Different tumor growth pattern of clinically nonfunctioning pituitary neuroendocrine tumor according to sex and age: a longitudinal study.

PURPOSE: Asymptomatic patients with clinically non-functional pituitary neuroendocrine tumors (CNF-PitNETs) are usually followed up. However, the natural course of CNF-PitNETs according to sex and age remains unclear. Therefore, this study assessed growth patterns of CNF-PitNETs according to sex and age. METHODS: In this longitudinal study, we enrolled 431 consecutive patients with CNF-PitNETs who were treated at Seoul National University Hospital from 1997 to 2021. The patients underwent hormone function testing and visual field testing, and were subsequently followed up with imaging over a median duration of 66 months. RESULTS: The median age of the patients was 53.0 years, and 37.1% (n = 160) were men. Men were older and harbored more macroadenomas than women. The annual tumor volume change was higher in men than in women (0.21 vs. 0.04 cm3/year, P < 0.001). The estimated cutoff value of age for significant tumor growth was 51 years. In men, the annual tumor volume change was similar across all age groups. In women, those aged ≤ 50 years showed significantly lower annual tumor volume change than those aged > 50 years (0.01, 0.11, and 0.17 cm3/year, P = 0.001). When comparing sexes within the same age group, the annual tumor volume changes was significantly lower for women than for men, only in patients aged ≤ 50 years (0.01 vs. 0.15 cm3/year, P < 0.001). CONCLUSIONS: Among patients with CNF-PitNET, tumor growth was slower in women aged ≤ 50 years than in men and women aged > 50. These findings may guide the customization of surveillance strategies for CNF-PitNETs according to sex and age.

Study of structural and magnetic properties and heat induction of gadolinium-substituted manganese zinc ferrite nanoparticles for in vitro magnetic fluid hyperthermia.

This article outlines the synthesis of gadolinium (Gd)-doped manganese zinc ferrite magnetic nanoparticles (MNPs) as potential magnetic carriers for magnetic fluid hyperthermia (MFH). MNPs with high specific loss power (SLP; 146 W/g) have been developed and used for an in vitro hyperthermia study. The treatment of MFH is fruitful if there is an adequate number of MNPs in tumor cells with the highest SLP to rapidly generate heat while minimizing thermal injury to surrounding healthy tissue. X-ray diffraction patterns of the studied particles confirm the formation of a cubic spinel structure. Field emission scanning electron micrographs showed homogeneous distributions of particles with some agglomerates with a granular appearance. Transmission electron microscopy analysis showed the presence of agglomerated spherical particles at the surface. The substitution of Gd resulted in superparamagnetism at room temperature as confirmed by vibrating sample magnetometer analysis. The estimated saturation magnetization reduced from 48.6 to 28.2 emu/g with an increase in Gd concentration. However, the coercivity increased from 1093 Oe to 1597 Oe. Field cooled and zero field cooled measurements showed Curie temperatures from 315 to 326 K, as required for MFH applications. Cell viability measurements indicated that the MNPs are nontoxic to A549 cells for the studied concentrations of particle fraction and a contact time of up to 24 h. The interaction of the MNPs with A549 cells was highlighted from an image captured by an inverted microscope. In order to treat cancer in vivo, an in vitro hyperthermia study has initially been carried out with A549 cells.

Staged lengthening and reconstruction for children with a leg-length discrepancy after excision of an osteosarcoma around the knee.

AIMS: Children treated for osteosarcoma around the knee often have a substantial leg-length discrepancy at skeletal maturity. The aim of this study was to investigate the results of staged skeletal reconstruction after a leg lengthening procedure using an external fixator in these patients. PATIENTS AND METHODS: We reviewed 11 patients who underwent staged reconstruction with either an arthroplasty (n = 6) or an arthrodesis (n = 5). A control group of 11 patients who had undergone wide excision and concurrent reconstruction with an arthroplasty were matched for gender, location, and size of tumour. We investigated the change in leg-length discrepancy, function as assessed by the Musculoskeletal Tumor Society Scale (MSTS) score and complications. RESULTS: A mean 5.2 cm (1.7 to 8.9) of lengthening was achieved. The mean MSTS scores significantly improved after staged reconstruction (p = 0.003) but were still worse than those of the control group (p = 0.049). However, the MSTS scores of the arthroplasty subgroup were comparable with those of the controls, although the extensor lag was greater and the range of movement was less. The patient group experienced more complications, but all of these resolved. CONCLUSION: Approximately 5 cm of lengthening and significant functional improvement can be achieved by staged reconstruction and lengthening, without major complications. Although it has limitations, this method of treatment seems to be a satisfactory surgical option for growing children with a significant leg-length discrepancy after excision of an osteosarcoma around the knee. Cite this article: Bone Joint J 2017;99-B:401-8.

Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer.

BACKGROUND: The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases. EXPERIMENTAL DESIGN: Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ(2) or Fisher's exact test were used for analysis. RESULTS: We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009). CONCLUSIONS: We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment.

Validity and reliability of the Korean version of the Speech Handicap Index in patients with oral cavity cancer.

The aims of this study were to evaluate the cross-cultural adaptation of the Speech Handicap Index (SHI) for Korean subjects and to determine its reliability and utility in patients with oral cavity cancer. The Korean version of the SHI was administered to 50 healthy subjects and 56 patients with speech problems resulting from treatment for oral cavity cancers. The content and construct validity, internal consistency, and test-retest reliability were examined. Healthy subject and patient group scores were compared, and the Mann-Whitney U-test was used to determine discriminatory ability. The Korean version of the SHI had high internal consistency (Cronbach's alpha=0.99) and test-retest reliability for the total and subscales: total (T) 0.98, speech (S) 0.99, and psychosocial (P) 0.97. Mean scores in the healthy group were 0.5 (T), 0.2 (S), and 0.2 (P), whereas those in the patient group were 34.3 (T), 16.6 (S), and 15.5 (P). The scores differed significantly between the groups (P<0.05). The Korean version of the SHI can be a useful tool to evaluate a patient's self-perception of their speech dysfunction in daily life and to better understand postoperative speech disorders in patients with oral cavity cancer.

Wound infections and healing: are they contributing factors for carcinogenesis?

The link between inflammation and tumourisation has long been considered as a key event in clinical cancer development. Inflammation and inflammatory diseases can be caused by many factors including infectious agents, altered genetics and various degrees of injuries from simple cuts to traumatic wounds, such as those suffered in battlefield. Improved management of all wound types is critical in protecting affected individuals against the development of tumourisation cues, which may potentially lead to cancer development. There have been numerous studies on the mechanism of inflammation-induced tumourisation. Thus, in this mini review, we summarised evidence demonstrating the potential link between infectious agents and their moonlight proteins, wounding, trauma, overactive repair mechanisms, and carcinogenesis.

Macular pigment and macular volume in eyes of patients with cystic fibrosis.

BACKGROUND: Because patients with cystic fibrosis (CF) are living longer, chronic malabsorption of carotenoids associated with CF resulting in decreased macular pigment (MP) may affect macular long-term health in later-life pathology. This study compared the macular pigment optical density (MPOD) and corresponding central macular volume (MV) of adult CF subjects and age-matched normal controls subjects to determine whether chronic malabsorption associated with CF could adversely affect macular photoreceptor anatomy. OBJECTIVE: Our aim was to compare MPOD with measurements of central MV in CF patients with age-matched controls. Design. In nine adult CF patients (ages: 29-46) without a history of carotenoid supplementation or known retinal or optic nerve disease MPOD and MV were measured by heterochromatic flicker photometry (HFP) and optical coherence tomography (OCT), respectively, and compared to results obtained from 14 age-matched controls. RESULTS: MPOD was significantly reduced at 15' and 30' eccentricities in CF subjects compared to normal subjects (mean difference -0.21 at 15', -0.25 at 30', p < 0.005). No significant difference, in MV noted at any of the eccentricities tested between CF and normal subjects (CF: normal MV ratios ranged from 0.94 to 1.1 for all eccentricities with p > 0.1 at all eccentricities). Best corrected vision acuity and fundus examination were normal in all subjects. CONCLUSIONS: Unsupplemented CF patients have markedly lower levels of macular carotenoids (e.g., lutein and zeaxanthin), but well-maintained visual function and no significant reductions in central MV primarily composed of macular photoreceptors. Future studies are needed to determine whether the lifelong decrease in protective central retinal carotenoids predisposes CF patients to later-life retinal pathology.

