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Background: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. Methods: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). Results: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. Conclusions: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.

Background: It is unclear for whom new anti-human epidermal growth factor receptor 2 (anti-HER2) agents, such as pertuzumab and T-DM1, should be considered. We investigated prognostic factors before neoadjuvant chemotherapy (NAC) among HER2-positive invasive breast cancer patients and those after NAC among patients who did not achieve pathological complete response (pCR) using conventional adjuvant trastuzumab. Methods: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and June 2017 at the Osaka Breast Clinic. Patients with distant metastasis or using NAC containing pertuzumab were excluded. The main outcome was disease-free survival (DFS). We investigated pre- and post-NAC prognostic factors using the log-rank test and Cox proportional hazards model. Results: In total, 157 patients were included. Among the pre-NAC prognostic factors, younger age (under 40 years old) and positive clinical nodal status were significantly poorer prognostic factors (hazard ratio [HR] 3.47, 95% CI 1.06–10.12, p = 0.041 and HR 3.32, 95% CI 1.03–14.78, p = 0.045) by multivariate analysis. Among the post-NAC prognostic factors, patients with non-pCR (3-year DFS; 85 vs. 96%, p = 0.022) had a poorer DFS than patients with pCR. DFS was assessed for non-pCR patients (n = 64). High post-NAC Ki-67 status (≥20%; HR 6.73, 95% CI 1.82–31.93, p = 0.004) was a significant and large post-NAC tumor size (≥2 cm; HR 3.65, 95% CI 0.97–14.71, p = 0.056) was a marginally significant prognostic factor by multivariate analysis. After having combined them, high post-NAC Ki-67 status or large post-NAC tumor size was also a significant prognostic factor (HR 5.75, 95% CI 1.32–16.12, p = 0.017). Conclusions: Positive clinical nodal status and young age were found to be prognostic factors before NAC in HER2-postive invasive breast cancer patients. A high post-NAC Ki-67 status and large post-NAC tumor size were significant and marginally significant prognostic factors, respectively, after NAC in patients who did not achieve pCR. New anti-HER2 agents, such as pertuzumab and T-DM1, should be considered for the patients with those prognostic factors.

Residual cancer burden or Ki67 expression levels in residual tumors reportedly provided significant prognostic information for a non-pathological complete response subset after neoadjuvant chemotherapy (NAC). However, the significance of Ki67 reduction for clinical response during chemotherapy in each subtype or menopausal status is yet to be determined. A total of 183 breast cancers surgically removed after chemotherapy were recruited for this study. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki67 were determined immunohistochemically for semiquantitative measurement and these biomarkers were compared in pre- and post-NAC samples from pathological non-responders (n = 125). Responses to chemotherapy were evaluated both clinically and pathologically. Ki67 expression levels after NAC (median 5 %, range 0–70 %) were significantly reduced compared with before NAC (25, 1–80 %, P

Indication for chemotherapy in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers is determined on the basis of Ki67 expression level. However, since Ki67-high cancers are not necessarily sensitive to chemotherapy, identification of such patients who do not need chemotherapy is an important issue. We used immunohistochemical staining to examine the expression levels of ER, progesterone receptor (PgR), Ki67, and geminin, a marker of S to G2/M phases, in 80 ER-positive/HER2-negative breast cancers. The labeling indices of Ki67 and geminin were determined and cutoff values were set at 15 and 6 %, respectively. Ki67 and geminin expression levels were significantly associated with nuclear grade. In the Ki67-low subset, 26 out of 28 (92.9 %) cancers were geminin low and in the Ki67-high subset, 31 out of 52 (59.6 %) were geminin high. Distant disease-free survival (DDFS) of the geminin-high subset was significantly poorer than that of the geminin-low subset (P = 0.009). In the Ki67-low subset, only one patient showed recurrence. Metastasis was detected in eight out of 31 (25.8 %) patients in the geminin-high group of the Ki67-high subset, but no recurrence was observed in the geminin-low group of the Ki67-high subset. Geminin-high breast cancers are significantly associated with worse prognosis. Since poorer prognosis was recognized only in the geminin-high group in Ki67-high cancers, we speculate that geminin may be useful for identifying patients in the Ki67-high subset who can avoid unnecessary chemotherapy.

