Publications by authors named "Pattatheyil Arun"

27 Publications

  • Page 1 of 1

Fabricating Flaps in the Forearm Prior to Tracheal Reconstruction.

Indian J Plast Surg 2021 Jan 30;54(1):53-57. Epub 2020 Nov 30.

Department of Head and Neck Surgery, TATA Medical Center, Kolkata, West Bengal, India.

 The process of reconstruction of tracheal defects is complex and still not optimum. Options range from using staged reconstructions, combining flaps with autologous or alloplastic implants, as well as use of tissue-engineered constructs combined with vascularized tissues which are lined with cell cultures. Staged reconstructions using prelaminated epithelium, and prefabricated flaps, help in reconstruction of this complex structure. Prefabricating the flap at a different site allows for integration of the tissues prior to its transfer.  This article reports two patients planned for tracheal reconstruction for the purpose of advanced papillary carcinoma of the thyroid invading the trachea. Staged reconstruction using a prefabricated radial artery forearm flap (RAFF) and split rib cartilage was performed. In the second patient, a young girl, a similar construct of the RAFF, prelaminated with buccal mucosa, was performed. However, in the latter case, an intraoperative decision by the head and neck team to limit excision of the trachea sparing the mucosa was taken; the reconstruct in the forearm was redundant and needed to be discarded, replacing the defect with a free superficial circumflex iliac artery perforator (SCIP) flap.  At 3 years follow-up, both the patients are free of disease, with the construct serving its purpose in the older female.
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http://dx.doi.org/10.1055/s-0040-1721522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012785PMC
January 2021

Radiation-induced hypothyroidism in patients of oral squamous cell carcinoma: A retrospective analysis of 195 patients.

Indian J Cancer 2021 Jan 27. Epub 2021 Jan 27.

Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal, India.

Background: Radiation-induced hypothyroidism (RIH) is common after neck irradiation, and biochemical evaluation of thyroid function is recommended periodically for early diagnosis and treatment. This study aimed to evaluate the predictors of RIH after completion of adjuvant radiotherapy (RT) for primary oral squamous cell carcinoma (OSCC).

Methods: This is a retrospective study involving 195 patients who received RT after surgery for OSCC between August 2011 and December 2016. Thyroid function tests were obtained every 6 months and patients were considered to be hypothyroid if thyroid-stimulating hormone level was >5 mIU/mL.

Results: The study cohort comprised 130 men with a median age of 52 years (range 21-77 years). About 107 (54.87%) patients developed hypothyroidism, with a median of 21 months (range 2-67 months) for the development of RIH. Women [41 (63.1%) versus 66 (50.8%), p=0.035], addition of chemotherapy [36 (63.2%) versus 71 (51.4%), p= 0.019], and higher cumulative dose to the thyroid gland (median dose 4690 cGy versus 2981 cGy, P < 0.001) resulted in higher incidence of RIH on univariate analysis. On multivariate Cox regression analysis, female sex (P = 0.042), bilateral irradiation (P = 0.046), and cumulative dose to the thyroid (P = 0.001) were factors associated with increased risk of developing RIH.

Conclusion: The addition of chemotherapy, high dose of radiation to the thyroid gland, bilateral irradiation, and female sex were at higher risk of developing RIH. However, more studies are required to identify the dose-volume constraints of the thyroid gland.
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http://dx.doi.org/10.4103/ijc.IJC_946_19DOI Listing
January 2021

Factors predicting contralateral nodal spread in papillary carcinoma of thyroid.

Indian J Cancer 2021 Jan 27. Epub 2021 Jan 27.

Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal, India.

Background: Lymph node metastasis (LNM) is evident in about 20-50% of cases at presentation in papillary carcinoma thyroid (PTC). There are no clear recommendations for the need and extent of lateral and central compartment dissection in PTC.

Methods: A total of 83 patients who underwent total thyroidectomy and bilateral selective neck dissection for diagnosed PTC from September 2011 to October 2017 were retrospectively analyzed.

Results: Tumor site was bilobar or involving isthmus in 40 patients. Contralateral LNM was seen in 42 patients. Both radiological (median size 2.6 cm, P = 0.051) and pathological (median size 3.65 cm, P = 0.015) size of tumor, tumor involving isthmus or bilateral lobes (P = 0.006), and lymphovascular invasion (LVI) (P = 0.026) had significant correlation with contralateral LNM.

Conclusion: Size and site of tumor, ipsilateral lateral compartment nodes involvement, and LVI status of tumor significantly increases the probability of contralateral LNM in patients of PTC.
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http://dx.doi.org/10.4103/ijc.IJC_684_19DOI Listing
January 2021

Two novel cell culture models of buccal mucosal oral cancer from patients with no risk-habits of tobacco smoking or chewing.

Oral Oncol 2021 02 30;113:105131. Epub 2020 Dec 30.

