent hypoparathyroidism, and transient/persistent vocal cord paralysis, did not differ between the CS and IS groups. None of the patients in the CS group had permanent vocal cord paralysis; however, this occurred in 15 patients (0.9%) in the IS group and was caused by accidental injury in 4 patients and carcinoma invasion in 11 patients. The incidence of surgery, levothyroxine administration, postoperative hematoma, transient/permanent hypoparathyroidism, and vocal cord paralysis was significantly higher (p < 0.001) in the IS group than in the AS group. There were no differences in the incidence of lymph node recurrence and overall mortality between the AS and IS groups. None of the patients in the AS and IS groups showed distant metastasis or died from thyroid carcinoma. Conclusions: There were no differences in the incidence of unfavorable events between the CS group and the IS group. Although none of the CS and AS groups had permanent vocal cord paralysis, accidental injury of the recurrent laryngeal nerve occurred in four patients (0.2%) in the IS group. The IS group had a significantly higher incidence of unfavorable events than the AS group. The prognoses of patients in both the AS and IS groups were excellent. Therefore, we recommend AS as the first-line management for low-risk PTMC.

Real-world Efficacy and Safety of Bevacizumab for Advanced or Recurrent Müllerian Cancer: A Single-institutional Experience.

BACKGROUND/AIM: The efficacy and safety of bevacizumab for ovarian cancer have been reported in randomized phase III clinical trials. It is important to gather experience and data in a real-world setting. The objective of the present study was to evaluate the efficacy and safety of bevacizumab for patients with ovarian cancer in a real-world setting. PATIENTS AND METHODS: For front-line settings, patients with FIGO stage III-IV ovarian cancer treated using bevacizumab and chemotherapy after debulking surgery (Chemo + Bev group, n=79), in addition to those treated with only chemotherapy after debulking surgery (Chemo group; n=66), at our institute were reviewed retrospectively. For recurrent settings, patients with recurrent ovarian cancers treated with bevacizumab and any chemotherapy were reviewed retrospectively (n=65). RESULTS: In the front-line setting, the disease-free survival was significantly longer in the Chemo + Bev group compared with that in the Chemo group (p=0.021). Hypertension and proteinuria were found to be statistically more frequent in the Chemo + Bev group compared with that in the Chemo group (p=0.002 and p=0.004). In the recurrent setting, in platinum-sensitive patients, the response rate (RR) and the disease control ratio (DCR) were 78.4 and 94.1%, respectively. In platinum-resistant patients, the RR and the DCR were 28.6 and 57.1% respectively. The median progression-free survival was 18.3 and 7.1 months for platinum-sensitive recurrence and platinum-resistant recurrence, respectively. The major ≥ grade 3 adverse event was neutropenia. CONCLUSION: The present study provided encouraging real-world evidence of the efficacy and safety of bevacizumab for ovarian cancer in real-world.

Intestinal­type mucinous carcinoma of the endometrium showing a polypoidal exophytic form: A case report.

Although endometrial cancer is a common malignancy in women, rare histological subtypes can pose diagnostic challenges. Primary endometrial intestinal-type mucinous carcinoma is a newly recognized subtype of endometrial cancer that differs from Müllerian-type endometrial mucinous carcinoma. The present case report documents a rare case of intestinal-type mucinous carcinoma of the endometrium showing a polypoidal exophytic form. The patient, an 80-year-old female, was incidentally diagnosed with a uterine tumor during a follow-up for vulvar Paget's disease. Clinical and imaging examinations revealed a localized mass within the uterine cavity. Hysteroscopy and subsequent histological examination confirmed the presence of intestinal-type mucinous carcinoma of the endometrium. Microscopically, the tumor displayed adenocarcinoma containing an intestinal-type glandular epithelium with mild nuclear atypia. It stained positive for the gastrointestinal markers mucin 2 and caudal type homeobox 2, and stained negatively for estrogen receptor α. The patient underwent surgery and adjuvant chemotherapy, with no evidence of recurrence at the latest follow-up 6 months after surgery. Endometrial intestinal-type mucinous carcinoma is a rare histological subtype of endometrial cancer. Differential diagnoses include Müllerian-type endometrial mucinous carcinoma, endocervical adenocarcinoma, metastasis from gastrointestinal tract adenocarcinoma and non-neoplastic gastric/intestinal metaplasia. However, the prognosis of endometrial intestinal-type mucinous carcinoma remains unclear due to limited reported cases. Existing evidence suggests a poorer prognosis compared with classical mucinous carcinomas of the endometrium. The present case, which is characterized by a polypoidal exophytic tumor without myometrial invasion, showed a favorable outcome. Further documentation and characterization of the aforementioned rare malignancy are necessary to enhance the understanding of its clinical physiology and outcomes. The present case report highlights the diagnostic challenges associated with intestinal-type mucinous endometrial carcinoma. The inclusion of this type of malignancy in the latest World Health Organization classification emphasizes the need for further comprehensive studies and case reports to expand the current knowledge on this rare histological subtype.

