PIEZO1 activation may serve as an early tissue biomarker for the prediction of irradiation-induced salivary gland dysfunction.

Irradiation (IR)-induced xerostomia is the most common side effect of radiation therapy in patients with head and neck cancer (HNC). Xerostomia diagnosis is mainly based on the patient's medical history and symptoms. Currently, no direct biomarkers are available for the early prediction of IR-induced xerostomia. Here, we identified PIEZO1 as a novel predictive tissue biomarker for xerostomia. Our data demonstrate that PIEZO1 is significantly upregulated at the gene and protein levels during IR-induced salivary gland (SG) hypofunction. Notably, PIEZO1 upregulation coincided with that of inflammatory (F4/80) and fibrotic markers (fibronectin and collagen fibers accumulation). These findings suggest that PIEZO1 upregulation in SG tissue may serve as a novel predictive marker for IR-induced xerostomia.

Guidelines for the Use of Botulinum Toxin in Otolaryngology From the Korean Society of Laryngology, Phoniatrics and Logopedics Guideline Task Force.

The Korean Society of Laryngology, Phoniatrics and Logopedics created a task force to establish clinical practice guidelines for the use of botulinum toxin (BT) in otolaryngology. We selected 10 disease categories: spasmodic dysphonia, essential vocal tremor, vocal fold granuloma, bilateral vocal fold paralysis, Frey's syndrome, sialocele, sialorrhea, cricopharyngeal dysfunction, chronic sialadenitis, and first bite syndrome. To retrieve all relevant papers, we searched the CORE databases with predefined search strategies, including Medline (PubMed), Embase, the Cochrane Library, and KoreaMed. The committee reported 13 final recommendations with detailed evidence profiles. The guidelines are primarily aimed at all clinicians applying BT to the head and neck area. In addition, the guidelines aim to promote an improved understanding of the safe and effective use of BT by policymakers and counselors, as well as in patients scheduled to receive BT injections.

Clinical Utility of Quantitative Parameters of Salivary Gland Scintigraphy for Diagnosing Burning Mouth Syndrome.

Burning mouth syndrome (BMS) is a chronic disorder characterized by a burning sensation in the oral cavity, often accompanied by xerostomia, with no relevant clinical or laboratory findings. This study aimed to investigate diagnostic values of quantitative parameters of salivary gland scintigraphy for BMS in patients with xerostomia. A total of 164 patients who underwent salivary gland scintigraphy for the workup of xerostomia were retrospectively reviewed. All patients were classified into patient groups with primary BMS, secondary BMS, and non-specific xerostomia. From salivary gland scintigraphy, 22 quantitative parameters were calculated and their diagnostic values were assessed based on the area under the receiver operating characteristic curve (AUC) values. Among salivary gland scintigraphy parameters, uptake speed in the left submandibular gland showed the highest AUC value (0.647) for detecting BMS and pre-stimulatory oral activity showed the highest AUC value (0.710) for detecting primary BMS. A salivary gland scintigraphy scoring system based on these two parameters further enhanced the diagnostic ability, demonstrating AUC values of 0.731 for BMS and 0.782 for primary BMS. These results suggest a potential diagnostic value of the quantitative parameters of salivary gland scintigraphy for detecting BMS in patients with xerostomia.

Considerations for Balance Between Fundamental Treatment and Improvement of Quality of Life of Pediatric Thyroid Cancer Patient: Comparative Analysis With Adult Using Propensity Score Matching.

Background: Thyroid cancer is very rarely observed in children and adolescents, some reports have shown that the long-term outcome of treatment is better than that of adult patients, despite many treatment failures or a high risk of recurrence. This study considers whether it is appropriate to treat pediatric thyroid cancer patients aggressively, as per the ATA guidelines, based on the balance between the fundamental treatment of thyroid cancer and the improvement of the long-term quality of life of pediatric patients. Methods: A total of 1,950 patients were recruited, including 83 pediatric and 1,867 adult patients, who were diagnosed with thyroid cancer and underwent surgical treatment at one of our medical center hospitals from March 2000 to January 2020. Results: Sixty-nine pairs of pediatric and adult patients were matched in a ratio of 1:2 through propensity score matching. When compared through propensity score matching, there was no significant difference in prognosis such as recurrence rate in children and adults at the same stage. Conclusion: This study showed that the prognosis of both pediatric and adult patients who underwent a total thyroidectomy and lobectomy was not significantly different. If more pediatric patients can be considered for the less-aggressive lobectomy than a total thyroidectomy through various preoperative examinations and meticulous pre-diagnosis, it may be possible to properly determine the balance between improving long-term quality of life while providing fundamental cancer treatment.