National Institute of Biomedical Genomics, Kalyani, India. Electronic address:

Objective: Tobacco consumption is one of the major etiological factors for oral cancer, but it also develops in non-tobacco users, with unknown etiologies. Cellular models for tobacco associated oral cancer are available, however; reports of cellular models for studying non-tobacco associated oral cancer are limiting. We report here the establishment and characterization of two novel buccal mucosal cancer cell lines 'GBC02' and 'GBC035' derived from non-tobacco users.

Materials And Methods: Short tandem repeats (STR) profiling, Next-generation sequencing for whole-genome, exome and copy number alterations, immunofluorescence, flow-cytometry, proliferation, live-cell chemotaxis, 3D-spheroid formation, chemotherapy response, gene-expression microarray, gene-set enrichment analysis and xenograft development were performed.

Results: Sources of the established cultures were matched to their donors through STR profiling. Genome sequence analysis revealed somatic mutations in TP53, CASP8, CDKN2A for GBC02 with deletions and amplifications encompassing CDKN2A, FAT1 and CCND1, PIK3CA, SOX2, EGFR, MYC genes, respectively. GBC035 harbored mutations in FAT1, NOTCH1, HRAS, CDKN2A, HLA-B, HLA-A genes. While GBC035 cells showed higher E-Cadherin positive cell-cell junctions and collective cell migration in chemotaxis; GBC02 cells were vimentin-positive and demonstrated individual cell migration. Further, exhibiting their relevance to preclinical research, GBC02 3D-spheroids demonstrated enrichment of development-related gene-signatures in microarray transcriptome analysis and were resistant to Cisplatin, but showed sensitivity to cancer stem cells-targeting drug, Salinomycin. Additionally, tumorigenic ability of GBC02 was demonstrated.

Conclusions: Altogether, we present here comprehensively characterized unique cell lines established from non-tobacco associated tumors, which may serve as models for preclinical investigations of oral cancers caused independent of tobacco usage.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105131DOI Listing
February 2021

Nodal yield and topography of nodal metastases from oral cavity squamous cell carcinoma - An audit of 1004 cases undergoing primary surgical resection.

Oral Oncol 2021 02 16;113:105115. Epub 2020 Dec 16.

Head and Neck Surgery, Tata Medical Center, Kolkata, India.

Objectives: Nodal metastasis is an important prognostic factor in oral squamous cell carcinoma (OSCC). Detailed topographic study of metastasis can guide surgical and adjuvant radiation treatment protocols.

Methods: Retrospective analysis of distribution of nodal spread was done by auditing pathology records of 1004 patients who underwent primary surgical management at our center.

Results: The median nodal yield was 41 (range of 9-166) nodes, per patient. Metastasis was present in 42.9% patients, of which 52.3% demonstrated extranodal extension. Reclassification by AJCC8 criteria resulted in up-staging in 35.6% patients (pN1, pN2a, pN2b, pN2c, pN3a and pN3b in 13.1%, 3.7%, 6.9%, 0.9%, 0%, 18.1% respectively). Ipsilateral levels Ib and IIa were involved in a quarter of patients each, while IIb, IV and V were involved in < 4%, 3% and 1% of patients, respectively. Contralateral nodal metastasis was present in 5.4%. Skip metastases to level IV were 2.2% and 1.2% for tongue and gingivobuccal primaries. Tongue primaries had a lower likelihood of involving level Ib, but higher of level IIa and III, compared to gingivobuccal primaries, and a lower likelihood of extranodal extension. Primary site did not influence nodal metastasis to levels IIb, IV or V, but other factors like lymphovascular invasion, pT stage and margin status had an influence.

Conclusion: This large series with high nodal yield, shows low level of metastasis to level IIb, IV and V, which can help modify future guidelines for extent of surgery and avoid targeted adjuvant radiation to specific levels.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105115DOI Listing
February 2021

Lymph node characteristics and their prognostic significance in oral squamous cell carcinoma.

Head Neck 2021 Feb 6;43(2):520-533. Epub 2020 Oct 6.

Department of Head and Neck Surgical Oncology, Tata Medical Center, Kolkata, West Bengal, India.

Background: The prognostic significance of various histopathologic lymph node-based biomarkers in oral squamous cell carcinoma (OSCC) needs further evaluation.

Methods: Retrospective analysis of 212 OSCC patients with regional metastasis to determine the association of extranodal extension (ENE), extent of ENE, size of metastatic deposit, lymph node yield (LNY), lymph node ratio (LNR), and topography of involvement with survival outcomes.

Results: The presence of ENE, larger nodal deposit, higher pN stage, lymph nodes in the lower levels, and patients who did not receive adjuvant treatment had poor disease-free survival (DFS). In addition, more positive nodes and high LNR showed worse overall survival (OS). ENE beyond 5 mm resulted in poorer outcomes. Larger sizes of metastatic deposit predisposed to ENE. Multivariate analyses showed only lower level of neck involvement to affect both DFS and OS.

