Localization of Ectopic Mediastinal Parathyroid Adenomas Using Indigo Carmine Injection for Surgical Management: A Preliminary Report.

An ectopic parathyroid adenoma (EPA) is a rare entity. The aim of this study was to report our experience in the preoperative localization and surgical management of EPAs. This was a multicenter retrospective study involving patients diagnosed with an EPA (three males and seven females) from January 2005 to November 2021. The clinical features, preoperative management, and surgical procedures were analyzed. A cervical neck ultrasound was performed in all patients and showed a focus in eight patients. Cervicothoracic enhanced computed tomography was performed in all patients and showed a focus in nine patients. The 99mTc-MIBI scintigraphy was performed in eight patients and showed uptake in six of them. We performed a neck dissection and thoracotomy in one patient, a thoracoscopy in one patient, surgery with a focused approach in seven patients, four of whom were injected with indigo carmine blue, and surgery with a bilateral approach in one patient. 1 h following the parathyroidectomy, the parathyroid hormone (PTH) concentration was decreased to 40-80% of the baseline value. Establishing a preoperative diagnosis of an EPA is challenging for the surgeon, despite the progress in the morphologic assessment. An intraoperative PTH assay and injection of indigo carmine have been shown to be valuable tools in the appropriate surgical management of an EPA.

Comparing the extent of breast cancer tumors through contrast-enhanced ultrasound vs B-mode, opposed with pathology: evergreen study.

BACKGROUND: To prove the efficacy of contrast-enhanced ultrasound (CEUS) in determining the extent of resection, more evidence about B-mode and CEUS as opposed to pathology is required. We compared maximum tumor width measured on B-mode/CEUS images with that determined pathologically. METHODS: In this retrospective multicenter study, 152 operable breast cancer patients who had undergone both B-mode and CEUS were analyzed. Maximum tumor width on B-mode and CEUS, and on the postoperative pathological examination (P), was measured by the participating investigators. In addition, maximum width was assessed in B-mode and CEUS image sets by independent reviewers blinded to all patient information. We analyzed differences in maximum width between CEUS, B-mode and P. RESULTS: The mean widths as measured by the participating investigators were 15 ± 7 mm (B-mode), 19 ± 8 mm (CEUS), and 17 ± 9 mm (P). The difference subtracted P from B-mode was - 3 ± 7 mm (p < 0.0001), and that from CEUS was 1 ± 6 mm (p = 0.0163). The mean widths as measured by the independent reviewers were 16 ± 7 mm (B-mode) and 18 ± 7 mm (CEUS). The difference subtracted P from B-mode was - 2 ± 8 mm (p = 0.0114), while that from CEUS was 1 ± 7 mm (p = 0.1921). CONCLUSIONS: Maximum lesion width measurement showed a tendency to increase in the order of B-mode, to P and CEUS. The difference in measurement between P and B-mode was significant, but there was no significant between CEUS and P. These results provide additional information of tendency patterns in measuring the maximum lesion width through enhancement on CEUS.

Case Report: 84-Month Disease-Free Survival after Surgery for Anaplastic Thyroid Carcinoma.

We present a rare case of a patient with anaplastic thyroid carcinoma (ATC) who survived for 87 months after surgery. The patient was a 71-year-old man who presented with a painful enlarged mass in the right side of his neck that rapidly enlarged over 2 months. He was diagnosed with T4a, stage IVA ATC with no distant metastasis and underwent total thyroidectomy with modified neck dissection. Although only radiation and radioactive iodine therapy were administered after surgery, he remained disease-free for 84 months. Bone metastasis occurred after 84 months, and he was treated with Lenvatinib, but he died from a decline in his general condition 3 months later. We suggest that surgery is effective for stage IVA ATC, but adjuvant therapy is necessary for long-term disease-free survival in this patient population.

Liver Metastasis of a Triple-Negative Breast Cancer and Complete Remission for 5 Years After Treatment With Combined Bevacizumab/Paclitaxel/Carboplatin: Case Report and Review of the Literature.