Recent Developments of ICG-Guided Sentinel Lymph Node Mapping in Oral Cancer.

Sentinel lymph node (SLN) biopsy has gained attention as a method of minimizing the extent of neck dissection with a similar survival rate as elective neck dissection in oral cancer. Indocyanine green (ICG) imaging is widely used in the field of surgical oncology. Real-time ICG-guided SLN imaging has been widely used in minimally invasive surgeries for various types of cancers. Here, we provide an overview of conventional SLN biopsy and ICG-guided SLN mapping techniques for oral cancer. Although ICG has many strengths, it still has limitations regarding its potential use as an ideal compound for SLN mapping. The development of novel fluorophores and imaging technology is needed for accurate identification of SLNs, which will allow precision surgery that would reduce morbidities and increase patient survival.

Effect of human acellular dermal matrix (Megaderm™) on infra-auricular depressed deformities, Frey's syndrome, and first bite syndrome following parotidectomy: a multi-center prospective study.

BACKGROUND: Parotidectomy is the primary treatment for parotid gland tumors. However, complications may include a prominent facial scar or infra-auricular depressed deformity, Frey's syndrome, first bite syndrome, or other facial pain, numbness, and paralysis. Acellular dermal matrix (ADM) has been widely used to prevent these complications in parotid surgery, but there have been no prospective, multi-center trials documenting its efficacy. This study evaluates the effectiveness of ADM implantation in preventing infra-auricular depressed deformity, Frey's syndrome and first bite syndrome after parotidectomy. METHODS: We analyzed 51 cases of standard parotidectomy and 58 cases of parotidectomy with implantation of Megaderm™ ADM through prospective multicenter trial. Acute complications including infection, seroma, hematoma, skin necrosis, and acute parotid area pain were evaluated 1 week postoperatively. Clinician grading of Frey's syndrome and blinded clinician evaluation of infra-auricular depressed deformities were conducted at 3, 6, and 12 months. Patients evaluated subjective satisfaction with neck appearance, Frey's syndrome quality, and acute parotid area pain at 3, 6, and 12 months. RESULTS: There was a higher incidence of seroma in the Megaderm™ group than in the control group at week 1. The incidence and total clinician-evaluated Frey's syndrome scores were significantly lower in the Megaderm™ group than in the control group at 3, 6, and 12 months. Both the objective and subjective evaluations of the facial contour showed a better outcome in the Megaderm™ group compared to the control group at 3, 6, and 12 months. There were no significant differences between the groups in the patient-reported Frey's syndrome quality scores at 3, 6, and 12 months, but the Megaderm™ group reported significantly less acute pain than the control group. CONCLUSIONS: ADM implantation can effectively reduce the occurrence of Frey's syndrome, infra-auricular depressed deformity, and first bite syndrome after parotidectomy. ADM may be especially advantageous in complex parotidectomy cases when significant complications are expected.

DIM-C-pPhtBu induces lysosomal dysfunction and unfolded protein response - mediated cell death via excessive mitophagy.