Conclusions: Lymph node metastasis to lower levels and other lymph node characteristics affect prognosis and must be considered in the evolution of staging systems for OSCC.
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http://dx.doi.org/10.1002/hed.26499DOI Listing
February 2021

Functional Landscape of Dysregulated MicroRNAs in Oral Squamous Cell Carcinoma: Clinical Implications.

Front Oncol 2020 12;10:619. Epub 2020 May 12.

Saroj Gupta Cancer Centre and Research Institute, Kolkata, India.

MicroRNA (miRNA) dysregulation is associated with the pathogenesis of oral squamous cell carcinoma (OSCC), and its elucidation could potentially provide information on patient outcome. A growing body of translational research on miRNA biology is focusing on precision oncology, aiming to decode the miRNA regulatory network in the development and progression of cancer. Tissue-specific expression and stable presence in all body fluids are unique features of miRNAs, which could be potentially exploited in the clinical setting. Recent understanding of miRNA properties has led them to be useful, attractive, and potential tools either as biomarkers (distinct miRNA expression signature) for diagnosis and prognostic outcomes or as targets for novel therapeutic entities, enabling personalized treatment for OSCC. In this review, we discuss recent research on different aspects of alterations in miRNA profiles along with their clinical significance and strive to identify probable potential miRNA biomarkers for diagnosis and prognosis of OSCC. We also discuss the current understanding and scope of development of miRNA-based therapeutics against OSCC.
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http://dx.doi.org/10.3389/fonc.2020.00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274490PMC
May 2020

Contribution of Weight and Volume of the Extirpated Thyroid Gland on Voice Alterations After Total Thyroidectomy in Patients With Papillary Carcinoma of the Thyroid.

J Voice 2020 Mar 19. Epub 2020 Mar 19.

Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal, India. Electronic address:

Purpose: Voice change after thyroid surgery is common despite preservation of laryngeal nerves. In this study, we sought to find if the change in voice after total thyroidectomy is related to the weight and volume of the removed thyroid gland.

Methods: This is a prospective cohort study of 50 patients of papillary carcinoma of the thyroid treated with total thyroidectomy from December 2016 through May 2018. Both objective and subjective voice parameters were analyzed preoperatively and at 1 and 3 months following surgery.

Results: A cohort of 29 patients, with a median age of 31 years (18-64 years), comprising 22 women were eligible for final analysis. Speaking fundamental frequency showed a mean change of 17.21 Hz (SD 34.49) while the mean intensity change was 5.54 dB (SD 18.21). The mean weight and volume of thyroid gland was 18.99 g (SD 8.93) and 15.67 ml (SD 8.70), respectively. On multivariate analysis, both weight and volume affected the range of frequency (P = 0.002 and 0.035, respectively) and range of intensity (P = 0.014 and 0.008, respectively).

Conclusion: Larger thyroid tumors are more likely to be associated with transient change in voice quality following their surgical removal despite physical preservation of external and recurrent laryngeal nerves, which may persist up to 3 months. This study affirms that perturbations in voice after thyroidectomy can still exist in spite of clinical demonstration of integrity of neuromuscular function.
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http://dx.doi.org/10.1016/j.jvoice.2020.02.014DOI Listing
March 2020

Adenoid Cystic Carcinoma with Transformation to High Grade Carcinomatous and Sarcomatoid Components: A Rare Case Report with Review of Literature.

Head Neck Pathol 2020 Dec 2;14(4):1094-1104. Epub 2020 Jan 2.

Department of Pathology, Tata Medical Center, 14 Main Arterial Road (E-W), Newtown, Rajarhat, Kolkata, India.

Adenoid cystic carcinoma (AdCC) comprises of less than 1% of all head and neck cancers and less than 10% of all salivary gland neoplasms. Dedifferentiation/high-grade transformation (HGT) in AdCC is a rare but well known phenomenon which is associated with aggressive clinical behaviour and poor prognosis. We herein report the clinical, cytologic, histologic and immunohistochemical findings of a left submandibular gland AdCC with transformation to high grade carcinomatous and probable dedifferentiation to sarcomatoid component, occurring in a 64 year old male patient. To the author's best knowledge, this is the first case report of such dual transformation occurring in adenoid cystic carcinoma.
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http://dx.doi.org/10.1007/s12105-019-01120-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669942PMC
December 2020

Redefining adequate margins in oral squamous cell carcinoma: outcomes from close and positive margins.

Eur Arch Otorhinolaryngol 2020 Apr 2;277(4):1155-1165. Epub 2020 Jan 2.

Department of Head and Neck Surgery, Tata Medical Center, Calcutta, West Bengal, 700160, India.

Purpose: Adequacy of surgical margins impacts outcomes in oral cancer. We sought to determine whether close and positive margins have different outcomes in patients with oral cancer.

