Effectiveness of PET/CT and VATS for detecting and treating internal mammary lymph node metastasis: a case series.

OBJECTIVE: We occasionally observed internal mammary lymph node metastases of breast cancer in a clinical setting. However, unlike a standard treatment in axillary metastasis, surgical resection for internal mammary lymph node metastasis is not prevalent because of unclear safety and benefits. Thus, we aimed to evaluate the diagnostic ability and clinical outcomes of positron emission tomography/computed tomography and video-assisted thoracoscopic surgery. METHODS: We retrospectively investigated 34 patients with breast cancer with abnormal 18F-fluorodeoxyglucose uptake in internal mammary lymph nodes, at a single centre, between January 2015 and June 2022 and identified 11 female patients (mean age ± SD, 51.5 ± 12.9 years) who underwent video-assisted thoracoscopic surgery resection. Positron emission tomography/computed tomography was used to determine the clinical stage. We reviewed the surgical pathology of eleven and two patients who underwent direct-view internal mammary lymph node resection to calculate the positive predictive value of positron emission tomography/computed tomography. RESULTS: Ipsilateral fluorodeoxyglucose accumulation was observed, with an average maximum standardized uptake value of 8.9 (range, 3.1-24.0). No perioperative complications occurred, and all patients who underwent video-assisted thoracoscopic surgery alone were discharged from the hospital on post-operative day 2 or 3. The estimated positive predictive value was 80%. All patients were alive, and seven of nine patients with metastasis were relapse-free, at a mean follow-up period of 17.9 months (range, 1-51). However, two patients had recurrence at 16 and 14 months after surgery for internal mammary lymph node relapse. CONCLUSIONS: Radiotherapy is the standard treatment for suspected internal mammary lymph node metastasis detected using positron emission tomography/computed tomography; however, we could safely perform minimally invasive video-assisted thoracoscopic surgery resection, leading to a definite pathological diagnosis.

Identification of nuclear localization signals in the human homeoprotein MSX1.

MSX1 is one of the homeoproteins with the homeodomain (HD) sequence, which regulates proliferation and differentiation of mesenchymal cells. In this study, we investigated the nuclear localization signal (NLS) in the MSX1 HD by deletion and amino acid substitution analyses. The web-based tool NLStradamus predicted 2 putative basic motifs in the N- and C-termini of the MSX1 HD. Green fluorescent protein (GFP) chimera studies revealed that NLS1 (161RKHKTNRKPR170) and NLS2 (216NRRAKAKR223) were independently insufficient for robust nuclear localization. However, they can work cooperatively to promote nuclear localization of MSX1, as was shown by the 2 tandem NLS motifs partially restoring functional NLS, leading to a significant nuclear accumulation of the GFP chimera. These results demonstrate a unique NLS motif in MSX1, which consists of an essential single core motif in helix-I, with weak potency, and an auxiliary subdomain in helix-III, which alone does not have nuclear localization potency. Additionally, other peptide sequences, other than predicted 2 motifs in the spacer, may be necessary for complete nuclear localization in MSX1 HD.

Idiopathic Isolated Unilateral Hypoglossal Nerve Palsy: A Report of 2 Cases and Review of the Literature.

Hypoglossal nerve palsy (HNP) is a common finding in neurologic diseases when associated with other cranial nerve palsies or further pathology and exhibits characteristic clinical manifestations, including unilateral atrophy of the musculature of the tongue. It occasionally appears as the initial or solitary sign of an intracranial or extracranial space-occupying lesion, head or neck injury, or vascular abnormality of the internal carotid artery. There are few cases of idiopathic isolated unilateral HNP, which should be diagnosed through exclusion. This report describes 2 patients who had different outcomes and presents a literature review of idiopathic isolated unilateral HNP. Case 1 was a 71-year-old man who was referred with a 1-month history of dysphagia and speech impairment. Intraoral examination disclosed marked left-side hemiatrophy of the tongue and deviation toward the left on protrusion. At coronal Tl-weighted magnetic resonance imaging, left-side hemiatrophy of the tongue was clearly visible through deviation of the median septum to the left. The patient was diagnosed with idiopathic isolated unilateral HNP through exclusion and was treated with steroids and mecobalamin, but he did not recover. Case 2 was a 32-year-old man complaining of tongue weakness for 2 days. On examination, left HNP was evident, with deviation of the tongue to the left on protrusion. He was diagnosed with idiopathic isolated unilateral HNP through exclusion and was treated with steroids. After 3 weeks, the patient had completely recovered. To the best of the authors' knowledge, this is the first detailed literature review on idiopathic isolated unilateral HNP. This condition is very rare but should be considered for diagnosis. It warrants a thorough and stepwise approach for etiologic diagnosis.