Triple-negative breast cancer (TNBC) is aggressive, with high risk of visceral metastasis and death. A substantial proportion of patients with TNBC is associated with BRCA mutations, implying that these tumors are sensitive to DNA-damaging agents. We report successful treatment of a metastatic TNBC in a woman with a BRCA2 germline mutation using combined bevacizumab/paclitaxel/carboplatin (BPC) therapy. The patient was pregnant and had liver metastases, and a complete clinical response was sustained for approximately 5 years. Mastectomy was performed during the 29th week of pregnancy, and the baby was later delivered by caesarean section. Subsequently, multiple metastases in both liver lobes were detected using computed tomography and magnetic resonance imaging and the patient was treated with a BPC regimen, which led to complete disappearance of metastatic lesions in the liver. No additional treatment was provided, and after 5 years the patient consented to direct sequencing of BRCA2 and a 6781delG mutation was identified. At the most recent (5-year) follow-up, the patient was alive with good quality of life and no evidence of metastases.This finding suggests that BPC therapy might be considered a good therapeutic option for the treatment of metastatic TNBC in a woman with a BRCA2 germline mutation.

Metastatic nonpalpable invasive lobular breast carcinoma presenting as rectal stenosis: a case report.

INTRODUCTION: Invasive lobular carcinomas have an increased propensity for distant metastases, particularly to the peritoneum, ovaries, and uterus. In contrast, distant metastases of nonpalpable lobular carcinomas are extremely rare, and the causes of underlying symptoms of primary carcinomas remain unclear. We report a case of an asymptomatic invasive lobular carcinoma with a primary mammary lesion in a patient with rectal stenosis. CASE PRESENTATION: A 69-year-old Japanese woman presented to our hospital for treatment of constipation. Although rectal stenosis was confirmed, thorough testing of her lower digestive tract did not identify its cause. Thus, an exploratory laparotomy and tissue biopsy was performed, and the presence of an invasive lobular carcinoma was confirmed. Subsequent breast examinations showed that the invasive lobular carcinoma that led to the rectal stenosis was a metastatic lesion from a primary lesion of the breast duct. As the present breast lobular carcinoma was asymptomatic and nonpalpable, we did not initially consider metastatic breast cancer as a cause of her symptoms, and the final diagnosis was delayed. CONCLUSIONS: Peritoneal metastasis from nonpalpable invasive lobular carcinomas is very rare. However, breast cancer metastasis should be considered when carcinomatous peritonitis is present in a patient with an unknown primary cancer.

[Remarkable improvement in a patient with metastatic and locally advanced HER2-positive breast cancer treated with trastuzumab plus vinorelbine].

A 39-year-old premenopausal nulliparous woman presented with severe pain in her right breast, bleeding and pus-like discharge, and a deep ulcer approximately 18 cm in diameter.Contralateral breast metastasis, bilateral axillary lymph node metastases, and multiple lung and bone metastases were detected on computed tomography.Five years previously she had undergone surgery for ovarian cancer and had prematurely discontinued adjuvant chemotherapy because of side effects. Following the administration of pain control, the patient received trastuzumab(Tr)plus vinorelbine(VNR)for her breast cancer as first-line therapy to avoid hair loss.The ulcer on her right chest wall underwent complete epithelialization and the patient's performance status improved from 3 to 0.The pus-like discharge, pain, bleeding, and odor from the breast resolved completely, and 5 months later, her quality of life had improved.The lung metastases also resolved completely.No adverse affects, including hematotoxicity and hair loss, were seen until treatment failure 12.5 months later. Second-line and third-line treatments were performed, but brain metastases developed, and the patient's overall condition deteriorated because of the development of ileus of unknown etiology.She died 21 months later.The patient received all therapies on an outpatient basis. Combination therapy using Tr and VNR is superior in safety and tolerability, and has been considered an option for first-line treatment of metastatic, locally advanced HER2-positive breast cancer.

Phase II clinical study of DD-723 (perflubutane): dose-response study in patients with breast tumors.

PURPOSE: We compared the contrast effect of three doses of DD-723 in subjects with breast tumors to determine the recommended dose. We then evaluated differential diagnosis results using plain ultrasonography, contrast-enhanced ultrasonography (plain + enhanced), and contrast-enhanced magnetic resonance imaging (MRI) compared to the pathological diagnosis. METHODS: To evaluate the contrast effect, contrast-enhanced ultrasonic images were independently evaluated in a randomized sequence by three blinded reviewers trained in the evaluation method beforehand. Multiple evaluation results from the three reviewers were used to assess the overall contrast effect. The differential diagnosis was evaluated independently by three blinded reviewers using contrast-enhanced ultrasonic images and contrast-enhanced magnetic resonance images in a randomized sequence; reviewers were also blinded to subject characteristics. Multiple evaluation results from the three reviewers were used to assess the overall differential diagnosis. RESULTS: The recommended dose of DD-723 is an intermediate dose of 0.12 µL MB/kg. Accuracy, sensitivity, and specificity were improved more in the differential diagnosis by contrast-enhanced ultrasonography than in plain ultrasonography. Accuracy and specificity were better and sensitivity similar compared to contrast-enhanced MRI. CONCLUSIONS: An intermediate dose showed the highest efficacy in terms of overall contrast effect. Contrast-enhanced ultrasonography is safe and useful when used in differential diagnosis.

