Level Ib Research Articles

Kinomic Profiling Identifies Pathways of HER2 Targeted Therapy Resistance in HER2 Positive Breast Cancer Cell Lines

Common practice is to irradiate at least the ipsilateral IB level. However, elective irradiation of level IB increases dose to the larynx, oral cavity, and mandible, potentially increasing acute and long-term toxicity. This study reports regional control rates and long-term toxicity for employing a policy of withholding radiation to the level IB lymph nodes unless clinically indicated. Materials/Methods: Between 2003 and 2010, 95 patients with stage I IVB oropharyngeal cancer were treated with definitive IMRT with simultaneous-integrated boost technique. The median age was 59. The T and N stage distributions were: 28% T1, 40% T2, 22% T3, 10% T4, 9% N0, 15% N1, 16% N2a, 35% N2b, 11% N2c, and 14% N3. The primary sites were tonsil (52%), base of tongue (45%), and others (3%). Of 55 patients with HPV data, 89% were positive. Median dose to the gross tumor volume was 70 Gy. Ninety-four percent of patients had concurrent chemotherapy, and 12% had pre-radiation (RT) neck dissection. Indications for ipsilateral IB nodal coverage were: (1) a grossly enlarged level IB node, (2) primary or nodal tumor invasion of the ipsilateral level IB or submandibular gland (SMG), and (3) tumor involvement of the oral cavity or other structures that drain primarily to the ipsilateral level IB. Contralateral IB level was not covered in the absence of the above clinical factors in the contralateral neck. Adverse late effects were determined using the Common Terminology Criteria Adverse Event (CTCAE) v4.03. Results: Of 82 patients that did not have a pre-RT neck dissection, 28% (23/82) had ipsilateral level IB coverage and 1 had bilateral IB coverage. Of 23 patients with ipsilateral IB coverage, 13 were for SMG involvement, 5 for IB node involvement, 2 for oral cavity involvement, 2 for oral cavity +/SMG +/IB node involvement, and 1 for unknown reasons due to incomplete data. Of 11 patients that had a pre-RT neck dissection, none had the contralateral IB level covered. With a median follow-up of 2.7 years, only one patient failed in the neck (in the tracheostomy stoma site) at 11.3 months. At 2 years, regional control, local control, disease-free survival and overall survival were 99%, 99%, 89%, and 94%, respectively. No patients developed grade 3 xerostomia or grade 4 osteonecrosis. At 2 years, rates of grade 1-2 xerostomia, gastrostomy tube dependency, and grade 3 osteoradionecrosis were 15%, 4%, and 1%, respectively. Conclusions: Our data supports that in the absence of level IB and oral cavity involvement, the ipsilateral and the contralateral level IB nodal levels do not need to be covered in IMRT plans for oropharyngeal carcinoma. Author Disclosure: J.W. Jang: None. R.J. Parambi: None. L.S. Liliana: None. N.J. Liebsch: None. A.W. Chan: None.

Intensity Modulated Radiation Therapy and Level 1B Nodal Coverage for Oropharyngeal Carcinoma

The rate of pathologic level IB lymph node involvement in clinically node negative oropharyngeal cancer is very low, ranging from 0 to 3%. It is controversial whether or not this nodal level should be included in intensity modulated radiation therapy (IMRT) plans. Common practice is to irradiate at least the ipsilateral IB level. However, elective irradiation of level IB increases dose to the larynx, oral cavity, and mandible, potentially increasing acute and long-term toxicity. This study reports regional control rates and long-term toxicity for employing a policy of withholding radiation to the level IB lymph nodes unless clinically indicated.

External haemorrhoidal thrombosis: evidence for current management

External haemorrhoidal thrombosis (EHT) may be managed surgically or conservatively. The optimal treatment is, however, unclear, as is the long-term outcome following treatment. A literature search was undertaken to review and grade the evidence available for EHT management, determine the optimal management modality and assess long-term outcome after each treatment. Among 800 articles on haemorrhoids, only two prospective studies encompassing 248 patients and two retrospective studies of 571 patients were found. Excision significantly relieves presenting symptoms by postoperative day 4 compared with incision or topical GTN (Level IB evidence). Symptoms last over 3weeks with conservative treatment (Level III evidence) and this period may be reduced by combining topical nifedipine and lignocaine rather than using lignocaine alone (Level IB evidence). There is no evidence regarding the optimal time for non-surgical options. There is a remarkable paucity of studies on EHT and few of those available provide high levels of evidence. Surgery may be superior to conservative treatment but there is no evidence regarding the optimal period of initiation of conservative management. Prospective comparative studies are needed.