The most effective treatment for thyroid cancer (TC) invading into the larynx and trachea is a complete surgical resection of the tumor, but currently employed techniques are less than ideal. We report a novel surgical technique, which we named Windmill resection and Tetris reconstruction, for patients with TC invading into the laryngeal lumen. We treated eight cases of TC with invasion into the laryngeal lumen by Windmill resection and Tetris reconstruction. We analyzed complications, clinical data, and pathological findings for all patients. Patients included one man and seven women (mean age 69 ± 10 years). Histopathology of TC indicated papillary cancer in five patients, poorly differentiated cancer in one patient, anaplastic cancer in one patient, and squamous cell carcinoma in one patient. Unilateral recurrent laryngeal nerve (RLN) palsy was confirmed preoperatively by laryngoscope in four patients, and none had bilateral RLN palsy. All patients underwent Windmill resection and Tetris reconstruction along with total thyroidectomy (three patients), subtotal thyroidectomy (three patients), and lobectomy (two patients). Neck dissection was performed in all patients. The average resected length of the larynx and trachea was 29 ± 6 mm. Air leakage at the suture line occurred in three patients; two required further surgery, while the third was closed by insertion of a Penrose drain. Postoperative RLN palsy occurred in five patients. Aspiration was observed in two patients and resolved within 4 weeks. Pneumonia, atelectasis, and pleural effusion occurred in some patients. No other complications, including hemorrhage, wound infection, or airway stenosis, occurred. There was no postoperative mortality and no recurrence at the anastomotic site. Two patients underwent permanent tracheostomy due to permanent bilateral RLN palsy. Two patients, one with anaplastic cancer and the other with poorly differentiated cancer, recurred 13 and 21 months after surgery, while patients with papillary thyroid cancer had no local recurrence. Importantly, laryngeal functions such as phonation and swallowing were preserved in all patients. This novel surgical technique may be as effective as window resection of the larynx for local control of TC and contributes to the quality of life of patients by resulting in a less unsightly surgical wound.

Cancer of the thyroid gland is rare in children and adolescents. A history of neck irradiation is a well-established risk factor for tumor development, and most previous reports focused on cases that were induced by radiation exposure. We present here a retrospective review of the clinical features, treatment, and long-term outcome of children and adolescents with papillary thyroid cancer (PTC) without a history of radiation exposure who were treated at our institution over a period of ~50 years.We retrospectively investigated 142 PTC patients without an irradiation history who were younger than 20 years of age when treated from 1961 to 2005 (17 males and 125 females; mean age = 16.3 ± 2.7 years; follow-up = 21.8 ± 12.0 years). The clinicopathological results were evaluated using the medical records. Disease-free survival (DFS) and cause-specific survival (CSS) were assessed with the Kaplan-Meier method and compared with the log-rank test. Parametric analyses were performed using Student's t test and nonparametric analyses were performed using the Mann-Whitney U test.At diagnosis, three patients had distant lung metastasis and 33 had gross neck lymph node (LN) metastasis. All patients were treated with surgery (hemi/partial thyroidectomy in 45 patients, subtotal thyroidectomy in 85, total thyroidectomy in 12, no LN dissection in 50, central compartment dissection in 20, and modified radical neck dissection in 72), and postoperative external beam radiation therapy was administered to 59. Postoperative ablative therapy using I(131) was not performed in this series. Recurrence was found for regional LN (n = 25), lung (n = 9), remnant thyroid (n = 5), and others (n = 4). DFS and CSS at 40 years were 74.1 and 97.5%, respectively. DFS was significantly worse in patients aged16 years with a family history of thyroid cancer, preoperative neck gross LN metastasis, maximum tumor diameter, and extrathyroidal invasion. Preoperative gross neck LN metastasis and distant metastasis at diagnosis were significant factors for CSS. No other factors contributed to DFS and CSS. When the clinical features of children and adolescents were compared, the incidence of preoperative gross neck LN metastasis and distant metastasis at diagnosis and tumors with a maximum diameter10 mm were significantly higher in the children group than in the adolescent group. DFS was significantly shorter in the children group than in the adolescent group, but no significant difference was found in CSS between these two groups.The prognosis of PTC in children and adolescents is excellent, regardless of the extent of thyroidectomy and LN dissection. We recommend that only children or adolescents with preoperative gross neck LN metastasis and distant metastasis at diagnosis should be subjected to postoperative ablative therapy.