Microsatellite instability at tetranucleotide repeats in sporadic colorectal cancer in Japan.

Most tumors of patients with Lynch syndrome and a fraction of sporadic colorectal cancers (CRCs) exhibit high levels of microsatellite instability (MSI) at mono- and dinucleotide repeat loci. A different type of instability, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been found in non-colonic cancers. Our previous study demonstrated that EMAST is common in sporadic CRC. Here, we focused on the relationships between EMAST and other genomic instability parameters or clinicopathological features in an unselected series of 88 sporadic CRCs. Of the tumors in the sample, 4 (4.5%) were MSI-high (MSI-H), 9 (10.2%) were MSI-low (MSI-L) and 75 (85.2%) were microsatellite stable. EMAST status was determined using 7 EMAST markers. Fifty-three (60.2%) tumors without MSI-H showed instability at >or=1 EMAST loci. All 4 MSI-H tumors showed instability at several EMAST loci. Instability profiles of MSI-H tumors at EMAST loci were more complex than those of non-MSI-H tumors. A tendency of positive association was observed between MSI-L and EMAST (P=0.023). The frequency of loss of heterozygosity (LOH) for the 14 loci in EMAST-positive tumors was significantly higher than negative tumors (P=0.048). Among the clinicopathological parameters, only tumor location at the distal colon was associated with EMAST-negative tumors (P=0.0084, one-tailed). A relatively higher frequency of well-differentiated adenocarcinomas was observed in EMAST tumors as opposed to non-EMAST tumors, though the survival rate was similar. These results suggest that overlapping mechanisms that cause MSI-L, EMAST and LOH in CRCs may exist.

Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer.

Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency. High levels of MSI at mononucleotide and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the MMR genes, hMLH1 and hMSH2. CRC with low levels of MSI (MSI-L) exists; however, its molecular basis is unclear. There is another type of MSI--elevated microsatellite alterations at selected tetranucleotide repeats (EMAST)--where loci containing [AAAG](n) or [ATAG](n) repeats are unstable. EMAST is frequent in non-CRCs; however, the incidence of EMAST and its cause in CRC is not known. Here, we report that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAST phenotype and low levels of mutations at dinucleotide repeats. About 60% of 117 sporadic CRC cases exhibit EMAST. All of the cases defined as MSI-H (16 cases) exhibited high levels of EMAST. Among 101 non-MSI-H cases, all 19 cases of MSI-L and 35 of 82 cases of MSS exhibited EMAST. Although non-MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2% to 50% of the total tumor cell population, the tissues exhibiting EMAST contained more MSH3-negative cells (average, 31.5%) than did the tissues not exhibiting EMAST (8.4%). Taken together, our results support the concept that MSH3 deficiency causes EMAST or EMAST with low levels of MSI at loci with dinucleotide repeats in CRC.

A single nucleotide substitution (-107C-->G) in the hMLH1 promoter found in colorectal cancer population reduces transcriptional activity.

Inactivation of the DNA mismatch repair gene hMLH1 predisposes one to colorectal cancer. We have identified a C to G nucleotide substitution at position -107 relative to the hMLH1 gene translation initiation site in three of 163 colorectal cancer patients with an allele frequency of 0.0092 (3/326). One of the three -107G alleles occurred in one patient out of five with reduced hMLH1 expression in the tumor tissue. The -107G was not found in 63 healthy individuals. This substitution reduced transcriptional activity by 51% compared with -107C (P<0.01) and impeded the promoter-binding capacity of nuclear proteins. Although the small number of identified -107G alleles is insufficient to evaluate the contribution to the carcinogenesis and clinicopathological properties of the tumors, the effects of -107G on hMLH1 gene transcription and nuclear protein binding to the promoter sequence implicate the site, including -107C, as a crucial element interacting with the activator that maintains hMLH1 gene expression.