Nasopharyngeal cancer: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Nasopharyngeal cancer: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Guillotine versus dissection tonsillectomy: randomised, controlled trial

This trial aimed to compare the guillotine technique of tonsillectomy with 'cold steel' dissection, the current 'gold standard'. A single centre, randomised, controlled trial. One hundred children aged 3 to 11 years who were listed for bilateral tonsillectomy were recruited. Patients had one tonsil removed by each technique, and were blinded to the side. The operative time, intra-operative blood loss, haemostasis requirement and post-operative pain scores were recorded and compared. Operative time and intra-operative blood loss were both significantly less for the guillotine technique (p < 0.001) and there was a significantly reduced haemostasis requirement (p < 0.001). Pain was also less on the guillotine side (p < 0.001). There were no tonsillar remnants or palatal trauma for either technique. There was no significant difference between techniques in the frequency of secondary haemorrhage. This study provides level Ib evidence that guillotine tonsillectomy in children with mobile tonsils is an effective and time-efficient procedure which produces less intra-operative blood loss and post-operative pain than cold steel dissection.

Lymph node metastasis in sinonasal squamous cell carcinoma treated with IMRT/3D-CRT

To analyze the patterns of neck and retropharyngeal lymph nodes (RPLNs) metastases with magnetic resonance imaging (MRI) in patients with sinonasal squamous cell carcinoma (SCC), and to explore the patterns of treatment failure treated with intensity modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT). We also attempt to discuss the role of elective neck irradiation (ENI) in the treatment of cervical negative patients. Between July 2004 and February 2011, 59 patients with histopathologically proven sinonasal SCC were treated with curative intent at our hospital. Among them, 18 (30.5%) patients had neck or RPLN lymph node involvement at diagnosis. RPLN, level Ib, and level IIa were the most common sites of initial nodal involvement. All patients received IMRT or 3D-CRT, while 19 patients further received surgical resection, and other 40 patients received cisplatin based chemotherapy. Median follow-up durations were 28 months (range, 6-81 months) for the entire patient population and 40 months (range, 7-81 months) among the surviving patients, respectively. The estimated 3-year local-regional control rate, distant-metastasis free survival rate, disease-free survival rate, and overall survival rate were 63.3%, 81.9%, 60.1%, and 68.9%, respectively. On multivariate analysis, old age (>60 years) significantly influenced the overall survival rate(HR=9.428, p=0.000). As for the pattern of treatment failures developed in 26 patients in the follow-up time, local failure, neck recurrence, and distant metastases were seen in 18, 7, and 9 patients, respectively. Level Ib and level IIa were the most common sites of cervical nodal recurrence. None of the 11 patients who received ENI developed failure in the neck. For sinonasal SCC patients treated with IMRT or 3D-CRT, our results were generally consistent with findings of other studies, local failure still remain the predominant pattern of treatment failure. However, RPLN metastasis occurred more frequently than previously recognized through detection by MRI in our study. ENI seems to have effectively prevented regional relapse. We recommend ipsilateral level Ib and level IIa neck irradiation for T3-4 sinonasal SCC patients.

Salivary gland adenoid cystic carcinoma with cervical lymph node metastasis: a preliminary study of 62 cases

Adenoid cystic carcinoma (ACC) is an infrequent malignant neoplasm that originates most commonly in the major and minor salivary glands of the head and neck region. This study provides new information on head and neck ACC with cervical lymph node metastasis. Of 616 patients who underwent primary tumour resection from 1995 to 2008 in the authors’ hospital, 62 cases with cervical lymph node metastasis were analyzed. The general incidence of cervical lymph node metastasis in ACC was approximately 10%. The base of tongue, mobile tongue and mouth floor were the most frequent sites of lymph nodes metastasis, with incidences of 19.2%, 17.6% and 15.3%, respectively. Most cases occurred via a classic ‘tunnel-style’ metastasis and the level Ib and II regions were the most frequently involved. Primary site and lymphovascular invasion were significantly associated with lymph node metastasis. High patient mortality was significantly correlated with lymph node positive cases. The tongue–mouth floor complex has a high propensity for cervical lymph node metastasis, which occurs through a classic ‘tunnel-style’ metastasis. Peritumoral lymphovascular invasion could be taken as strong predictor for lymph node metastasis, which ultimately leads to poor prognosis of ACC patient. Selective neck dissection should be considered in such cases.

