Insulin-Like Growth Factor Binding Protein-3 Binds to Histone 3.

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is an essential protein that regulates cellular processes such as cell proliferation, apoptosis, and differentiation. It is known to bind with several proteins to carry out various cellular functions. In this study, we report for the first time that IGFBP-3 is a histone 3 (H3) binding protein. Sub-cellular fractionation was performed to separate into cytosolic fraction, nucleic acid binding protein fraction and insoluble nuclear fraction. Using ligand blot analysis, we identified a ~15 kDa protein that can interact with IGFBP-3 in the insoluble nuclear fraction. The 15 kDa protein was confirmed as histone 3 by far-Western blot analysis and co-immunoprecipitation experiments. A dot-blot experiment further validated the binding of IGFBP-3 with H3. The intensity of IGFBP-3 on dot-blot showed a proportional increase with H3 concentrations between 2.33 pmol-37.42 pmol. Our results support the presence of protein-protein interaction between IGFBP-3 and H3. The physical binding between IGFBP-3 and H3 could indicate its yet another cellular role in regulating the chromatin remodeling for gene transcription.

Stage II differentiated thyroid cancer: A mixed bag.

BACKGROUND AND OBJECTIVES: AJCC-TNM Stage II well-differentiated thyroid cancer (WDTC) comprises T2N0M0 tumors in patients ≥45 years of age or metastatic WDTC in patients younger than 45 years. The objectives of this study were to assess the oncological outcome of stage II WDTC and to compare the oncological outcome of metastatic WDTC in patient younger (stage II) and older (stage IVC) than 45 years. METHODS: This study involved review of clinical presentation and oncological outcome of population cohort of 2,128 consecutive WDTC, diagnosed during 1970-2010 that includes 215 Stage II WDTC and 61 metastatic WDTC. Cox proportional hazard model was used to assess independent impact of prognostic factors on disease-specific survival (DSS) and disease-free survival (DFS) as calculated by Kaplan-Meier method. RESULTS: Metastatic and non-metastatic stage II WDTC had a 15-year DSS of 41.7% and 96.7%, respectively (P < 0.001). Multivariable analysis showed a 52 times higher risk of death in metastatic stage II WDTC and the DSS of metastatic stage II WDTC was not statistically different from that of stage IVC WDTC. CONCLUSION: Metastatic stage II WDTC is very different from non-metastatic stage II WDTC with oncological outcome similar to stage IVC WDTC.

Merkel Cell Carcinoma of the Head and Neck.

Merkel cell carcinoma (MCC) of the head and neck is a rare and aggressive non-melanoma skin cancer. The objective of this study was to assess the oncological outcome of MCC by retrospective review of electronic and paper records of a population-based cohort of 17 consecutive cases of the head and neck MCC without distant metastasis, diagnosed in Manitoba between 2004 and 2016. The average age of the patients at initial presentation was 74.1 ± 14.4 years with 6 patients presenting with stage I, 4 with stage II, and 7 with stage III disease. Both surgery or radiotherapy alone were the primary treatment modalities in 4 patients each and the remaining 9 patients had a combination of surgery with adjuvant radiotherapy. During the median follow-up of 52 months, 8 patients had recurrent/residual disease and 7 eventually died of it (P = .001). Metastatic spread of disease to the regional lymph nodes was observed in 11 patients either at presentation or during the follow-up and to the distant sites in 3 patients. At the time of the last contact on November 30, 2020, 4 patients were alive and disease-free, 7 had died of disease, and 6 had died of other causes. The case fatality rate was 41.2%. Five-year disease-free and disease-specific survivals were 51.8% and 59.7%, respectively. The 5-year disease-specific survival was 75% for early stage MCC (stage I and II) and 35.7% for stage III MCC. Early diagnosis and intervention are crucial for disease control and improving survival.