[Liver metastasis from sigmoid colon cancer with peritoneal dissemination showed a complete response to TS-1].

A 64-year-old man with unresectable sigmoid adenocarcinoma due to peritoneal dissemination (P3) and liver metastasis (H2) treated with TS-1, showed a complete response. TS-1 is an oral anticancer drug that produces biochemical modulation. It is composed of tegafur, gimestat and ostat potassium in a molar ratio of 1:0.4:1 to increase the effect of 5-FU and to decrease toxicity in the digestive canal. Treatment with TS-1 requires no hospitalization and can enhance the quality of life of the patient. TS-1 is expected to be an effective agent for the treatment of colon cancer with liver metastasis and peritoneal dissemination.

Oncogenic pathway of sporadic colorectal cancer with novel germline missense mutations in the hMSH2 gene.

The deficiency of the DNA mismatch repair (MMR) system is involved in tumorigenesis of either familial or sporadic colorectal cancers showing microsatellite instability (MSI). To investigate the involvement of the mutated hMSH2 gene in carcinogenesis, we searched for alteration of the gene in 15 MSI tumors of Japanese patients with sporadic colorectal cancer by a polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and DNA sequencing analyses. We found 20 alterations including 7 novel mutations, 6 germline and one somatic. To assume an oncogenic pathway of tumor of two patients carrying germline missense mutations, G40S located in an evolutionarily conserved amino-terminal motif and Y619C in a domain interacting with either hMSH3 or hMSH6, somatic mutations in 9 target genes of the MMR defect and in the p53 and K-ras genes and loss of heterozygosity (LOH) at the hMLH1 and p53 gene loci were then studied. In the tumor carrying G40S, other somatic hMSH2 mutations, G203R and 687delA in the (A)(7) repeat, and 5 one-bp deletions in the target genes were found, while no mutation in the p53 and K-ras genes. These results indicate that G40S may affect the hMSH2 function and the tumor may be developed by a typical MSI pathway. In another tumor with Y619C, LOH at the hMLH1 gene locus, no mutation in MMR target genes, and two-hit inactivation of the p53 gene were detected. This MSI tumor seems to be developed by another than MSI pathway. These results indicate that there are different oncogenic pathways in the MSI sporadic colorectal cancers with germline missense mutations in the hMSH2 gene. We conclude that familial colorectal cancer-suspected cases exist in a small population of sporadic colorectal cancers.

Establishment of cisplatin-resistant variants of human neuroblastoma cell lines, TGW and GOTO, and their drug cross-resistance profiles.

PURPOSE: The emergence of multidrug resistance (MDR) in neuroblastoma is a critical issue for chemotherapy. In order to study low-level MDR, we developed variants derived from two neuroblastoma cell lines, TGW and GOTO, by exposure to low doses of cisplatin (CDDP). The cross-resistance to other cytotoxic agents and expression of MDR-related proteins in the variants and their clones were examined. MATERIALS AND METHODS: Cells were exposed to 3 or 10 micro M CDDP and three variants were obtained from each cell line, TGW and GOTO. Clones TR1 and TR2, derived from the TGW variants, were also established. Cytotoxicity was determined using a dye-staining method. Expression of MDR-related proteins was detected by immunoblotting. RESULTS: Resistant variants exhibited 1.1- to 2.5-fold increased resistance to CDDP, N-methyl- N'-nitro- N-nitrosoguanidine (MNNG), doxorubicin and vincristine. The cytotoxicity of these agents varied between clones of resistant variants. The microsatellite profiles of the TR1 clones differed, indicating that the TR1 variant comprised a heterogeneous cell population. The cytotoxicities of cytosine beta- D-arabinofuranoside (Ara-C) and chlorambucil in these variants and clones were similar to those in the parent cells. No significant changes in the cellular levels of MDR1, MRP, hMLH1 and hMSH2 were detected in the TGW variants. Cyclosporin A increased the sensitivity of both parental cell lines and the variants to doxorubicin and vincristine, but not to CDDP or MNNG. CONCLUSIONS: Ara-C and chlorambucil may be useful for the treatment of neuroblastoma exhibiting an MDR phenotype. These CDDP-resistant variants and clones may be useful for studying the mechanisms of low-level drug resistance in neuroblastoma.