Despite technological advances in cancer treatment, the survival rate of patients with head and neck cancer (HNC) has not improved significantly. Many studies have shown that endoplasmic reticulum (ER) stress-related signals are associated with mitochondrial damage and that these signals determine whether cells maintain homeostasis or activate cell death programs. The unfolded protein response (UPR) is regulated by ER membrane proteins such as double-stranded RNA-activated protein kinase R(PKR)-like ER kinase (PERK), which directly activate transcription of chaperones or genes that function in redox homeostasis, protein secretion, or cell death programs. In this study, we focused on the role of mitophagy and ER stress-mediated cell death induced by DIM-C-pPhtBu in HNC cancer. We found that DIM-C-pPhtBu, a compound that activates ER stress in many cancers, induced lysosomal dysfunction, excessive mitophagy, and cell death in HNC cells. Moreover, DIM-C-pPhtBu strongly inhibited HNC progression in a xenograft model by altering mitophagy related protein expression. Taken together, the results demonstrate that DIM-C-pPhtBu induces excessive mitophagy and eventually UPR-mediated cell death in HNC cells, suggesting that new anti-cancer drugs could be developed based on the connection between mitophagy and cancer cell death.

Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer.

BACKGROUND: We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. METHODS: Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. RESULTS: From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P < 0.001). Specimens obtained from metastatic sites showed a significantly higher engraftment rate than did those from primary sites (100% [9/9] vs. 11.3% [6/53], P < 0.001). Three PDX models from HPV-positive tumors were established, as compared to 12 from HPV-negative (15.8% [3/19] and 27.9% [12/43] respectively, P = 0.311), suggesting that HPV positivity tends to show a low engraftment rate. Drug responses in PDX recapitulated the clinical responses of the matching patients with pan-HER inhibitors and pan-PI3K inhibitor. CONCLUSIONS: Genetically and clinically annotated HNSCC PDXs could be useful preclinical tools for evaluating biomarkers, therapeutic targets, and new drug discovery.

ICG-Guided Sentinel Lymph Node Sampling during Robotic Retroauricular Neck Dissection in cN0 Oral Cancer.

In this study, we sought to evaluate the clinical feasibility of indocyanine green (ICG)-guided sentinel lymph node (SLN) sampling during robotic retroauricular neck dissection (RAND) in patients with cN0 oral cancer. Nine adult patients diagnosed with T1 to T2 oral squamous cell carcinoma were consecutively recruited. All of them underwent transoral partial glossectomy and robotic RAND (levels I-III) simultaneously. Twelve hours prior to surgery, ICG was injected into the 4 quadrants around primary tongue tumors. During robotic RAND, intraoperative and ex vivo ICG-stained LNs were identified using the Firefly system and examined for the presence of fluorescence. ICG-stained LNs were identified in all patients. Thirty-one ICG-stained LNs were detected in 313 retrieved LNs (9.9%). Occult metastases were detected among the ICG-stained LNs in 2 patients (22.2%). There was no metastasis identified in the ICG-unstained LNs. Upstaging rates, sensitivity, specificity, and negative predictive value of ICG-guided SLN sampling were 22.2%, 100%, 91.5%, and 100%, respectively.

Objective Assessment of Postoperative Swallowing Difficulty Through Ultrasound in Patients Undergoing Thyroidectomy.

Swallowing discomfort is a common postoperative complaint in patients undergoing thyroidectomy. Contraction of the strap muscles might cause resistance to elevation of the laryngotracheal unit, and downward movement of the laryngotracheal unit may lead to swallowing discomfort. However, few studies have evaluated the mechanism related to limited laryngotracheal elevation after thyroidectomy. We aimed to objectively verify the presence of postoperative impaired laryngotracheal elevation through ultrasound evaluation in patients undergoing thyroidectomy and evaluate its relationship with limitation of laryngotracheal elevation. This is a prospective clinical study. Among patients undergoing hemithyroidectomy and total thyroidectomy, the patients who were followed up for ≥ 6 months were selected (N = 40). Ultrasound evaluation was done preoperatively and at 1, 3, and 6 months postoperatively. Laryngotracheal movement was recorded and the length of elevation was measured. Symptom after thyroidectomy was evaluated through swallowing-related items of thyroidectomy-related voice questionnaire. Ultrasound evaluation verified the presence of limited laryngotracheal elevation postoperatively in patients undergoing thyroidectomy. After thyroidectomy, the swallowing-related score was significantly increased, and was recovered time-dependently at 1 month. Laryngotracheal elevation showed significant decrease after thyroidectomy. The symptom score of swallowing was significantly correlated with the length of laryngotracheal elevation. Post-thyroidectomy ultrasound evaluation verified that laryngotracheal elevation was significantly impaired. Presence of adhesion between the laryngotracheal unit and the superficial soft tissue was the probable cause of the limitation at 6 months after thyroidectomy. The length of laryngotracheal elevation was related to the symptom score of swallowing after thyroid surgery.