Cervical chyloma after neck dissection: a case report.

Cervical chylomas are rare pseudocystic collections that lack an epithelial lining and arise from the thoracic duct or its tributaries; although they typically develop after neck surgery or trauma, they can arise from unknown causes. Treatment options include not only conservative therapy, such as dietary modification, repeated aspirations, and sclerotherapy, but also include surgical excision. We describe a case of a chyloma in a 64-year-old Japanese woman with squamous cell carcinoma of the gingiva. The chyloma developed following left segmental mandibulectomy with radical neck dissection and reconstruction, using a titanium plate and a pectoralis major myocutaneous flap. One month after surgery, a left supraclavicular swelling was noted, so ultrasound-guided fine-needle aspiration and cytology were performed to exclude a recurrence of neck metastasis. The aspiration yielded a milky fluid without atypical or malignant cells on cytology, confirming the diagnosis of chyloma. Although we performed continuous compressive dressing and started the patient on a low-fat diet, the mass persisted. When the patient died of bone, lung, and liver metastases five months after the second surgery, the mass had not changed in size. Awareness of this complication is important to ensure timely diagnosis and appropriate treatment.

Characterisation of novel RUNX2 mutation with alanine tract expansion from Japanese cleidocranial dysplasia patient.

Cleidocranial dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal dysplasia characterised by hypopalstic and/or aplastic clavicles, midface hypoplasia, absent or delayed closure of cranial sutures, moderately short stature, delayed eruption of permanent dentition and supernumerary teeth. The molecular pathogenesis can be explained in about two-thirds of CCD patients by haploinsufficiency of the RUNX2 gene. In our current study, we identified a novel and rare variant of the RUNX2 gene (c.181_189dupGCGGCGGCT) in a Japanese patient with phenotypic features of CCD. The insertion led an alanine tripeptide expansion (+3Ala) in the polyalanine tract. To date, a RUNX2 variant with alanine decapeptide expansion (+10Ala) is the only example of a causative variant of RUNX2 with polyalanine tract expansion to be reported, whilst RUNX2 (+1Ala) has been isolated from the healthy population. Thus, precise analyses of the RUNX2 (+3Ala) variant were needed to clarify whether the tripeptide expanded RUNX2 is a second disease-causing mutant with alanine tract expansion. We therefore investigated the biochemical properties of the mutant RUNX2 (+3Ala), which contains 20 alanine residues in the polyalanine tract. When transfected in COS7 cells, RUNX2 (+3Ala) formed intracellular ubiquitinated aggregates after 24h, and exerted a dominant negative effect in vitro. At 24h after gene transfection, whereas slight reduction was observed in RUNX2 (+10Ala), all of these mutants significantly activated osteoblast-specific element-2, a cis-acting sequence in the promoter of the RUNX2 target gene osteocalcin. The aggregation growth of RUNX2 (+3Ala) was clearly lower and slower than that of RUNX2 (+10Ala). Furthermore, we investigated several other RUNX2 variants with various alanine tract lengths, and found that the threshold for aggregation may be RUNX2 (+3Ala). We conclude that RUNX2 (+3Ala) is the cause of CCD in our current case, and that the accumulation of intracellular aggregates in vitro is related to the length of the alanine tract.

Novel nonsense mutation in MSX1 in familial nonsyndromic oligodontia: subcellular localization and role of homeodomain/MH4.