Effect of inhalers on the development of haemoptysis in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: The association of inhaler use with haemoptysis has rarely been reported in patients with non-cystic fibrosis (CF) bronchiectasis. OBJECTIVE: To elucidate the effect of inhaler use on the development of haemoptysis in patients with non-CF bronchiectasis. METHODS: In a case-crossover study of 192 non-CF bronchiectasis patients with a history of haemoptysis and inhaler use, the risk of haemoptysis associated with the use of inhalers was elucidated. Two inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA), one long-acting muscarinic antagonist and one short-acting ß2-agonist (SABA) were evaluated. The case and control periods were defined respectively as 030 and 180210 days before haemoptysis. RESULTS: The risk of haemoptysis during the case period was 3.51 times higher than during the control period with any use of inhalers (95%CI 1.966.28). The results of clinically significant haemoptysis showed good agreement with those of total events. These associations were consistent with the sensitivity analyses. In the sub-analysis according to inhaler type, ICS/LABA and SABA were significantly associated with an increased risk of haemoptysis (aOR 2.62, 95%CI 1.255.45; aOR 2.51, 95%CI 2.235.15). CONCLUSIONS: In patients with non-CF bronchiectasis, the use of inhalers, especially including 2-agonist, was associated with an increased risk of haemoptysis.

Germline mutations and genotype-phenotype correlations in patients with apparently sporadic pheochromocytoma/paraganglioma in Korea.

The aim of our study was to assess the frequency of germline mutations and develop the genetic testing strategy in patients with apparently sporadic pheochromocytoma/paraganglioma (PPGL) in Korea. We included 53 patients diagnosed with non-syndromic PPGL without a family history of PPGLs in three referral centers from 2004 to 2011. Succinate dehydrogenase complex B (SDHB), SDHD, Von Hippel-Lindau (VHL), and rearranged during transfection (RET) genes were examined by direct sequencing and multiple ligation-dependent probe amplification. The study patients were composed of 26 men and 27 women, and mean age was 50.1 ± 13.5 years. The frequency of germline mutations was 13.2% (7/53): RET (n = 2), VHL (n = 1), SDHB (n = 2), and SDHD (n = 2). Six of seven mutation carriers were diagnosed before the age of 50. One of two patients harboring an SDHB mutation had malignant PPGLs. One patient with multifocal head and neck paraganglioma (PGL) and pheochromocytoma (PHEO) carried a SDHD mutation. The carriers of germline mutations in patients with apparently sporadic PPGL were 13.2% in our study. We recommend genetic testing in patients below 50 years and SDHD genetic testing in patients with multifocal PPGLs. In malignant PPGLs, SDHB genetic testing may be performed.

Systematic review and meta-analysis of robotic surgery compared with conventional laparoscopic and open resections for gastric carcinoma.

BACKGROUND: Robot-assisted gastrectomy (RAG) has been developed in the hope of improving surgical quality and overcoming the limitations of conventional laparoscopically assisted gastrectomy (LAG) and open gastrectomy (OG) for gastric cancer. The aim of this study was to determine the extent of evidence in support of these ideals. METHODS: A systematic review of the three operation types (RAG, LAG and OG) was carried out to evaluate short-term outcomes including duration of operation, retrieved lymph nodes, estimated blood loss, resection margin status, technical postoperative complications and hospital stay. RESULTS: Nine non-randomized observational clinical studies involving 7200 patients satisfied the eligibility criteria. RAG was associated with longer operating times than LAG and OG (weighted mean difference 61.99 and 65.73 min respectively; P ≤ 0.001). The number of retrieved lymph nodes and the resection margin length in RAG were comparable with those of LAG and OG. Estimated blood loss as significantly less in RAG than in OG (P = 0.002), but not LAG. Mean hospital stay for RAG was similar to that for LAG (P = 0.14). In contrast, hospital stay was significantly shorter, by a mean of 2.18 days, for RAG compared with OG (P < 0.001). Postoperative complications were similar for all three operative approaches. CONCLUSION: Short-term oncological outcomes of RAG were comparable with those of the other approaches. LAG was a shorter procedure and less expensive than RAG. Future studies involving RAG should focus on minimizing duration of operation and reducing cost.

Diagnostic accuracy of Xpert® MTB/RIF on bronchoscopy specimens in patients with suspected pulmonary tuberculosis.