Methods: Retrospective data from 612 patients with oral carcinoma were analyzed for the effect of margin status on locoregional recurrence-free survival (LRFS), disease-free survival (DFS) and overall survival (OS).

Results: A total of 90 cases (14.7%) had close margins and 26 patients (4.2%) had positive margins. Recurrences were documented in 173 patients (28%), of which 137 (22% of the study sample) were locoregional, and 164 patients (27%) had died. Among patients with close or positive margins, a cutoff of 1 mm optimally separated LRFS (adjusted p = 0.0190) and OS curves (adjusted p = 0.0168) whereas a cutoff of 2 mm was sufficient to significantly separate DFS curves (adjusted p = 0.0281).

Conclusions: Patients with oral carcinoma with positive margins (< 1 mm) had poorer outcomes compared to those with close margins (1-5 mm) in terms of LRFS, DFS and OS. There is a suggestion that a cutoff of < 2 mm might provide slightly more separation for DFS.
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http://dx.doi.org/10.1007/s00405-019-05779-wDOI Listing
April 2020

Clinicopathologic Determinants of Outcome in Pathologic T4a (pT4a) Squamous Cell Carcinoma of the Gingivobuccal Subsite of the Oral Cavity.

Indian J Surg Oncol 2019 Dec 27;10(4):594-599. Epub 2019 Jun 27.

1Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal 700160 India.

Carcinoma of the gingivobuccal complex is one of the most common cancers in India and patients usually present in an advanced stage. There is limited data in literature regarding the factors predicting outcome in pathological T4a patients. In this study, we aimed to study the clinic-pathological factors which may influence treatment outcomes in pT4a patients. This is a retrospective study of 121 patients who underwent surgery for oral squamous cell carcinoma between August 2011 and December 2016, staged pT4a. Overall survival (OS) and disease-free survival (DFS) were analyzed for variables including age, depth of invasion, margin status, differentiation, nodal status, extranodal spread, lymphovascular and perineural spread, and adjuvant treatment. The study cohort comprised 93 males with mean age 60.28 years (S.D. 11.25). Median DFS was 21 months (range 9 to 2374 days) whereas median OS was 24.5 months (range 9 to 2374 days). On univariate analysis, lymphovascular invasion, perineural invasion, cervical nodal metastasis, and extranodal extension had a statistically significant effect on both DFS and OS. On multivariate analysis, age ( = 0.014) and adjuvant radiotherapy ( = 0.010) were the statistically significant factors affecting OS. None of the factors affected DFS on multivariate analysis. Patients staged pT4a with cervical nodal metastasis, extranodal extension, lymphovascular invasion, and perineural invasion have reduced OS and DFS. On multivariate analysis, lower age at presentation and adjuvant radiation improved patient outcome.
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http://dx.doi.org/10.1007/s13193-019-00950-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895327PMC
December 2019

Factors Affecting Postoperative Complications After Reconstructive Surgery in Oral Carcinoma Patients: A Prospective Study of 100 Patients.

Indian J Otolaryngol Head Neck Surg 2019 Oct 19;71(Suppl 1):341-347. Epub 2018 Mar 19.

1Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal 700156 India.

Postoperative complications may result in significant functional morbidity, poor cosmetic results, prolonged hospitalization, preclusion of optimal treatment for the cancer, or even be pose threat to life. We prospectively assessed postoperative complications in 100 patients who underwent surgical resection with free or pedicled flap reconstruction as a primary modality of treatment in patients with carcinoma of the oral cavity. One hundred consecutive patients who underwent reconstructive surgery for oral cancer were prospectively analyzed for age, gender, comorbidities, tumor stage, nodal stage, primary sub-site of tumour, reconstructive procedure (free or pedicled), duration of surgery, blood transfusions during surgery, preoperative weight and body mass index, patient generated subjective global assessment status and tracheostomy to determine their effect on postoperative complications as determined on the CD scale. The sample comprised 100 patients with a mean age of 52.12 years (range 24-80 years) and 74% men (M:F ratio 3:1). A total of 40 patients developed surgical complications (including two deaths) while medical complications were seen in 10 patients (including one death). Tracheostomy (52 vs. 7%,  = 0.002) and age (54 vs. 49 years,  = 0.031) were associated with higher complication rate. Higher age and tracheostomy is associated with higher complications in postoperative period.
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http://dx.doi.org/10.1007/s12070-018-1304-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848619PMC
October 2019

Novel Technique to Increase the PMMC Flap Pedicle Length by Coplanar Rotation Along the Pedicle Axis.

J Maxillofac Oral Surg 2019 Dec 23;18(4):637-639. Epub 2019 Jan 23.

Department of Head and Neck Surgical Oncology, Tata Medical Center, Kolkata, West Bengal 700 156 India.