Nonsyndromic tooth agenesis is one of the most common anomalies in human development. Part of the malformation is inherited and is associated with paired box 9 (PAX9), msh homeobox 1 (MSX1), and axin 2 (AXIN2) mutations. To obtain a comprehensive understanding of the genetic and molecular mechanisms that underlie this genetic disease, we investigated six familial and seven sporadic Japanese cases of nonsyndromic tooth agenesis. Searches for mutations in these candidate genes detected a novel nonsense mutation (c.416G>A) in exon 1 of MSX1 from a family with oligodontia. This mutation co-segregated in the affected family members. Moreover, this mutation produced a termination codon in the first exon and therefore the gene product (W139X) was truncated at the C terminus, hence, the entire homeodomain/MH4, which has many functions, such as DNA binding, protein-protein interaction, and nuclear localization, was absent. We characterized the properties of this truncated MSX1 by investigating the subcellular localization of the mutant gene product in transfected cells. The wild-type MSX1 localized exclusively at the nuclear periphery of transfected cells, whereas the mutant MSX1 was stable but localized diffusely throughout the whole cell. These results indicate that W139X MSX1 is responsible for tooth agenesis.

Severe retinopathy of prematurity with retinal detachment in monozygotic twins.

We report a monochorionic diamniotic twin pair born at 29 weeks of gestation in which both twins developed severe retinopathy of prematurity (ROP) with retinal detachment. The pregnancy was terminated due to reversal of donor-recipient phenotypes in possible TTTS. Both twins had unstable cardiopulmonary status during the first week, and developed chronic lung disease. The larger twin, born at 1372 g, developed stage 4a ROP in both eyes, and the smaller twin, born at 1168 g, developed stage 4a ROP in the left eye. Genetic analysis of NDP, FZD4, LRP5, TSPAN12 genes revealed no mutations; however, VEGF gene polymorphism analysis showed heterozygous carrier state of the VEGF 936T allele in both twins, which is a risk factor for threshold ROP in Japanese newborn infants. We speculate the synergistic effects of unstable perinatal cardiopulmonary status and genetic predisposition due to VEGF 936C>T polymorphism caused the development of severe ROP with retinal detachment.

Novel treatment strategy for Japanese newborns with high serum unbound bilirubin.

BACKGROUND: Serum unbound bilirubin (UB) is a measure of bilirubin not bound to albumin, and has been reported to be better than total bilirubin level at identifying infants at risk of developing bilirubin-induced neurotoxicity, including auditory abnormalities. A detailed treatment strategy for newborns with high serum UB has not been established. The aim of this study was to assess auditory outcomes in newborns with serum UB ≥1.00 µg/dL who were treated according to a novel treatment protocol. METHODS: A prospective clinical study was conducted in newborns weighing >1500 g with serum UB ≥1.00 µg/dL who were admitted to Kobe University Hospital and Kakogawa Municipal Hospital, Japan from 2006 to 2011. Enrolled newborns were treated as follows: (i) if serum UB was 1.00-1.50 µg/dL, phototherapy and infusion were given with or without albumin or immunoglobulin therapy; and (ii) if serum UB was >1.50 µg/dL, exchange transfusion was performed immediately. Auditory brainstem responses were evaluated at the time of discharge. RESULTS: A total of 89 Japanese newborns with UB ≥1.00 µg/dL were enrolled at a median age of 4 days. Of these, 85 had UB 1.00-1.50 µg/dL and four had UB >1.50 µg/dL. After being treated according to the protocol, no newborns were diagnosed with auditory brainstem response abnormalities. CONCLUSIONS: The present treatment protocol for Japanese newborns with serum UB ≥1.00 µg/dL may be useful for the prevention of bilirubin-induced auditory abnormalities.

Severely high serum unbound bilirubin level after abdominal surgery in a newborn.

We report a newborn with intestinal malrotation who developed a severely high serum unbound bilirubin level and a low serum albumin level without a marked increase in serum total bilirubin level after abdominal surgery, which required exchange transfusion and albumin supplementation. The serum unbound bilirubin level may be highly relative to the serum total bilirubin level in newborns who have undergone abdominal surgery soon after birth and are hypoalbuminemic after surgery.

High-accuracy prediction of axillary lymph node metastasis in invasive lobular carcinoma using focal cortical thickening on magnetic resonance imaging.