Parathyroid cancer is a rare endocrine tumor, and the prognostic factors for this cancer remain unclear. The standard therapy is en bloc resection of the primary tumor at the time of the initial operation. However, the clinical significance of prophylactic neck dissection (PND) in the management of parathyroid cancer has not yet been established. In this study, we investigated its clinical significance in patients with parathyroid cancer and the association of gene mutations with tumor progression. A total of 12 patients with parathyroid cancer were treated and have been followed at Noguchi Thyroid Clinic and Hospital Foundation since 1977. In all, 11 patients were treated with the initial surgery for the cancer, and 1 patient underwent surgery for a metastatic lung lesion. Somatic and germ-line mutations of the HRPT2 and MEN1 were examined by polymerase chain reaction and automated DNA sequencing. En bloc resections of thyroid tissue were performed in 10 patients, and 1 patient underwent only parathyroidectomy with limited resection of the thyroid gland. PND was performed in eight patients, and no lymph node metastases were found in the histological specimens. Six of the eight patients had no evidence of the disease, and two had recurring disease (neck lymph node and lung in one patient and local, lung, and brain in another). PND was not performed in three patients, two of whom had no evidence of the disease and one with recurrence at the site of a regional lymph node. There were no significant differences in disease-free survival and cause-specific survival between the patients who underwent PND and the patients who did not (P = 0.98 and P = 0.32, respectively). Among the 12 patients with parathyroid cancer, 1 had a germ-line mutation of the HRPT2 at exon 7, codon 234, CGA (Arg) to TGA (Stop), and 1 patient had a tumor-specific mutation at exon 1, nucleotide 34–37 delAACA. Two of the four patients with recurrent disease had an HRPT2 gene mutation. MEN1 gene analysis revealed one somatic missense mutation at exon 2, codon 121, GTC (Val) to GAC (Asp) in one patient. PND for patients with parathyroid cancer resulted in no evidence of lymph node metastasis and does not improve the prognosis. HRPT2 gene mutation may be associated with tumor recurrence.

The purpose of this study was to identify the factors that predict incomplete low-dose radioiodine remnant ablation (RRA) with recombinant human thyroid-stimulating hormone (rhTSH) and to report the adverse events associated with this treatment. Between 2012 and 2014, 43 consecutive patients with thyroid cancer received low-dose RRA with rhTSH after total thyroidectomy. We retrospectively investigated the adverse events during low-dose RRA and during diagnostic whole body scan (DxWBS) using rhTSH, and analyzed the rate of RRA completion and the associations between RRA completion and various clinical/pathological factors. Complete RRA was seen in 33 (76.7%) patients, and incomplete RRA was observed in 10 (23.3%). Patients with incomplete RRA had stronger neck accumulation of 131I than those with complete RRA (P

We determined the activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways in 108 cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with high and low Ki-67 expression. The expression levels of Ki-67, p53, phosphorylated MAPK (pMAPK), and protein S6 (pS6; downstream molecule of PI3K/Akt/mammalian target of rapamycin/S6 kinase pathway) were determined immunohistochemically. pS6 positivity, but not pMAPK positivity, was significantly associated with the high Ki-67 expression subset.Evaluation of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered important. Although the phosphoinositide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are thought to be involved in the luminal B subtype, the details of their contribution to breast cancer remain unclear.We determined the activation of these pathways (phosphorylated MAPK [pMAPK] and protein S6 [pS6; a downstream molecule of PI3K/Akt/mammalian target of rapamycin (mTOR)/S6 kinase (S6K)]) in 108 ER(+), HER2(-) breast cancer cases with high and low Ki-67 expression. The ER, progesterone receptor (PgR), Ki-67, p53 expression levels were also determined immunohistochemically. The cutoff value for Ki-67 was set at 15%.A significantly greater percentage of cancer cases with high Ki-67 expression showed pS6 positivity than did those with low Ki-67 expression (53.2% vs. 19.7%; P = .0003). No significant differences were found between the cases with high and low expression levels were detected for p53 (23.4% vs. 11.5%; P = .12) or pMAPK (36.2% vs. 34.4%; P = .85) positivity. Multivariate analysis showed that pS6 positivity (odds ratio 5.16, 95% confidence interval 1.95-13.63; P = .0009), nuclear grade 2 and 3, and low PgR expression (≤ 20%) were independently associated with the high Ki-67 subset.From our findings, we have concluded that the pS6 expression level is associated with the characteristics of breast cancer with high Ki-67 expression. Because these associations were observed, irrespective of menopausal status, the biologic difference seems to be less affected by estrogen signaling than by activation of S6 protein, especially in terms of proliferation. Our findings have also indicated that targeting the mTOR/S6K pathway might be a useful strategy for the treatment of ER(+)/HER2(-) breast cancer with high Ki-67 expression.