Pectoralis major myocutaneous flap (PMMC) continues to be a prime tool in the armamentarium for the reconstruction of head and neck malignancies even though free flaps have proved their versatility in functional and cosmetic outcomes. It still holds significance in both primary reconstruction and salvage procedures in head and neck malignancies. Inadequate infrastructure and resources make PMMC a preferred choice in many high-volume centres of developing countries. However, the length of the PMMC flap becomes a limiting factor for the distance that flap can be transferred when extensive reconstructions are being planned (Kudva et al. in J Maxillofac Oral Surg 14:481-483, 2015). We propose a modification in the conventional technique that maximises the length of the pedicle in orofacial reconstruction. Our technique allows the rotation of skin paddle along the longitudinal axis of the pedicle at the distal end along the same plane. This technique provides an easily reproducible and reliable technique that enables the surgeon to enhance the reach of the skin paddle and flexibility considerably.
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http://dx.doi.org/10.1007/s12663-019-01184-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795666PMC
December 2019

Unusual loco-regional presentation in papillary carcinoma of thyroid: A case series.

Indian J Cancer 2019 Oct-Dec;56(4):325-329

Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal, India.

Background: Papillary carcinoma of thyroid (PTC) is usually indolent with good prognosis and excellent long-term survival. However, PTC sometimes presents itself in unusual situations, posing diagnostic and therapeutic challenges. Owing to paucity of data, there is lack of consensus as to what treatment should be prescribed in patients with loco-regional spread other than the usual sites.

Materials And Methods: Six patients of PTC presenting with involvement of the aero-digestive tract, retropharyngeal, and para-pharyngeal lymph nodes and great vessels of the neck are included in this case series.

Results And Conclusion: Though rare, unusual loco-regional presentation of PTC poses challenges in diagnosis and treatment. A keen clinical sense is paramount in effectively diagnosing these cases. Aggressive surgical resection and reconstruction results in good functional and aesthetic outcomes. Further studies are required for establishing specific guidelines on the approach to the treatment of these cases.
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http://dx.doi.org/10.4103/ijc.IJC_368_18DOI Listing
February 2020

A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma.

Oncogenesis 2018 Oct 5;7(10):78. Epub 2018 Oct 5.

National Institute of Biomedical Genomics, Kalyani, India.

Cancer-associated fibroblasts (CAFs) demonstrate the characteristics of myofibroblast differentiation by often expressing the ultrastructure of alpha-smooth muscle actin (αSMA). However, heterogeneity among cancer-associated fibroblasts (CAFs), with respect to αSMA expression, has been demonstrated in several clinical studies of oral cancer. Like normal stem cells, stem-like cancer cells (SLCCs) are also regulated extrinsically by its microenvironment; therefore, we postulated that the heterogeneous oral-CAFs would differently regulate oral-SLCCs. Using transcriptomics, we clearly demonstrated that the gene expression differences between oral tumor-derived CAFs were indeed the molecular basis of heterogeneity. This also grouped these CAFs in two distinct clusters, which were named as C1 and C2. Interestingly, the oral-CAFs belonging to C1 or C2 clusters showed low or high αSMA-score, respectively. Our data with tumor tissues and in vitro co-culture experiments interestingly demonstrated a negative correlation between αSMA-score and cell proliferation, whereas, the frequency of oral-SLCCs was significantly positively correlated with αSMA-score. The oral-CAF-subtype with lower score for αSMA (C1-type CAFs) was more supportive for cell proliferation but suppressive for the self-renewal growth of oral-SLCCs. Further, we found the determining role of BMP4 in C1-type CAFs-mediated suppression of self-renewal of oral-SLCCs. Overall, we have discovered an unexplored interaction between CAFs with lower-αSMA expression and SLCCs in oral tumors and provided the first evidence about the involvement of CAF-expressed BMP4 in regulation of self-renewal of oral-SLCCs.
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http://dx.doi.org/10.1038/s41389-018-0087-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172238PMC
October 2018

Encouraging Outcomes With Manageable Toxicity Using Neoadjuvant Chemotherapy and Intensity-modulated Radiotherapy in Advanced Pediatric Nasopharyngeal Carcinoma: Single-Center Experience From a Developing Country.

J Pediatr Hematol Oncol 2017 05;39(4):318-319

Departments of *Pediatric Hematology-Oncology †Radiation Oncology ‡Head and Neck Surgery §Histopathology ∥Radiology, Tata Medical Center Kolkata, India.

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http://dx.doi.org/10.1097/MPH.0000000000000794DOI Listing
May 2017

Simultaneous Triple Primary Head and Neck Malignancies: A Rare Case Report.

Head Neck Pathol 2016 Jun 17;10(2):233-6. Epub 2015 Oct 17.

Department of Head & Neck Surgical Oncology, Tata Medical Center, Kolkata, India.