BACKGROUND: Invasive lobular carcinoma (ILC) grows diffusely in a single-cell fashion, sometimes presenting only subtle changes in preoperative imaging; therefore, axillary lymph node (ALN) metastases of ILC are difficult to detect using magnetic resonance imaging (MRI). Preoperative underestimation of nodal burden occurs more frequently in ILC than in invasive ductal carcinoma (IDC), however, the morphological assessment for metastatic ALNs of ILC have not fully been investigated. We hypothesized that the high false-negative rate in ILC is caused by the discrepancy in the MRI findings of ALN metastases between ILC and IDC and aimed to identify the MRI finding with a strong correlation with ALN metastasis of ILC. METHOD: This retrospective analysis included 120 female patients (mean ± standard deviation age, 57.2 ± 11.2 years) who underwent upfront surgery for ILC at a single center between April 2011 and June 2022. Of the 120 patients, 35 (29%) had ALN metastasis. Using logistic regression, we constructed prediction models based on MRI findings: primary tumor size, focal cortical thickening (FCT), cortical thickness, long-axis diameter (LAD), and loss of hilum (LOH). RESULTS: The area under the curves were 0.917 (95% confidence interval [CI] 0.869-0.968), 0.827 (95% CI 0.758-0.896), 0.754 (95% CI 0.671-0.837), and 0.621 (95% CI 0.531-0.711) for the FCT, cortical thickness, LAD, and LOH models, respectively. CONCLUSIONS: FCT may be the most relevant MRI finding for ALN metastasis of ILC, and although its prediction model may lead to less underestimation of the nodal burden, rigorous external validation is required.

Correlation and precision of serum free bilirubin concentrations determined by single and two peroxidase concentration methods in term or late-preterm newborn infants using a FDA-approved analyzer.

BACKGROUND: Free bilirubin concentration (B(f)) is an index for identifying newborns at risk for developing bilirubin-induced neurotoxicity. It has been suggested that B(f) measured by a single peroxidase concentration (B(f-single)) does not equal the equilibrium concentration of B(f), which is confirmed by B(f) at two different peroxidase concentrations (B(f-two)). However, the differences between B(f-single) and B(f-two) are unknown in the serum of term or late-preterm newborn infants. Furthermore, to apply B(f-single) with savings on time and cost to the clinical setting, it is very important for us to clarify the differences between B(f-single) and B(f-two). METHODS: Forty serum samples were obtained from 21 term or late-preterm newborns who were admitted at Kobe University Hospital. Using a peroxidase method, B(f-single) was measured at one peroxidase concentration, and B(f-two) was determined at two different peroxidase concentrations (the manufacturer's recommended peroxidase concentration and half the manufacturer's recommended peroxidase concentration). To clarify the relationship between B(f-single) and peroxidase concentrations, B(f-single) was measured at five different concentrations of peroxidase reagent. Intra-day and inter-day analyses were performed to assess the precision of B(f-single) and B(f-two). RESULTS: 1/B(f-single) increased as peroxidase concentration increased. B(f-single) was significantly lower than B(f-two) (B(f-single): 0.50 microg/dL [0.13 - 1.22 microg/dL] versus B(f-two): 0.59 microg/dL [0.15 - 1.76 microg/dL], p < 0.001), but B(f-single) was significantly correlated with B(f-two) (r = 0.953, p < 0.0001). Intra-day analysis showed that the CV was 9.7% for B(f-two) and 3.3% for B(f-single), and the inter-day CV was 12.4% for B(f-two) and 3.2% for B(f-single). CONCLUSIONS: Although B(f-single) and B(f-two) are not identical, B(f-single) is significantly correlated with B(f-two) and it is more precise than B(f-two) in term or late-preterm newborns.

Is bilirubin/albumin ratio correlated with unbound bilirubin concentration?

