Robotic resection of ectopic mediastinal parathyroid adenoma with intraoperative parathyroid hormone monitoring: a case report.

BACKGROUND: Primary hyperparathyroidism is a disease caused by the secretion of excess parathyroid hormone (PTH) owing to the enlargement of the parathyroid gland. Ectopic parathyroid glands exist in the mediastinum in approximately 1-2% of cases, which is relatively rare. Intraoperative monitoring of serum PTH level is important to assess whether the source of hyperparathyroidism has been eliminated. CASE PRESENTATION: A 53-year-old asymptomatic woman was diagnosed with ectopic mediastinal parathyroid adenoma. A three-port robotic partial resection of the thymus containing the tumor was attempted, but bleeding from a swollen pericardial diaphragmatic vein led to the addition of an assist port along the way. The PTH level was measured intraoperatively. After confirming that the 15-min PTH level after removal of the tumor was less than 50% of the baseline value, the operation was completed. The tumor was positive for PTH and was diagnosed as an ectopic mediastinal parathyroid adenoma. Some small ectopic parathyroid gland tissues were observed in other parts of the thymic tissue. Serum calcium and PTH levels decreased and normalized. CONCLUSIONS: We report the usefulness of robotic resection for ectopic mediastinal parathyroid adenoma with PTH monitoring. However, histopathologically, small parathyroid gland tissues may remain in the surrounding thymus. Hence, we believe that a strict follow-up is required for parathyroid function in the future.

PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features.

To examine effects of PP6 gene (Ppp6c) deficiency on pancreatic tumor development, we developed pancreas-specific, tamoxifen-inducible Cre-mediated KP (KRAS(G12D) plus Trp53-deficient) mice (cKP mice) and crossed them with Ppp6cflox / flox mice. cKP mice with the homozygous Ppp6c deletion developed pancreatic tumors, became emaciated and required euthanasia within 150 days of mutation induction, phenotypes that were not seen in heterozygous or wild-type (WT) mice. At 30 days, a comparative analysis of genes commonly altered in homozygous versus WT Ppp6c cKP mice revealed enhanced activation of Erk and NFκB pathways in homozygotes. By 80 days, the number and size of tumors and number of precancerous lesions had significantly increased in the pancreas of Ppp6c homozygous relative to heterozygous or WT cKP mice. Ppp6c-/- tumors were pathologically diagnosed as pancreatic ductal adenocarcinoma (PDAC) undergoing the epithelial-mesenchymal transition (EMT), and cancer cells had invaded surrounding tissues in three out of six cases. Transcriptome and metabolome analyses indicated an enhanced cancer-specific glycolytic metabolism in Ppp6c-deficient cKP mice and the increased expression of inflammatory cytokines. Individual Ppp6c-/- cKP mice showed weight loss, decreased skeletal muscle and adipose tissue, and increased circulating tumor necrosis factor (TNF)-α and IL-6 levels, suggestive of systemic inflammation. Overall, Ppp6c deficiency in the presence of K-ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis with generalized cachexia and early death. This study provided the first evidence that Ppp6c suppresses mouse pancreatic carcinogenesis and supports the use of Ppp6c-deficient cKP mice as a model for developing treatments for cachexia associated with pancreatic cancer.

Ppp6c deficiency accelerates K-rasG12D -induced tongue carcinogenesis.

BACKGROUND: Effective treatments for cancer harboring mutant RAS are lacking. In Drosophila, it was reported that PP6 suppresses tumorigenicity of mutant RAS. However, the information how PP6 regulates oncogenic RAS in mammals is limited. METHODS: We examined the effects of PP6 gene (Ppp6c) deficiency on tongue tumor development in K (K-rasG12D)- and KP (K-rasG12D + Trp53-deficient)-inducible mice. RESULTS: Mice of K and KP genotypes developed squamous cell carcinoma in situ in the tongue approximately 2 weeks after the induction of Ppp6c deficiency and was euthanized due to 20% loss of body weight. Transcriptome analysis revealed significantly different gene expressions between tissues of Ppp6c-deficient tongues and those of Ppp6c wild type, while Trp53 deficiency had a relatively smaller effect. We then analyzed genes commonly altered by Ppp6c deficiency, with or without Trp53 deficiency, and identified a group concentrated in KEGG database pathways defined as 'Pathways in Cancer' and 'Cytokine-cytokine receptor interaction'. We then evaluated signals downstream of oncogenic RAS and those regulated by PP6 substrates and found that in the presence of K-rasG12D, Ppp6c deletion enhanced the activation of the ERK-ELK1-FOS, AKT-4EBP1, and AKT-FOXO-CyclinD1 axes. Ppp6c deletion combined with K-rasG12D also enhanced DNA double-strand break (DSB) accumulation and activated NFκB signaling, upregulating IL-1ß, COX2, and TNF.

Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis.

According to TCGA database, mutations in PPP6C (encoding phosphatase PP6) are found in c. 10% of tumors from melanoma patients, in which they coexist with BRAF and NRAS mutations. To assess PP6 function in melanoma carcinogenesis, we generated mice in which we could specifically induce BRAF(V600E) expression and delete Ppp6c in melanocytes. In these mice, melanoma susceptibility following UVB irradiation exhibited the following pattern: Ppp6c semi-deficient (heterozygous) > Ppp6c wild-type > Ppp6c-deficient (homozygous) tumor types. Next-generation sequencing of Ppp6c heterozygous and wild-type melanoma tumors revealed that all harbored Trp53 mutations. However, Ppp6c heterozygous tumors showed a higher Signature 1 (mitotic/mitotic clock) mutation index compared with Ppp6c wild-type tumors, suggesting increased cell division. Analysis of cell lines derived from either Ppp6c heterozygous or wild-type melanoma tissues showed that both formed tumors in nude mice, but Ppp6c heterozygous tumors grew faster compared with those from the wild-type line. Ppp6c knockdown via siRNA in the Ppp6c heterozygous line promoted the accumulation of genomic damage and enhanced apoptosis relative to siRNA controls. We conclude that in the presence of BRAF(V600E) expression and UV-induced Trp53 mutation, Ppp6c haploinsufficiency promotes tumorigenesis.

Enhanced recovery after surgery program involving preoperative dexamethasone administration for head and neck surgery with free tissue transfer reconstruction: Single-center prospective observational study.

BACKGROUND: There are few reports on Enhanced Recovery After Surgery (ERAS)-based perioperative management following head and neck surgery with free tissue transfer reconstruction (HNS-FTTR). Here, we prospectively evaluated our ERAS program involving preoperative glucocorticoid administration in HNS-FTTR. METHODS: This prospective study included 60 patients who underwent HNS-FTTR at the Miyagi Cancer Center from June 2017 to December 2018. Their treatment plan included receiving perioperative management in accordance with our head and neck ERAS program. Major outcomes of hospitalization periods, early mobilization, early enteral nutrition, and patient satisfaction were assessed, and blood date and vital signs were compared with control patients who underwent HNS-FTTR from January 2014 to September 2016 at our institution before ERAS was implemented. RESULTS: The duration of hospital stay and the duration until completion of the discharge criteria was a median of 25 days and 17 days, respectively. Early mobilization was achieved in 86.0% of the patients at postoperative-day (POD)1 and 96.5% at POD2. Enteral nutrition was started in 80.1% at POD1 and 100% at POD2. Postoperative pain was controlled at mean VAS scores of 1.51-3.13. Clavien-Dindo grade II or higher postoperative complications were evident in 27.6% of the patients. The mean QOR40 score was 179.6 preoperatively, 146.1 at POD3, and 167.8 at POD7. Compared with the control group, there were significantly lower C-reactive protein levels, higher albumin levels, a lower body temperature, a lower neutrophil-to-lymphocyte ratio, less body weight fluctuation, and fewer incidences of decreased blood pressure in the ERAS group. CONCLUSION: Patients who underwent HNS-FTTR with ERAS-based perioperative management achieved early mobilization, early enteral nutrition, favorable pain control, remarkable recovery of patient satisfaction at POD7, and there was evidence of better hemodynamic stability and less inflammatory response compared with control patients.

Preoperative prognostic nutritional index as a method to predict postoperative complications after major head and neck surgery with free tissue transfer reconstruction.