Clinical Analysis of Pediatric Thyroid Cancer: A Single Medical Institution Experience of 18 Years.

OBJECTIVE: The incidence of pediatric thyroid cancer is relatively low compared to the disease in adults. This study aims to present the data in our institution on pediatric thyroid cancer patients, with particular emphasis on the risk factors of recurrence together with treatment outcomes. SUBJECTS AND METHODS: Between January 2000 and July 2018, patients <20 years who were diagnosed with thyroid carcinoma and primarily treated with surgery at a major large-volume tertiary medical center specializing in thyroid cancer were enrolled. A total of 83 patients were eligible for this study. RESULTS: The majority of the studied patients were girls and adolescents (age ≥13 years). Papillary thyroid carcinoma (PTC) was the most common pathology (n = 74). PTC tumors >1 cm showed higher rate of lymph node metastasis and extrathyroidal extension than tumors ≤1 cm. All patients survived with nine PTC patients who displayed treatment failure. Age, tumor size, multifocality, lateral lymph node metastasis, and postoperative thyroglobulin levels were significant prognosticators for disease recurrence. CONCLUSION: Pediatric thyroid cancer is relatively rare and should be considered a specific disease entity with respect to the thyroid cancer in adults, since there are several distinctive characteristics.

A Case of Unexpected Clinostomum complanatum Infection Initially Presenting as Foreign Body in Pharynx.

A 46-year old man visited our outpatient clinic with complaint of foreign body sensation in throat after consuming raw freshwater fish 5 days ago. Laryngoscopic examination revealed a motile worm attached on posterior pharyngeal wall. The worm was removed using biopsy forceps under transnasal endoscopy and evidently identified as Clinostomum complanatum after microscopic examination. Patient's subjective foreign body sensation of throat and hyperemia of laryngeal mucosa remained for approximately 2 weeks post-removal, which were eventually resolved after administration of non-steroidal anti-inflammatory drug and anti-refluxant drug for 2 weeks. Treatment was ended at three weeks since the first visit. C. complanatum infections in humans are rare, and only four cases have been reported in Korea. Symptoms resembling pharyngitis or laryngitis occurs by consumption of raw, infected freshwater fish and treatment is done by mechanically removing the parasite.

Beyond EGFR inhibition: multilateral combat strategies to stop the progression of head and neck cancer.

Epidermal growth factor receptor (EGFR) overexpression is common in head and neck squamous cell carcinoma. Targeted therapy specifically directed towards EGFR has been an area of keen interest in head and neck cancer research, as EGFR is potentially an integration point for convergent signaling. Despite the latest advancements in cancer diagnostics and therapeutics against EGFR, the survival rates of patients with advanced head and neck cancer remain disappointing due to anti-EGFR resistance. This review article will discuss recent multilateral efforts to discover and validate actionable strategies that involve signaling pathways in heterogenous head and neck cancer and to overcome anti-EGFR resistance in the era of precision medicine. Particularly, this review will discuss in detail the issue of cancer metabolism, which has recently emerged as a novel mechanism by which head and neck cancer may be successfully controlled according to different perspectives.

Clinical Characteristics and Management of Saccular Cysts: A Single Institute Experience.