BACKGROUND: The American Academy of Pediatrics guidelines recommend that the total bilirubin (TB)/albumin (Alb) ratio (B/A ratio), instead of serum concentration of unbound bilirubin (UB), can be used with TB for determining treatment modality for jaundiced newborns ≥ 35 weeks of gestation. It is unknown, however, whether the B/A ratio is actually correlated with serum UB. METHODS: Four hundred and ninety-seven serum samples were obtained from 209 newborns ≥ 35 weeks of gestation, who were admitted to Kobe University Hospital. Serum UB concentration was measured using the glucose oxidase-peroxidase method. Serum TB and Alb concentrations were measured on spectrophotometry. B/A ratios were calculated and were linearly compared with serum UB. Furthermore, the accuracy of the B/A ratio was evaluated. RESULTS: The B/A ratio was significantly correlated with serum UB concentration. A serum UB concentration of 0.6 µg/dL was in agreement with a B/A ratio of 0.5. For comparison of the number of newborns who had serum UB concentrations ≥ or <0.6 µg/dL and B/A ratios ≥ or <0.5, we found the following characteristics: the concordance rate between serum UB concentrations and the B/A ratio was 94%, sensitivity was 51%, and specificity was 99%. CONCLUSIONS: The B/A ratio is significantly correlated with serum UB concentration in newborns ≥ 35 weeks of gestation. The B/A ratio, however, is underestimated when serum UB concentrations are >0.6 µg/dL.

Solitary fibrous tumor of male breast: A case report and literature review.

BACKGROUND: Solitary fibrous tumors (SFT) are uncommon mesenchymal neoplasms which can arise in any anatomical location. Pleural SFTs have been most frequently documented; however, breast SFT is an exceedingly rare entity and seldom present in male breast, with only 8 previously reported cases. Recently, STAT6 immunostaining was considered to be a definitive marker of SFT, however, no case of the male breast SFT showing STAT6 positivity preoperatively has been reported. METHODS AND RESULTS: We describe a case of breast SFT in a 73-year-old male patient with a 12-month history of a palpable breast mass. The only associated clinical symptom was bilateral gynecomastia. An ultrasound scan examination revealed an oval, well-circumscribed and hypoechoic mass with hypervascularity. A core-needle biopsy was performed, and microscopic examination with immunohistochemistry confirmed the diagnosis of SFT. He underwent a complete surgical resection with clear margins, and there were no signs of high cellularity, remarkable mitotic activity, pleomorphism, hemorrhage or necrosis. CONCLUSION: A perioperative immunohistochemical evaluation for diffuse and intense nuclear expression of STAT6 was helpful to distinguish SFT from myofibroblastoma. We, herein, describe the first case of SFT in a male breast, confirmed by STAT6 immunostaining positivity. We also conducted a literature review of all previous cases of breast SFTs.

Lymphangiography as a Treatment for Refractory Congenital Chylothorax Due to RASopathies: A Report of Two Cases.

In this study, we report two cases in which intranodal lymphangiography helped improve congenital chylothorax due to RASopathies. We performed lymphangiography after conservative treatments failed to improve chylothorax in an 8-year-old girl with cardiofaciocutaneous syndrome and a 2-month-old boy with Noonan syndrome. Inguinal lymph nodes were punctured with 25-gauge needles under ultrasonographic guidance, and 4 and 1 mL of iodized oil were injected, respectively, showing a backflow of iodized oil into the lungs. Chylothorax had improved in both patients after nodal lymphangiography. However, the second child experienced worsening of disease-associated extremity edema and died of sepsis 4 months later.

The prognostic significance of intratumoral heterogeneity of 18F-FDG uptake in patients with oral cavity squamous cell carcinoma.

PURPOSE: This study aimed to evaluate the prognostic significance of two major indices of intratumoral heterogeneity of 18F-fluorodeoxyglucose uptake by positron emission tomography (PET)/computed tomography (CT), namely heterogeneity index (HI) and heterogeneity factor (HF), in patients with oral squamous cell carcinoma. METHODS: We performed a retrospective analysis of 62 patients who underwent resective surgery. HI, HF, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained from pretreatment PET. HI was obtained by dividing SUVmax by SUVmean for the primary lesion; HF was obtained by taking the derivative (dV/dT) of the volume-threshold function from 30 to 70%. Univariate and multivariate analyses for the overall survival (OS) and disease-free survival (DFS) were performed using PET and clinicopathological parameters. RESULTS: Univariate and multivariate analyses of OS revealed that higher HI levels (threshold for the SUVmean is 30% of the SUVmax) were associated with poorer OS [hazard ratio (HR) = 11.57; 95% confidence interval (CI) = 1.45-92.28; P = 0.021]. Moreover, univariate and multivariate analyses of DFS revealed that higher TLG levels (threshold for the MTV and SUVmean is 4.0 of the SUV) were associated with poorer DFS (HR = 14.48; 95% CI = 1.27-164.78; P = 0.031). CONCLUSIONS: HI and TLG may be statistically significant prognostic factors for OS and DFS, respectively.