Le carcinome à cellules de Merkel (CCM) de la tête et du cou est un cancer de la peau non mélanique rare et virulent. La présente étude visait à évaluer le pronostic oncologique du CCM par une analyse rétrospective des dossiers électroniques et papier d'une cohorte en population de 17 cas consécutifs de CCM de la tête et du cou sans métastases distantes, diagnostiqués au Manitoba entre 2004 et 2016. Les patients avaient un âge moyen de 74,1±14,4 ans à la première consultation. Six d'entre eux étaient atteints d'un cancer de stade I, quatre d'un cancer de stade II et sept, d'un cancer de stade III. La chirurgie était la modalité thérapeutique primaire chez quatre patients, la radiothérapie, chez quatre autres, et les neuf derniers ont reçu une combinaison de chirurgie et de radiothérapie adjuvante. Pendant le suivi médian de 52 mois, huit patients ont souffert d'une récurrence ou d'une maladie résiduelle, et sept ont fini par en mourir (p=0,001). Onze patients ont présenté une propagation métastatique aux ganglions lymphatiques soit à la présentation, soit pendant le suivi, et trois en ont souffert à un siège distant. Au moment du dernier contact, le 30 novembre 2020, quatre patients étaient vivants et exempts de maladie, sept étaient décédés de la maladie et six étaient décédés d'autres causes, pour un taux de létalité de 41,2 %. La survie exempte de toute maladie et de cette maladie au bout de cinq ans s'élevait à 51,8 % et à 59,7 %, respectivement. La survie exempte de cette maladie au bout de cinq ans s'élevait à 75 % pour le CCM des stades I et II, et à 35,7 % pour le CCM de stade III. Il est essentiel de poser le diagnostic et d'intervenir rapidement pour contrôler la maladie et accroître la survie.

Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3): Unraveling the Role in Mediating IGF-Independent Effects Within the Cell.

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), one of the six members of the IGFBP family, is a key protein in the IGF pathway. IGFBP-3 can function in an IGF-dependent as well as in an IGF-independent manner. The IGF-dependent roles of IGFBP-3 include its endocrine role in the delivery of IGFs from the site of synthesis to the target cells that possess IGF receptors and the activation of associated downstream signaling. IGF-independent role of IGFBP-3 include its interactions with the proteins of the extracellular matrix and the proteins of the plasma membrane, its translocation through the plasma membrane into the cytoplasm and into the nucleus. The C-terminal domain of IGFBP-3 has the ability to undergo cell penetration therefore, generating a short 8-22-mer C-terminal domain peptides that can be conjugated to drugs or genes for effective intracellular delivery. This has opened doors for biotechnological applications of the molecule in molecular medicine. The aim of this this review is to summarize the complex roles of IGFBP-3 within the cell, including its mechanisms of cellular uptake and its translocation into the nucleus, various molecules with which it is capable of interacting, and its ability to regulate IGF-independent cell growth, survival and apoptosis. This would pave way into understanding the modus operandi of IGFBP-3 in regulating IGF-independent processes and its pleiotropic ability to bind with potential partners thus regulating several cellular functions implicated in metabolic diseases, including cancer.

Brachytherapy boost: a novel approach for epiglottic carcinoma.

PURPOSE: Epiglottic (epilaryngeal) carcinoma has been treated conventionally by radical external beam radiotherapy or partial laryngectomy. The aim of this study is to evaluate the role of brachytherapy boost as a novel approach for lingual epiglottic lesions. METHODS AND MATERIALS: Twenty-three patients with T(2-3)N(0-1) lingual epiglottic carcinoma (SCC) were treated with curative intent between January 1990 and December 2001 using low dose rate interstitial (192)Ir implant boost, moderate dose of 25Gy at 0.5cm (mean dose rate, 50.5 cGy/h) 3 weeks after moderate dose of external beam radiotherapy (mEBRT) of 46Gy/23#/28-31d. RESULTS: Complete response after mEBRT was observed in 18 of the 23 patients (78%) and partial response was seen in 5 of the 23 patients (22%). After implant, all patients had complete response. Locoregional control was seen in 19 of the 23 patients (82.6%). Two patients developed distant metastases. Disease-free survival and overall survival at 5 years were 68.3% and 66.7%, respectively. Disease-free survival at 5 years showed a trend toward better outcome for biologically equivalent doses >85Gy compared with biologically equivalent doses <85Gy (80% vs. 68%) (p=0.18). All patients had minimal to acceptable xerostomia. CONCLUSIONS: Interstitial boost with mEBRT is feasible, effective, and a novel approach for lingual epiglottic lesions.

Selective neck dissection (I-III) for node negative and node positive necks.

Selective neck dissection (I-III) for oral cancers offers similar regional control rates with less morbidity as compared with modified radical neck dissection. Charts of 414 patients with oral cancer, who underwent selective neck dissection (I-III) during 1994-2001, were analysed retrospectively. Seventy nine percent of the patients had a primary tumour in the gingivo-buccal complex. Cancer of tongue showed a trend towards higher regional failure (12.3%) as compared to gingivo-buccal cancers (6.5%). Primary tumour was staged as T1-8%, T2-47%, T3-19% and T4-26%. Sixty five percent of the patients were clinically node negative. Isolated neck failure was observed in 4.8% of patients at 2 years and in 5.8% at 5 years. De-differentiation of primary tumour and perineural spread were associated with regional failures. Eighty three percent of the neck recurrences were in the ipsilateral neck and only 16% of these were at levels IV or V. In all, 30% of all regional failures were outside the field of dissection.