We examined the prognostic significance of progesterone receptor (PgR) expression in immunohistochemical-based luminal subtypes defined by Ki-67 expression, taking menopausal status into consideration. The study included 327 surgically removed estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancers. High Ki-67 expression (15%) and low PgR expression (£ 20%) were significant independent factors resulting in worse distant relapse-free survival. This association was observed in postmenopausalwomen but not in premenopausal women.Accurate classification of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered clinically important for determining effective adjuvant treatment. Although Ki-67 expression has been identified as an essential constituent for this classification, the role of progesterone receptor (PgR) expression has yet to be fully elucidated. Because PgR expression is influenced by the estrogen milieu, we examined the prognostic significance of PgR expression in immunohistochemical (IHC)-based luminal subtypes defined by Ki-67 expression, taking menopausal status into consideration.We examined 327 surgically removed ER(+) and HER2(-) breast cancer specimens. ER, PgR, and Ki67 expression was determined IHC for semiquantitative measurement. We used 1%, 20%, and 15% as the cutoff value for ER, PgR, and Ki-67, respectively.Breast cancer with low PgR (≤ 20%) expression was significantly associated with postmenopausal status, a large tumor size, and low ER expression. The low PgR expression subset had significantly worse distant relapse-free survival (DRFS) than the high PgR expression subset (P = .0067). This association was observed consistently in postmenopausal women but not in the premenopausal women. Multivariate analysis demonstrated that high Ki-67 expression (hazard ratio [HR], 3.80; 95% confidence interval [CI], 1.57-10.58; P = .003) and low PgR expression (HR, 2.54; 95% CI, 1.08-6.40; P = .038) were significant independent factors affecting DRFS.Low PgR expression was independently associated with a poorer prognosis for ER(+) and HER2(-) breast cancer. Determination of PgR expression combined with that of Ki-67 could thus improve the accuracy of IHC-based classification of luminal A and luminal B breast cancer, especially for postmenopausal women.

Malignant lymphomas of the breast, whether they are primary or secondary, are rare diseases, constituting only around 0.1 to 0.15% of the primary neoplasm of the breast. Although the most prevalent histological subtype is diffuse large B-cell lymphoma, primary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) also occurs in the breast as in other extranodal sites, comprising about 15% of malignant lymphomas of the breast. In many cases, primary MALT lymphoma of the breast is low grade lymphoma, localized in the breast with indolent behavior and good prognosis. Here we report a case of spontaneous regression of primary MALT lymphoma of the breast. The lymphoma collided with invasive ductal carcinoma in the breast. Both tumors were identified in the Vacora biopsy specimen before the operation. However, the lymphoma disappeared, while the carcinoma remained, in the resected mass. To our knowledge, this is the first case report of spontaneous regression of MALT lymphoma of the breast colliding with breast cancer.

Children and adolescents represent 1-1.5% of all patients with thyroid cancer (TC). The vast majority of TC in children and adolescents is papillary TC; follicular TC (FTC) is exceedingly rare. In this study, we evaluate the clinical and pathological features of FTC in children and adolescents. We also report the risk factors for post-operative tumor recurrence and the associated outcomes. Twenty children and adolescents (under 21 years old) with FTC have been treated and followed at Noguchi Thyroid Clinic and Hospital Foundation since 1946. All patients underwent surgery (lobectomy, 11; subtotal thyroidectomy, 8; and total thyroidectomy, 1), and 8 patients received postoperative external beam radiation therapy. The incidence of FTC in children and adolescents was 1.9% among all FTC patients treated in our hospital. Histopathology revealed vascular and capsular invasion in 9 and 20 patients, respectively. The tumor recurrence rate in FTC with vascular invasion is significantly higher than in those without it (p = 0.038). No other factors were significant. Patients with recurrences were treated with completion thyroidectomy and ¹³¹I radioactive iodine therapy. There were no significant differences in the rates of disease-free survival or cause-specific survival when pediatric/adolescent FTC patients were compared to adults with FTC. FTC is very rare among children and adolescents, but the outcomes are similar to those observed among adults. Vascular invasion is poor prognostic indicator in pediatric/adolescent FTC patients.