Evaluation index for asymmetric ventricular size on brain magnetic resonance images in very low birth weight infants.

OBJECTIVE: Asymmetric ventriculomegaly is often evident on brain magnetic resonance imaging (MRI) in very low birth weight infants (VLBWI) and is interpreted as white matter injury. However, no evaluation index for asymmetric left-right and anterior-posterior ventricular sizes has been established. METHODS: In this retrospective multicenter cohort study, brain T2-weighted MRI was performed at term-equivalent ages in 294 VLBWI born between 2009 and 2011. The value of a lateral ventricular index (LVI) to evaluate asymmetric ventricular size, as well as the relationship between the LVI value and walking at a corrected age of 18 months was investigated. At the level of the foramen of Monro in a horizontal slice, asymmetry between the left and right sides and between the anterior and posterior horns was identified by the corrected width and was detected by a low concordance rate and κ statistic value. An LVI representing the sum of the widths of the four horns of the lateral ventricle corrected for cerebral diameter was devised. RESULTS: Asymmetric left-right and anterior-posterior ventricular sizes were confirmed. The LVI value was significantly higher in the non-walking VLBWI group (n = 39) than in the walking VLBWI group (n = 255; 18.2 vs. 15.8, p = 0.02). An LVI cut-off value of 21.5 was associated with non-walking. Multivariate analysis revealed that an LVI value >21.5 was an independent predictor of walking disability at the corrected age of 18 months (odds ratio 2.56, p = 0.008). CONCLUSIONS: The LVI value calculated via MRI may predict walking disability at a corrected age of 18 months in VLBWI.

Quantitative analysis of chronological changes in the volume of flaps used for reconstruction of oral cavity defects.

Reconstruction of oral defects using flaps following resection of oral cancer has become a standard approach for restoration of oral function. The purpose of this study was to investigate chronological changes in the volume of such flaps used for reconstruction and the factors affecting flap volume. We performed a retrospective analysis of 17 patients who had undergone oral cancer resection and reconstruction with flaps. Measurements were performed using data from computed tomography, and the flaps were selected semi-automatically using a computer-operated region-of-interest system. The data indicated that the change in total flap volume at 1 year after surgery was 30.6%, and that body weight loss was a risk factor for volume reduction. Our results suggested that flaps should be at least 30% larger than the defects they are intended to repair. However, as large flaps have the potential to cause upper airway obstruction, flap volume should be determined on an individual basis according to defect size and location.

WNT10A variants isolated from Japanese patients with congenital tooth agenesis.

It has been reported that dozens of WNT10A variants are associated with human isolated tooth agenesis, however, little is known about the precise phenotypes. In 50 Japanese patients with severe congenital tooth agenesis, we identified 11 patients with WNT10A variants. Comparing phenotypes between the tooth agenesis patients carrying the wild-type and variants of WNT10A, we revealed that the development of lateral incisors is relatively susceptive to insufficiency of WNT/ß-catenin signaling.

A Case of Sialolithiasis in a Minor Salivary Gland of the Buccal Mucosa.

Sialolithiasis is a common disease of the major salivary glands. In contrast, Sialolithiasis of Minor Salivary Glands (SMSG) is very rare. Only 2% of all cases of sialolithiasis develop in minor salivary glands and sublingual glands. Furthermore, the clinical and imaging features of SMSG frequently differ from those encountered in major salivary glands thus, hindering proper clinical diagnosis of SMSG. Histologically, SMSG is characterized by ductal ectasia (sometimes with deep cystic dilatation), acinar atrophy and periductal inflammation. Herein, we describe a patient suffering from SMSG in the left buccal region. Based on the clinicopathological findings of this case and a review of the literature, we propose that this entity should be included in the differential diagnosis of intra-mucosal nodules.