OBJECTIVE: To determine the diagnostic accuracy of the Xpert® MTB/RIF assay using samples obtained through bronchoscopy in patients with suspected pulmonary tuberculosis (PTB). DESIGN: We retrospectively reviewed the records of patients with suspected PTB for whom the Xpert MTB/RIF assay was performed on bronchoscopy specimens. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of active PTB were calculated for acid-fast bacilli (AFB) smear microscopy and the Xpert assay using culture of Mycobacterium tuberculosis from sputum or bronchoscopy specimens as a reference standard. RESULTS: A total of 132 patients were included in the final analysis. Of these, 38 had culture-confirmed PTB. The sensitivity of the Xpert assay using bronchial washing or bronchoalveolar lavage (BAL) fluid for the diagnosis of PTB was 81.6%, and specificity was 100%. The PPV and NPV were 100% and 92.1%, respectively. The sensitivity and specificity of AFB smear microscopy were respectively 13.2% and 98.8%. CONCLUSION: The Xpert assay on bronchoscopy specimens provided an accurate diagnosis of PTB in patients who had a negative AFB smear or who could not produce sputum.

Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation.

The discovery of causal mechanisms associated with nonsyndromic craniosynostosis has proven to be a difficult task due to the complex nature of the disease. In this study, differential transcriptome correlation analysis was used to identify two molecularly distinct subtypes of nonsyndromic craniosynostosis, termed subtype A and subtype B. In addition to unique correlation structure, subtype A was also associated with high IGF pathway expression, whereas subtype B was associated with high integrin expression. To identify a pathologic link between altered gene correlation/expression and the disease state, phosphorylation assays were performed on primary osteoblast cell lines derived from cases within subtype A or subtype B, as well as on primary osteoblast cell lines with novel IGF1R variants previously reported by our lab (Cunningham ML, Horst JA, Rieder MJ, Hing AV, Stanaway IB, Park SS, Samudrala R, Speltz ML. Am J Med Genet A 155A: 91-97, 2011). Elevated IRS1 (pan-tyr) and GSK3ß (ser-9) phosphorylation were observed in two novel IGF1R variants with receptor L domain mutations. In subtype A, a hypomineralization phenotype coupled with decreased phosphorylation of IRS1 (ser-312), p38 (thr-180/tyr-182), and p70S6K (thr-412) was observed. In subtype B, decreased phosphorylation of IRS1 (ser-312) as well as increased phosphorylation of Akt (ser-473), GSK3ß (ser-9), IGF1R (tyr-1135/tyr-1136), JNK (thr-183/tyr-187), p70S6K (thr-412), and pRPS6 (ser-235/ser-236) was observed, thus implicating the activation of IRS1-mediated Akt signaling in potentiating craniosynostosis in this subtype. Taken together, these results suggest that despite the stimulation of different pathways, activating phosphorylation patterns for IRS1 were consistent in cell lines from both subtypes and the IGF1R variants, thus implicating a key role for IRS1 in the pathogenesis of nonsyndromic craniosynostosis.

Distal metatarsal osteotomy for hallux varus following surgery for hallux valgus.

We reviewed the outcome of distal chevron metatarsal osteotomy without tendon transfer in 19 consecutive patients (19 feet) with a hallux varus deformity following surgery for hallux valgus. All patients underwent distal chevron metatarsal osteotomy with medial displacement and a medial closing wedge osteotomy along with a medial capsular release. The mean hallux valgus angle improved from -11.6° pre-operatively to 4.7° postoperatively, the mean first-second intermetatarsal angle improved from -0.3° to 3.3° and the distal metatarsal articular angle from 9.5° to 2.3° and the first metatarsophalangeal joints became congruent post-operatively in all 19 feet. The mean relative length ratio of the metatarsus decreased from 1.01 to 0.99 and the mean American Orthopaedic Foot and Ankle Society score improved from 77 to 95 points. In two patients the hallux varus recurred. One was symptom-free but the other remained symptomatic after a repeat distal chevron osteotomy. There were no other complications. We consider that distal chevron metatarsal osteotomy with a medial wedge osteotomy and medial capsular release is a useful procedure for the correction of hallux varus after surgery for hallux valgus.

Selective soft-tissue release for recurrent or residual deformity after conservative treatment of idiopathic clubfoot.