The occurrences of multiple primary malignant tumours in the head and neck region are reported as simultaneous, synchronous, or metachronous based on their chronology of presentation. Lymphoid malignancies presenting in association with squamous cell carcinoma in the head and neck region are extremely rare. We report a case of a 71 year old male patient with simultaneous triple primary malignancies of different histologic origin, involving larynx (squamous cell carcinoma), thyroid (papillary thyroid carcinoma) and lymph nodes (non-Hodgkin's lymphoma).
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http://dx.doi.org/10.1007/s12105-015-0664-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838955PMC
June 2016

HSP90 Inhibitor SNX5422/2112 Targets the Dysregulated Signal and Transcription Factor Network and Malignant Phenotype of Head and Neck Squamous Cell Carcinoma.

Transl Oncol 2013 Aug 1;6(4):429-41. Epub 2013 Aug 1.

Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD.

Heat shock protein 90 (HSP90) is a chaperone protein that stabilizes proteins involved in oncogenic and therapeutic resistance pathways of epithelial cancers, including head and neck squamous cell carcinomas (HNSCCs). Here, we characterized the molecular, cellular, and preclinical activity of HSP90 inhibitor SNX5422/2112 in HNSCC overexpressing HSP90. SNX2112 inhibited proliferation, induced G2/M block, and enhanced cytotoxicity, chemosensitivity, and radiosensitivity between 25 and 250 nM in vitro. SNX2112 showed combinatorial activity with paclitaxel in wild-type (wt) TP53-deficient and cisplatin in mutant (mt) TP53 HNSCC lines. SNX2112 decreased expression or phosphorylation of epidermal growth factor receptor (EGFR), c-MET, v-akt murine thymoma viral oncogene homolog 1 (AKT), extracellular signal-regulated kinases (ERK) 1 and 2, inhibitor κB kinase, and signal transducer and transcription factor 3 (STAT3), corresponding downstream nuclear factor κB, activator protein-1, and STAT3 reporter genes, and target oncogenes and angiogenic cytokines. Furthermore, SNX2112 enhanced re-expression of TP53 and targets p21WAF1 and PUMA, while TP53 inhibitor Pifithrin or siRNA attenuated the antiproliferative activity of SNX2112 in wtTP53 HNSCC in vitro. Prodrug SNX5422 similarly down-modulated key signal targets, enhanced TP53 expression and apoptosis, and inhibited proliferation, angiogenesis, and tumorigenesis in a wtTP53-deficient HNSCC xenograft model. Thus, HSP90 inhibitor SNX5422/2112 broadly modulates multiple key nodes within the dysregulated signaling network, with corresponding effects upon the malignant phenotype. Our data support investigation of SNX5422/2112 in combination with paclitaxel, cisplatin, and radiotherapy in HNSCC with different TP53 status.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730018PMC
http://dx.doi.org/10.1593/tlo.13292DOI Listing
August 2013

Phase II 2-arm trial of the proteasome inhibitor, PS-341 (bortezomib) in combination with irinotecan or PS-341 alone followed by the addition of irinotecan at time of progression in patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck (E1304): a trial of the Eastern Cooperative Oncology Group.

Head Neck 2013 Jul 13;35(7):942-8. Epub 2012 Jul 13.

Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

Background: Constitutive activation of nuclear factor κB (NF-κB) is associated with poor prognosis. Irinotecan demonstrates single-agent activity in head and neck cancer but activates NF-κB, promoting cell survival and resistance. Bortezomib is a proteasome inhibitor that inactivates NF-κB.

Patients And Methods: We performed a randomized phase II trial of bortezomib on days 1, 4, 8, and 11 and irinotecan on days 1 and 8 of each 21-day cycle or single-agent bortezomib on days 1, 4, 8, and 11 on a 21-day cycle. The addition of irinotecan to bortezomib was allowed in patients who progressed on bortezomib alone.

Results: The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with addition of irinotecan at time of progression on bortezomib.

Conclusions: The bortezomib-based regimens evaluated in this study have minimal activity in recurrent or metastatic head and neck cancer.
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http://dx.doi.org/10.1002/hed.23046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689864PMC
July 2013

CK2 modulation of NF-kappaB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub-50-nm nanocapsules.

Clin Cancer Res 2010 Apr 6;16(8):2295-307. Epub 2010 Apr 6.

Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892-1419, USA.

Purpose: The aim of this study is to investigate the expression of CK2 subunits and CK2 effects on NF-kappaB-mediated and TP53-mediated signal activation and gene expression, the malignant phenotype, and chemosensitivity in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo.

Experimental Design: Protein expression of CK2 subunits was investigated by Western blot and immunohistochemistry. CK2 subunits were knocked down by small interfering RNA, and NF-kappaB activation was examined using DNA binding, Western blot, and luciferase reporter assays. Gene expression was measured by quantitative reverse transcription-PCR. Cell growth, survival, motility, and sensitivity to cisplatin were measured by MTT, flow cytometry, and migration assays. In vivo targeting of CK2alpha/alpha' in HNSCC xenograft models was achieved using anti-CK2alpha/alpha' oligodeoxynucleotide encapsulated in sub-50-nm tenfibgen nanocapsules.