FDG-PET characteristics of Hürthle cell and follicular adenomas.

OBJECTIVE: Follicular (FN) and Hürthle cell neoplasms (HCN) are considered indeterminate on thyroid fine needle aspiration cytology and are preoperative diagnostic challenges. The role of [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) in characterizing indeterminate thyroid nodules remains equivocal, because of the increased FDG uptake by some benign thyroid nodules. The objective of this study was to compare the FDG positron emission tomography/computerized tomography (PET/CT) characteristics of follicular (FA) and Hürthle cell adenomas (HCA). METHODS: Twenty-nine patients with 31 thyroid nodules underwent FDG-PET/CT scans of the neck and superior mediastinum for indeterminate FN/HCN, and were later found to have benign adenomas on final histopathology. All scans were reported by a single observer, who was blinded to the surgical and pathology findings. Receiver operating characteristic (ROC) curve analysis of maximum standardized uptake value (SUVmax) and the area under the curve (AUROC) were used to assess discrimination between FA and HCA. Youden index was used to identify the optimal cut-off SUVmax. Sensitivity, specificity, predictive values and overall accuracy were used as measures of performance. RESULTS: The mean age of our study cohort was 60.7 ± 12.6 years and 77 % of the patients were females. Age of the patients (p = 0.48), their gender (p = 0.52), and the size of thyroid nodules (p = 0.79) were similar for FA and HCA. Increased focal FDG uptake was observed in 100 % of HCA and 52 % of FA (p = 0.02). SUVmax of HCA was significantly higher (p < 0.001) than that of FA. SUVmax of 5 was the best cut-off for discrimination between HCA and FA, with AUROC of 0.90 (95 % CI, 0.79-1.00; p = 0.001). With this cut-off, FDG-PET/CT had sensitivity of identifying HCA of 88 % (95 % CI 47-99 %), specificity of 87 % (95 % CI 65-97 %), positive predictive value of 70 % (95 % CI 35-92 %), and negative predictive value of 95 % (95 % CI 74-99 %). The overall accuracy was 87 %. CONCLUSIONS: HCA shows significantly higher focal FDG uptake as compared to FA and should always be considered in the differential diagnosis of FDG-PET positive thyroid nodules.

What is the most appropriate intraoperative baseline parathormone? A prospective cohort study.

INTRODUCTION: The time of drawing pre-incision intraoperative parathyroid hormone (ioPTH) is crucial to provide the right baseline for post-excision PTH measurement. The objective of this study was to identify the optimal time and the numbers of baseline PTH samples that best predict excision of all hypercellular parathyroid tissue when compared with 10-min post-excision PTH level. MATERIALS AND METHODS: In this prospective study, two pre-incision (pre-induction and 10-min post-induction) baseline ioPTH samples along with pre- and post-excision ioPTH were collected and analyzed for 352 parathyroidectomies in 341 patients for sporadic primary hyperparathyroidism at a University hospital. Paired Wilcoxan signed rank test was used to compare the pre-incision ioPTH levels and their percent drop to 10-min post-excision levels. Sensitivity, specificity, predictive values and receiver operating characteristic (ROC) curves were used to compare the predictability of the two pre-incision levels. RESULTS: The difference between pre- and post-induction baseline PTH levels was highly significant (p < 0.001). In 4% cases the criterion of post-excision PTH drop of ≥50% was achieved only with the post-induction baseline PTH and not with pre-induction PTH measurement. Using pre-induction baseline, ioPTH had an overall accuracy of 90% whereas ≥50% fall in the post-excision PTH from the post-induction baseline PTH had the accuracy of 94.85%. DISCUSSION: There was a significant difference between pre- and post-induction PTH levels and Miami criteria was met in 95.45% cases with post-induction baseline. CONCLUSIONS: The optimal time for drawing pre-incision baseline PTH sample is at 10 min post-induction of general anesthesia and positioning of patient.

RAGE Mediates the Pro-Migratory Response of Extracellular S100A4 in Human Thyroid Cancer Cells.