OBJECTIVES: A saccular cyst is defined as a dilated saccule of the larynx, filled with mucus, and is located between the false vocal cords and the thyroid cartilage. Although this uncommon laryngeal condition is benign in nature, it could lead to dyspnea, stridor, and airway obstruction, depending on its size and location. Furthermore, some saccular cysts have been associated with laryngeal carcinoma. This study aimed to characterize this rather uncommon laryngeal condition to aid in determining the proper management of this pathology. METHODS: Medical records were retrospectively reviewed of all patients with saccular cysts diagnosed and treated between 2006 and 2017 at a tertiary otolaryngologic care center. RESULTS: Seven patients with saccular cysts were identified (male:female=2:5; mean age, 34.1 years); two were pediatric patients. Surgical intervention was performed in all patients by laryngo-microsurgery using CO2 laser. There was no recurrence after the initial surgical treatment. CONCLUSION: Saccular cysts can be managed endoscopically using CO2 laser, without requiring an external approach. Therefore, an endoscopic approach should be actively considered for an optimal treatment outcome.

Fibroblast growth factor receptor 3-mediated reactivation of ERK signaling promotes head and neck squamous cancer cell insensitivity to MEK inhibition.

Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has been a longstanding challenge for head and neck oncologists, and current treatments still have limited efficacy. ERK is aberrantly overexpressed and activated in HNSCC. Herein, we aimed to investigate the cause of the limited therapeutic effect of selumetinib, a selective inhibitor of MEK in HNSCC, as MEK/ERK reactivation inevitably occurs. We assessed the effects of combining selumetinib with fibroblast growth factor receptor 3 (FGFR3) inhibitor (PD173074) on tumor growth. Selumetinib transiently inhibited MAPK signaling and reactivated ERK signaling in HNSCC cells. Rebound in the ERK and Akt pathways in HNSCC cells was accompanied by increased FGFR3 signaling after selumetinib treatment. Feedback activation of FGFR3 was a result of autocrine secretion of the FGF2 ligand. The FGFR3 inhibitor PD173074 prevented MAPK rebound and sensitized the response of HNSCC cells to selumetinib. These results provided rational therapeutic strategies for clinical studies of this subtype of patients that show a poor prognosis with selumetinib. Our data provide a rationale for combining a MEK inhibitor with inhibitors of feedback activation of FGFR3 signaling in HNSCC cells. ERK rebound as a result of the upregulation of FGFR3 and the ligand FGF2 diminished the antitumor effects of selumetinib, which was overcome by combination treatment with the FGFR3 inhibitor.

Clinicopathological significance of cancer-associated fibroblasts in papillary thyroid carcinoma: a predictive marker of cervical lymph node metastasis.

PURPOSE: Most tumors have obvious biologically active fibroblasts known variously as myofibroblasts or cancer-associated fibroblasts (CAFs) in the stroma. CAFs have been known as an important factor of cancer invasion and metastasis. This study aimed to investigate the presence of CAFs in patients with papillary thyroid carcinoma (PTC) and evaluate the correlation between CAFs and cervical lymph node (LN) metastasis in PTC through immunohistochemistry. METHODS: The medical records of 128 patients who were diagnosed with PTC from January 1, 2010 to December 31, 2010 were reviewed, and 78 patients who underwent total thyroidectomy with or without neck dissection, were included in this study. A retrospective pathological evaluation was performed to verify the presence of CAFs. CD34 and α-smooth muscle actin (SMA) were used as markers of CAFs. RESULTS: Among 78 patients with PTC, 65 had desmoplastic stromal reaction around the PTC. Through immunohistochemical study of anti-CD34 and α-SMA antibodies, CAFs were found in 42 (64.6%) cases with desmoplastic stroma around the PTC. Univariate analysis showed that tumor size and CAFs were the risk factors of LN metastasis in patients with PTC, while multivariate analysis revealed that CAFs were the only independent risk factor of LN metastasis in patients with PTC. CONCLUSION: This study revealed the presence of CAFs in PTC. Furthermore, CAFs were found to be a risk factor of LN metastasis in PTC. Therefore, CAFs may be used as a predictive marker for LN metastasis in patients with PTC.

Publisher Correction: Dose de-escalation to the normal larynx using conformal radiotherapy reduces toxicity while maintaining oncologic outcome for T1/T2 glottic cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Korean survey data reveals an association of chronic laryngitis with tinnitus in men.