Results: CK2 subunit proteins were overexpressed in HNSCC lines and tissues. Knockdown of CK2 subunits differentially inhibited IkappaBalpha degradation, NF-kappaB nuclear localization, phosphorylation, DNA binding, and reporter activity. CK2 subunits modulated gene expression and the malignant phenotype involved in cell cycle and migration, whereas CK2alpha is critical to promote proliferation, antiapoptosis, and cisplatin resistance in vitro. Furthermore, in vivo delivery of anti-CK2alpha/alpha' oligodeoxynucleotide nanocapsules significantly suppressed tumor growth in HNSCC xenograft models, in association with modulation of CK2 and NF-kappaB regulated molecules, TP53 family proteins, and induction of apoptosis.

Conclusions: Our study reveals a novel role of CK2 in coregulating NF-kappaB activation, TP53/p63 expression, and downstream gene expression. Downregulation of CK2 in HNSCC models in vitro and in vivo shows antitumor effects as well as sensitization to cisplatin.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-3200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861417PMC
April 2010

Nuclear NF-kappaB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer.

Clin Cancer Res 2009 Oct 29;15(19):5974-84. Epub 2009 Sep 29.

Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892-0001, USA.

Purpose: Aberrant nuclear activation and phosphorylation of the canonical NF-kappaB subunit RELA/p65 at Serine-536 by inhibitor kappaB kinase is prevalent in head and neck squamous cell carcinoma (HNSCC), but the role of other kinases in NF-kappaB activation has not been well defined. Here, we investigated the prevalence and function of p65-Ser276 phosphorylation by protein kinase A (PKA) in the malignant phenotype and gene transactivation, and studied p65-Ser276 as a potential target for therapy.

Experimental Design: Phospho and total p65 protein expression and localization were determined in HNSCC tissue array and in cell lines. The effects of the PKA inhibitor H-89 on NF-kappaB activation, downstream gene expression, cell proliferation and cell cycle were examined. Knockdown of PKA by specific siRNA confirmed the specificity.

Results: NF-kappaB p65 phosphorylated at Ser276 was prevalent in HNSCC and adjacent dysplastic mucosa, but localized to the cytoplasm in normal mucosa. In HNSCC lines, tumor necrosis factor-alpha (TNF-alpha) significantly increased, whereas H-89 inhibited constitutive and TNF-alpha-induced nuclear p65 (Ser276) phosphorylation, and significantly suppressed NF-kappaB and target gene IL-8 reporter activity. Knockdown of PKA by small interfering RNA inhibited NF-kappaB, IL-8, and BCL-XL reporter gene activities. H-89 suppressed cell proliferation, induced cell death, and blocked the cell cycle in G(1)-S phase. Consistent with its biological effects, H-89 down-modulated expression of NF-kappaB-related genes Cyclin D1, BCL2, BCL-XL, COX2, IL-8, and VEGF, as well as induced cell cycle inhibitor p21(CIP1/WAF1), while suppressing proliferative marker Ki67.

Conclusions: NF-kappaB p65 (Ser276) phosphorylation by PKA promotes the malignant phenotype and holds potential as a therapeutic target in HNSCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-1352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760015PMC
October 2009

Current and potential inflammation targeted therapies in head and neck cancer.

Curr Opin Pharmacol 2009 Aug 29;9(4):389-95. Epub 2009 Jun 29.

Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, 1 Cloister Ct, Bethesda, MD 20814, USA.

Inflammation often exists in the tumor microenvironment and is induced by inflammatory mediators (cytokines, chemokines, and growth factors) produced by the tumor, stroma, and infiltrating cells. These factors modulate tissue remodeling and angiogenesis and actively promote tumor cell survival and chemoresistance through autocrine and paracrine mechanisms. Head and neck squamous cell carcinomas (HNSCCs) are highly inflammatory and aggressive in nature, and they express a number of cytokines and growth factors involved in inflammation. These cytokines and growth factors activate important signal transduction pathways, including NF-kappaB, JAK/STAT, and PI3K/Akt/mTOR, which regulate the expression of genes controlling growth, survival, and chemosensitivity. This review provides an update on recent advances in the understanding of the mechanisms driving cancer-related inflammation in HNSCC and on molecular targeted therapies under preclinical and clinical investigation.
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http://dx.doi.org/10.1016/j.coph.2009.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731001PMC
August 2009

Attenuated transforming growth factor beta signaling promotes nuclear factor-kappaB activation in head and neck cancer.

Cancer Res 2009 Apr 7;69(8):3415-24. Epub 2009 Apr 7.

Howard Hughes Medical Institute-NIH Research Scholars Program, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA.