BACKGROUND: Expression of the small calcium-binding protein S100A4 is associated with poor prognosis in patients with thyroid cancer (TC). The authors have previously shown that S100A4 is a target for relaxin and insulin-like peptide 3 signaling in TC cells and that S100A4 is secreted from human TC cells. Although the pro-migratory role of intracellular S100A4 in binding to non-muscle myosin is well known, this study investigated here whether extracellular S100A4 contributes to TC migration. METHODS: Human cell lines of follicular, papillary, and undifferentiated thyroid cancer, primary patient TC cells, and TC tissues were utilized to discover the presence of the receptor of advanced glycation end products (RAGE) in TC cells and TC tissues. Fluorescence imaging, protein pull-down assays, Western blot, siRNA protein silencing, small GTPase inhibitors, cell proliferation, and cell migration assays were used to investigate the interaction of extracellular S100A4 with RAGE in promoting a TC migratory response. RESULTS: It was demonstrated that RAGE served as receptor for extracellular S100A4 mediating cell migration in TC cells. The RAGE-mediated increase in cell migration was dependent on the intracellular RAGE signaling partner diaphanous-1 (Dia-1) and involved the activation of the small GTPases Cdc42 and RhoA. Although extracellular S100A4 consistently activated ERK signaling in TC cells, it was shown that ERK signaling was not mediated by RAGE and not essential for the migratory response in TC cells. CONCLUSION: The data have identified the RAGE/Dia-1 signaling system as a mediator for the pro-migratory response of extracellular S100A4 in human TC. Thus, therapeutic targeting of the RAGE/Dia-1/small GTPases signaling may successfully reduce local invasion and metastasis in TC.

Spontaneous cerebrospinal fluid rhinorrhea as the primary manifestation of maxillary carcinoma--case report.

A 66-year-old man presented with a maxillary carcinoma manifesting as unrelenting spontaneous cerebrospinal fluid (CSF) rhinorrhea. Anterior craniofacial resection of the tumor was performed with multilayered repair of the dura mater. Maxillary carcinoma usually manifests as nasal blockage, epistaxis, or a mass lesion. This case highlights the necessity for a high index of suspicion for malignant tumor and the need for meticulous repair of the dura mater to seal off the CSF leakage.

Impact of use of frozen section assessment of operative margins on survival in oral cancer.

OBJECTIVE: This study looked at the independent impact of intraoperative frozen section assessment of the adequacy of margins of excision on disease control and survival. STUDY DESIGN: The design was a review of outcome of historical cohort of 416 surgically treated oral cancer patients at a comprehensive cancer center. Status of the margins at permanent sections, disease failure at the primary site, and survival data of 229 patients who had frozen sections were compared by univariate and multivariate analysis with 197 patients who did not have frozen sections. RESULTS: Failure at the primary site was independently influenced by age at diagnosis (P < .001), T stage (P = .016), N stage (P = .042), and status of margins on paraffin sections (P = .005). Chance of achieving clear margins on paraffin sections was, however, not significantly improved by the use of frozen sections. On multivariate analysis, the use of frozen sections did not independently have an impact on local failure or survival. CONCLUSIONS: Frozen section assessment of mucosal margins has not improved the disease outcome.

Buccal plate excision for buccal paramandibular spread.

Cancer of buccal gingival sulcus lie in close proximity to mandible but tend to invade bone late in the course of disease. Segmental mandibulectomy advocated for these tumors results in cosmetic disfigurement and functional impairment. We, for the first time, describe a mandibular preservation alternative, in form of buccal cortical plate excision, for these tumors.

Advanced squamous cell carcinoma of lower gingivobuccal complex: patterns of spread and failure.

BACKGROUND: Carcinoma of the gingivobuccal complex is commonly associated with the use of smokeless tobacco known as "quid." METHODS: We conducted a retrospective chart review of 511 patients with advanced cancer of gingivobuccal complex surgically treated during 1994 to 1995. We evaluated patterns of disease failure in these patients and correlated disease-free survival with various prognostic factors. RESULTS: During a median follow-up of 46 months, 159 locoregional recurrences and 11 distant metastases were detected in 148 patients. Seventy-nine percent of the recurrences appeared within 18 months of surgery, and the median survival for patients with recurrent disease was less than 4 months. Two-year and 5-year disease-free survival rates were 64% and 57%, respectively. On multivariate analysis, disease-free survival showed significant correlation with skin involvement and extracapsular spread. CONCLUSIONS: Gingivobuccal cancers usually fail locoregionally. Soft tissue infiltration and extracapsular spread of nodal disease influence disease-free survival.

Reconstruction of early lower gingivo buccal complex lesions using floor of mouth advancement augmented with hyoglossus release.

The surgical treatment in early cancers of the lower gingivobuccal (GB) complex involves wide resection of the buccal mucosa and GB sulcus with or without marginal mandibulectomy. To reconstruct this defect we endeavour to describe a method of advancement of the lateral floor of mouth and tongue to provide pliable, vascularised tissue to bridge the mucosal defect and achieve tension free, primary closure whilst preserving maximum tongue mobility and maintaining adequate mouth opening, thus offering an elegant and simple solution to the problems of reconstruction in early lesions of the lower gingivo buccal complex.