The association between chronic laryngitis and tinnitus is not a well-studied topic, unlike the association of these two conditions with many other disorders. Cross-sectional data of 11,347 adults (males: 4,934; females: 6,413), who completed the Korea National Health and Nutrition Examination Survey (KNHANES) from 2010 to 2012 were used to investigate this association. Lifestyle patterns, including smoking and alcohol habits, regular exercise, physical and mental health status, socioeconomic status, nutritional status, and other chronic diseases, were analyzed. Chronic laryngitis and tinnitus were diagnosed by field survey teams, which included otolaryngologists, who conducted chronic disease surveillance using a health status interview, a nutritional status questionnaire, and a physical examination. Chronic laryngitis was significantly associated with age, education beyond high school, depressed mood, voice change, metabolic syndrome, and tinnitus in men. In women, chronic laryngitis was associated with body mass index and diabetes mellitus. Chronic laryngitis in men was significantly associated with tinnitus (odds ratio 1.671, [95% confidence interval: 1.167-2.393]) after adjusting for age, body mass index, smoking status, alcohol intake, regular exercise, metabolic syndrome, education beyond high school, and depressed mood. Additionally, the prevalence of chronic laryngitis increased with increasing severity of tinnitus in men alone (P = 0.002). The study revealed a significant association between chronic laryngitis and tinnitus.

Impact of the Korean Diagnosis-Related Groups payment system on the outcomes of adenotonsillectomy: A single center experience.

OBJECTIVES: To report outcomes with regard to clinical aspects and medical costs of adenotonsillectomy and tonsillectomy at a single institution before and after implementation of the Diagnosis-Related Groups (DRG) payment system in Korea. METHODS: We retrospectively reviewed the records of patients treated with adenotonsillectomy or tonsillectomy between July 2012 and June 2014. The Korean DRG payment system was applied to seven groups of specific diseases and surgeries including adenotonsillectomy and tonsillectomy from July 2013 at all hospitals in Korea. We divided patients into four groups according whether the fee-for-service (FFS) or DRG payment system was implemented and operation type (FFS-adenotonsillectomy (AT), DRG-AT, FFS-tonsillectomy (T), and DRG-T). RESULTS: A total of 1402 patients were included (485 FFS-AT, 490 DRG-AT, 203 FFS-T, and 223 DRG-T). The total medical cost of the DRG-AT group was significantly lower than that of the FFS-AT group (1191±404 vs. 1110±279 USD, P<0.05). There were no significant differences in length of hospital stay or postoperative complications among groups. CONCLUSION: The Korean DRG system for adenotonsillectomy and tonsillectomy reduced medical costs and clinical outcomes were not significantly altered by the adoption of the DRG system. LEVEL OF EVIDENCE: 4.

Oncologic and functional outcomes of salvage supracricoid partial laryngectomy.

BACKGROUND: Supracricoid partial laryngectomy (SCL) can have a positive impact on patients' quality of life by circumventing dysphagia and voice problems resulting from creation of a permanent stoma after conventional total laryngectomy (TL) surgery. AIMS/OBJECTIVES: The aim of this study was to investigate the oncologic and functional outcomes of salvage SCL for recurrent laryngeal carcinoma. MATERIAL AND METHODS: Forty-five patients that underwent salvage surgery for recurrent laryngeal carcinoma between January 2004 and May 2015 after initial treatment failure were included in this retrospective study. RESULTS: Overall survival and disease free survival were non-significantly higher in the salvage SCL group (n = 14) than in the salvage TL group (n = 31) (87.5 versus 56.5%, 53.4 versus 41.9%). Multivariate analyses showed only positive resection margin to be significantly associated with survival and recurrence (HR 9.974, p = .007, and HR 9.196, p = .002, respectively). In the salvage SCL group, 92.8% achieved successful decannulation and all patients returned to an oral diet. All patients in the salvage TL group sustained a permanent stoma and conversation was possible only through esophageal voice or a voice prosthesis. 74.2% of patients in the group were able to tolerate an oral diet. CONCLUSIONS AND SIGNIFICANCE: Salvage SCL showed comparable oncologic outcomes and favorable functional outcomes relative to the classic salvage TL. This study could provide a sufficient basis of SCL as salvage treatment for recurrent laryngeal carcinoma in selected patients.