We reviewed the results of a selective à la carte soft-tissue release operation for recurrent or residual deformity after initial conservative treatment for idiopathic clubfoot by the Ponseti method. Recurrent or residual deformity occurred in 13 (19 feet) of 33 patients (48 feet; 40%). The mean age at surgery was 2.3 years (1.3 to 4) and the mean follow-up was 3.6 years (2 to 5.3). The mean Pirani score had improved from 2.8 to 1.1 points, and the clinical and radiological results were satisfactory in all patients. However, six of the 13 patients (9 of 19 feet) had required further surgery in the form of tibial derotation osteotomy, split anterior tibialis tendon transfer, split posterior tibialis transfer or a combination of these for recurrent deformity. We concluded that selective soft-tissue release can provide satisfactory early results after failure of initial treatment of clubfoot by the Ponseti method, but long-term follow-up to skeletal maturity will be necessary.

Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation.

The BRCA1 and BRCA2 genes are the strongest susceptibility genes identified for breast cancer worldwide. However, BRCA1/BRCA2 have been incompletely investigated due to their large size and the genomic rearrangements that occasionally occur within them. Here we performed a comprehensive mutational analysis for BRCA1/BRCA2 in 206 Korean patients with breast cancer. We analyzed all exons and flanking regions of BRCA1/BRCA2 by direct sequencing and screened deletions or duplications involving BRCA1/BRCA2 by multiplex ligation-dependent probe amplification. We reconstructed haplotypes using intragenic single nucleotide polymorphisms (SNPs) to investigate the possibility of a founder effect among recurrent mutations. In our series, 38 patients (18.4%) had one or more BRCA1/BRCA2 mutations including 10 novel ones. Three additional patients carried novel distinct unclassified variants with potentially harmful effects. No large deletions or duplications involving BRCA1/BRCA2 were identified in our series. Haplotype analyses and allele separation suggested that the most frequent mutation in Koreans, BRCA2:c.7480C>T, might have originated from a common ancestor. BRCA1/BRCA2 mutations were more frequent in a group with family history, bilateral cancer or multiple site cancer than in a group without the risk factors described or an unknown risk group. In contrast, mutation frequencies in the early-onset cancer group were not higher than in the unknown risk group. Our results will be helpful to understand the mutation spectrum in BRCA1/BRCA2 genes and establish a genetic screening strategy. In addition, this study suggests the possibility of the first true founder mutation of BRCA1/BRCA2 identified in the Korean population.

Reactive oxygen species in rats with chronic post-ischemia pain.

BACKGROUND: An emerging theme in the study of the pathophysiology of persistent pain is the role of reactive oxygen species (ROS). In the present study, we examined the hypothesis that the exogenous supply of antioxidant drugs during peri-reperfusion would attenuate pain induced by ischemia/reperfusion (IR) injury. We investigated the analgesic effects of three antioxidants administered during peri-reperfusion using an animal model of complex regional pain syndrome-type I consisting of chronic post-ischemia pain (CPIP) of the hind paw. METHODS: Application of a tight-fitting tourniquet for a period of 3 h produced CPIP in male Sprague-Dawley rats. Low-dose allopurinol (4 mg/kg), high-dose allopurinol (40 mg/kg), superoxide dismutase (SOD, 4000 U/kg), N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), or SOD (4000 U/kg)+L-NAME (10 mg/kg) was administered intraperitoneally just after tourniquet application and at 1 and 2 days after reperfusion for 3 days. The effects of antioxidants in rats were investigated using mechanical and cold stimuli. Each group consisted of seven rats. RESULTS: Allopurinol caused significant alleviation in mechanical and cold allodynia for a period of 4 weeks in rats with CPIP. Both SOD and L-NAME, which were used to investigate the roles of superoxide (O2(-)) and nitric oxide (NO) in pain, also attenuated neuropathic-like pain symptoms in rats for 4 weeks. CONCLUSIONS: Our findings suggest that O2(-) and NO mediate IR injury-induced chronic pain, and that ROS scavengers administered during the peri-reperfusion period have long-term analgesic effects.

Treatment of checkrein deformity of the hallux.

We studied 11 patients with checkrein deformities of the hallux who underwent surgical treatment. Six had lengthening of the flexor hallucis longus tendon by Z-plasty in the midfoot, and five underwent release of adhesions and lengthening of the tendon by Z-plasty at the musculotendinous junction at the fracture site. All six patients who underwent Z-plasty at the midfoot showed complete correction of the deformity without recurrence. Of the five who had release of adhesions and Z-plasty of the tendon at the fracture site, two showed partial and one showed complete recurrence.