Fyn expression is associated with the response of patients with locally advanced uterine cervical squamous cell carcinoma to neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) followed by surgery is the current standard of treatment for locally advanced uterine cervical cancer; however, its value and outcomes remain contested. Identifying biomarkers that allow for the prediction of the effect of NAC efficacy before initiation of treatment is essential, in order to assist in choosing the optimum therapeutic regimen to maximize the beneficial outcomes of treatment. In the present retrospective study, 44 patients with locally advanced uterine cervical squamous cell carcinoma who underwent NAC were divided into two groups: A NAC successful group and a NAC failure group, depending on the efficacy of NAC. Subsequently, the association between Fyn expression, a non-receptor tyrosine kinase that is a member of the Src family kinases, and NAC efficacy was determined; Fyn expression was detected by immunohistochemistry and assessed using a weighted scoring method. Additionally, the effect of Fyn knockdown on the sensitivity of a uterine cervical cancer cell line to cisplatin was determined. Notably, there were no significant differences between the two groups of patients regarding their characteristics. Regarding overall survival, the NAC successful group had a significantly longer survival time than the NAC failure group (P=0.01). Furthermore, the expression levels of Fyn in tumor tissues were significantly lower in the NAC successful group compared with those in the NAC failure group (P=0.003). The patients were subsequently divided into two groups (high expression group and low expression group) according to a cutoff value of 3, which was determined by producing a receiver operating characteristic curve from the weighted scores. The low expression group was significantly more sensitive to NAC than the high expression group (P<0.001). In vitro experiments revealed that Fyn knockdown significantly enhanced the sensitivity of uterine cancer cells to cisplatin (P<0.05). In conclusion, Fyn expression may be a potentially useful biomarker for predicting the response to NAC in patients with locally advanced uterine cervical squamous cell carcinoma, and may also be a promising molecular target for the management of uterine cancer.

Experience with the use of intraoperative continuous nerve monitoring in video-assisted neck surgery and external cervical incisions.

OBJECTIVES: Recurrent laryngeal nerve (RLN) injury is one of the severe complications in thyroid surgery. Therefore, intraoperative nerve monitoring (IONM) has been widely used to identify the RLN and confirm its integrity. Recently, the usefulness of continuous IONM (CIONM) with automatic, periodic stimulation to the vagus nerve during thyroid surgery was reported. This study aimed to report our experience with minimally invasive video-assisted endoscopic endocrine neck surgery (VANS), during which, CIONM was successfully applied for the first time. METHODS: Consecutive patients who underwent thyroid surgery with CIONM, performed in our department using either external neck incision surgery or VANS between July 2017 and June 2019, were retrospectively analyzed. RESULTS: A total of 22 patients who underwent thyroid surgery with neck incision (14 cases; 7 men and 7 women; age, 21-75 years [mean, 52 years]) or VANS (8 cases; 8 women, age, 20-61 years [mean, 41 years]) were enrolled in this study. The addition of CIONM in VANS prolonged the operation's duration by approximately 30 minutes as the endoscopic surgery was technically more difficult. No intra- and postoperative incidence of transient or permanent RLN palsy was observed in any patient, except for three patients who underwent external neck incision surgery in whom combined resection was unavoidable due to tumor invasion of the RLN. CONCLUSION: We reported the first successful application of CIONM during thyroidectomy using VANS. Future clinical trials should clarify the benefits of CIONM when compared to intermittent IONM in VANS. LEVEL OF EVIDENCE: 5.

Examination of Selective Low-pressure Fine Needle Aspiration Cytology Under Ultrasound Guidance.

Cytology by fine-needle cytology is indispensable for diagnosing head and neck tumor, especially for thyroid nodule. There are two methods of fine needle cytology; one of fine-needle aspiration cytology (FNAC and another of fine-needle non-aspiration cytology (FNNAC). These previous procedures has each disadvantage such as the mixing of blood or low yield of cells. We proposed a new technique: selective low-pressure fine needle aspiration cytology (SLOP-FNAC) to overcome the backwards of previous procedures. We used the scoring system by Mair et al. to evaluate smear quality of specimens obtained with FNNAC and SLOP-FNAC. SLOP-FNAC smears exhibited higher scores in amount of cellular material, degree of cellular degeneration and cell yield, and retention of appropriate architecture compared to FNNAC smears. The SLOP-FNAC smears scored significantly higher for amount of cellular material and retention of appropriate architecture evaluated (P = 0.0261 and P = 0.0024, Student's t-test). SLOP-FNAC may be a useful cell sampling technique that reduces blood contamination while securing a high cell yield with maintaining tissue structure.