BACKGROUND: Head and neck (H&N) cancer patients are often malnourished and have diminished immunity. H&N surgery with free tissue transfer reconstruction (HNS-FTTR) is associated with a relatively high incidence of postoperative complications. METHODS: Associations between possible risk factors and postoperative Clavien-Dindo (C-D) grades ≥ II and ≥ IIIa wound healing- or infection-related complications, postoperative overall complications and prolonged hospital stay were investigated in 188 patients who underwent HNS-FTTR during 2014-2018. The preoperative prognostic nutritional index (PNI) was calculated using the serum albumin level and total lymphocyte count. RESULTS: C-D ≥ II and ≥ IIIa complications were seen in 66 (35.1%) and 37 (19.7%) patients, respectively. Multivariate analysis showed that (i) previous irradiation was significantly associated with C-D ≥ II wound healing- or infection-related complications and prolonged hospital stays [odds ratio (OR) 3.096 and 3.328; P = 0.007 and 0.008, respectively]; and (ii) operation time of ≥9 h 20 min was a significant risk factor for C-D ≥ IIIa wound healing- or infection-related complications, and C-D ≥ IIIa overall complications (OR 2.987 and 2.257; P = 0.021 and 0.047, respectively). (3) Only preoperative PNI ≤ 40 was associated with all occurrences of C-D ≥ II and ≥ IIIa wound healing- or infection-related complications, C-D ≥ II and ≥ IIIa overall complications, and prolonged hospital stays (OR 3.078, 2.918, 2.627, 3.132 and 3.116; P = 0.020, 0.046, 0.036, 0.023 and 0.025, respectively). CONCLUSIONS: PNI, easily calculated, was the lone risk factor significantly predicting all C-D ≥ II and ≥ IIIa postoperative wound healing- or infection-related complications, C-D ≥ II and ≥ IIIa postoperative overall complications and prolonged hospital stay after HNS-FTTR.

Loss of protein phosphatase 6 in mouse keratinocytes enhances K-rasG12D -driven tumor promotion.

Here, we address the function of protein phosphatase 6 (PP6) loss on K-ras-initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen-inducible double mutant (K-rasG12D -expressing and Ppp6c-deficient) mice in which K-rasG12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly-mutant mice showed early onset tumor formation in lips, nipples, external genitalia, anus and palms, and had to be killed by 3 weeks after induction by tamoxifen, while comparably-treated K-rasG12D -expressing mice did not. H&E-staining of lip tumors before euthanasia revealed that all were papillomas, some containing focal squamous cell carcinomas. Immunohistochemical analysis of lips of doubly-mutant vs K-rasG12D mice revealed that cell proliferation and cell size increased approximately 2-fold relative to K-rasG12D -expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K-rasG12D -only mice. Moreover, AKT phosphorylation increased in K-rasG12D -expressing/Ppp6c-deficient cells, as did phosphorylation of the downstream effectors 4EBP1, S6 and GSK3, suggesting that protein synthesis and survival signals are enhanced in lip tissues of doubly-mutant mice. Finally, increased numbers of K14-positive cells were present in the suprabasal layer of doubly-mutant mice, indicating abnormal keratinocyte differentiation, and γH2AX-positive cells accumulated, indicating perturbed DNA repair. Taken together, Ppp6c deficiency enhances K-rasG12D -dependent tumor promotion.

Enhanced Recovery After Surgery program with dexamethasone administration for major head and neck surgery with free tissue transfer reconstruction: initial institutional experience.

OBJECTIVES: Enhanced Recovery After Surgery (ERAS) protocols promote recovery after various invasive surgeries. Likewise, preoperative glucocorticoid administration can reduce complications after some surgeries. However, the effects of ERAS protocols and glucocorticoid administration in patients undergoing major surgery for head and neck cancer have not been well described. The aim of this study was to evaluate the effect of an ERAS protocol with preoperative glucocorticoid administration in major surgery for head and neck cancer. METHODS: This retrospective study included 28 patients who underwent major head and neck surgery with free tissue transfer reconstruction at our institution from September 2016 to May 2017, after implementation of an ERAS protocol with preoperative glucocorticoid administration. Outcomes in that group were compared with those in a control group that underwent surgery from January 2015 to September 2016, before implementation of the protocol. RESULTS: Analysis revealed significantly less body weight fluctuation, lower C-reactive protein levels, higher albumin levels, and lower body temperature in the ERAS group than in the control group postoperatively. CONCLUSIONS: Patients undergoing major surgery for head and neck cancer who were treated with the ERAS protocol and preoperative glucocorticoid administration had evidence of better hemodynamic stability and less inflammatory response than control patients.

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

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

A case of generalized pustular psoriasis associated with Turner syndrome.

UNLABELLED: We report a 27-year-old Japanese woman with Turner syndrome who had generalized pustular psoriasis of the von Zumbusch type. She developed a febrile diffuse erythema and pustular eruption without any history of preceding psoriasis vulgaris or drug ingestion. Oral treatment with 3.2 mg/kg cyclosporin per day successfully resulted in rapid improvement, followed by a complete remission. To our knowledge, this is the first report describing the unusual coexistence of these two systemic disorders. We discuss a hormone imbalance that might have contributed to the predisposition to pustular psoriasis and difficulties in the management of the patent's treatment. ABBREVIATIONS: TS: Turner syndrome, GPP: generalized pustular psoriasis