Although constitutively activated nuclear factor-kappaB (NF-kappaB), attenuated transforming growth factor beta (TGFbeta) signaling, and TP53 mutations frequently occur in human cancers, how these pathways interact and together contribute to malignancy remains uncertain. Here, we found an association between overexpression of NF-kappaB-related genes, reduced expression of TGFbeta receptor (TbetaR) subunits and downstream targets, and TP53 genotype in head and neck squamous cell carcinoma (HNSCC). In response to recombinant TGFbeta1, both growth inhibition and TGFbeta target gene modulation were attenuated or absent in a panel of human HNSCC lines. However, in HNSCC cells that retained residual TGFbeta signaling, TGFbeta1 inhibited both constitutive and tumor necrosis factor alpha-stimulated NF-kappaB activity. Furthermore, HNSCC lines overexpressing mutant (mt) TP53 and human tumor specimens with positive TP53 nuclear staining exhibited reduced TbetaRII and knocking down mtTP53 induced TbetaRII, increasing TGFbeta downstream gene expression while inhibiting proinflammatory NF-kappaB target gene expression. Transfection of ectopic TbetaRII directly restored TGFbeta signaling while inhibiting inhibitor kappaBalpha degradation and suppressing serine-536 phosphorylation of NF-kappaB p65 and NF-kappaB transcriptional activation, linking these alterations. Finally, experiments with TbetaRII conditional knockout mice show that abrogation of TGFbeta signaling promotes the sustained induction of NF-kappaB and its proinflammatory target genes during HNSCC tumorigenesis and progression. Together, these findings elucidate a regulatory framework in which attenuated TGFbeta signaling promotes NF-kappaB activation and squamous epithelial malignancy in the setting of altered TP53 status.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-3704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696277PMC
April 2009

NF-kappaB in carcinoma therapy and prevention.

Expert Opin Ther Targets 2008 Sep;12(9):1109-22

National Institute on Deafness and Other Communication Disorders, Head and Neck Surgery Branch, Bethesda, MD 20892, USA.

Background: NF-kappaB includes a family of signal-activated transcription factors that normally regulate responses to injury and infection but which are aberrantly activated in many carcinomas.

Objective: To review the activation and role of NF-kappaB in pathogenesis and as a target for treatment and prevention in carcinoma.

Methods: Evidence from experimental, epidemiological, preclinical studies and clinical trials cited in the literature are reviewed.

Results/conclusion: Cumulative evidence implicates NF-kappaB in cell survival, inflammation, angiogenesis, spread and therapeutic resistance during tumor development, progression and metastasis of carcinomas. Non-specific natural and synthetic agents that inhibit NF-kappaB have demonstrated activity and safety in prevention or therapy. NF-kappaB-activating kinases and the proteasome are under investigation for targeted prevention and therapy of carcinoma.
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http://dx.doi.org/10.1517/14728222.12.9.1109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605706PMC
September 2008

Bortezomib-induced apoptosis with limited clinical response is accompanied by inhibition of canonical but not alternative nuclear factor-{kappa}B subunits in head and neck cancer.

Clin Cancer Res 2008 Jul;14(13):4175-85

Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA.

Purpose: Nuclear factor-kappaB (NF-kappaB)/REL transcription factors promote cancer cell survival and progression. The canonical (NF-kappaB1/RELA or cREL) and alternate (NF-kappaB2/RELB) pathways require the proteasome for cytoplasmic-nuclear translocation, prompting the investigation of bortezomib for cancer therapy. However, limited clinical activity of bortezomib has been observed in many epithelial malignancies, suggesting this could result from incomplete inhibition of NF-kappaB/RELs or other prosurvival signal pathways.

Experimental Design: To examine these possibilities, matched biopsies from 24 h posttreatment were obtained from accessible tumors of patients who received low-dose bortezomib (0.6 mg/m(2)) before reirradiation in a phase I trial for recurrent head and neck squamous cell carcinoma (HNSCC). Effects of bortezomib on apoptosis and proliferation by TUNEL and Ki67 staining were compared with nuclear staining for all five NF-kappaB subunits, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated signal transducers and activators of transcription 3 (STAT3) in tumor biopsies, and by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTP) and DNA binding assay for the five NF-kappaB subunits in HNSCC cell lines.

Results: HNSCC showed increased nuclear staining for all five NF-kappaB subunits, phosphorylated ERK1/2, and phosphorylated STAT3. Bortezomib treatment significantly enhanced apoptosis with inhibition of nuclear RELA in three of four tumors, but other NF-kappaB subunits, ERK1/2, and STAT3 were variably or not affected, and tumor progression was observed within 3 months. In HNSCC cell lines, 10(-8) mol/L bortezomib inhibited cell density while inhibiting tumor necrosis factor-alpha-induced and partially inhibiting basal activation of NF-kappaB1/RELA, but not NF-kappaB2/RELB.

Conclusions: Although low-dose bortezomib inhibits activation of subunits of the canonical pathway, it does not block nuclear activation of the noncanonical NF-kappaB or other prosurvival signal pathways, which may contribute to the heterogeneous responses observed in HNSCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-4470DOI Listing
July 2008