Are mastoid pressure dressings necessary after otologic surgery to prevent postoperative hematomas?

Are mastoid pressure dressings necessary after otologic surgery to prevent postoperative hematomas?

Preoperative concurrent chemoradiotherapy for stages II–IV oral squamous cell carcinoma: a retrospective analysis and the future possibility of this treatment strategy

This study evaluated survival in 154 patients with stages II–IV oral squamous cell carcinoma (OSCC) treated with preoperative concurrent chemoradiotherapy and assessed the future use of this treatment strategy. 14 patients exhibited advanced stage II, 73 exhibited stage III and 67 exhibited stage IV. All patients received 40Gy irradiation and concurrent cisplatin-based chemotherapy in two courses. Radical surgery was undertaken after 2–6 weeks. The clinical tumour response, histopathologic regression grade, residual tumour grade (RGrade) in the primary tumour and the level of residual pN+ were associated with prognosis. 90% of patients with complete response and 73% of patients with good partial response in the primary tumour were RGrade 0 (no residual tumour cells) or RGrade 1 (viable tumour cells remained within central superficial portion). In patients with complete response in the neck, residual pN+ was only seen in levels IB (8%) and IIA (8%); the higher the level of residual pN+, the lower the survival rate (p<0.0001). This treatment strategy was excellent for stages II–IV OSCC. It may be possible to perform minimally invasive surgery in which the extent of resection in primary tumour and neck is reduced in patients who achieve good response following preoperative chemoradiotherapy.

Clinico-Pathological Correlates of Cervical Lymphadenopathy: A Hospital Based Study

Neck is the most common site of peripheral lymph node enlargement and is very frequently encountered in oto-laryngological practice. This study was done to delineate distribution of clinico-demographic parameters in patients presenting with cervical lymphadenopathy in the otolaryngology out-patient department of a state hospital in India in a 1year period and to correlate them with fine needle aspiration cytological diagnosis. Record-based cross sectional study in the department of Otolaryngology and department of Pathology, Calcutta National Medical College and Hospital, Kolkata. Case reports and cytological reports of 423 patients who underwent Fine Needle Aspiration Cytology (FNAC) of cervical lymph nodes between January 2009 and December 2009 were reviewed in relation to their demographic and clinical profiles. The cases were divided into three groups according to age and different parameters were described according to these groups. In the cyto-pathological diagnosis, tubercular lymph-adenitis was most prevalent diagnosis (45.4%). Among the metastatic secondaries, squamous cell carcinoma was most common (8.5%). Non-specific/reactive lymphadenitis was significantly more common in <14years, TB lymph node in 15-59years and malignancy among the ≥60years age group. Jugulo-omohyoid (level III) and Supraclavicular (level VB) groups of Lymph nodes were found significantly more involved by malignancy whereas Jugulo-diagastric (level II), Post-auricular, Submandibular groups (level IB) were more commonly involved in TB. Malignancy patients presented late in respect to the tuberculosis patients. Knowledge about clinico-demographic perspectives of cervical lymphadenopathy in respect to their cytopathological diagnosis will help care giver practioners to detect/refer the respective cases early for investigations and treatment.

The functional neck dissection for lymph node neck metastasis in oral carcinoma

This is a report of 14 patients who suffered from oral cancer and underwent radical excisions of the oral cancer lesion with functional neck dissection at the Department of Oral and Maxillofacial Surgery in Annasawmy Mudaliar General Hospital, Bangalore, between 2010 and 2011. Eleven males and 3 females were involved, with the average age of 68.7 years. All patients had positive cervical lymph nodes proven by clinical and ultrasound examination. Level IB was positive in all cases and Level II of the neck was found additionally involved in five cases. A functional neck dissection in patients with a clinically positive node neck achieved better disease-free survival with minimal postoperative co-morbidity.

Computed Tomographic Findings of Kawasaki Disease With Cervical Lymphadenopathy

The purpose of this study was to describe CT findings in patients with Kawasaki disease with cervical lymphadenopathy. Twelve patients with cervical lymphadenopathy were difficult to diagnose at the initial visit and underwent CT for the assessment of lymphadenopathy. Computed tomographic images were assessed for numbers, sizes, locations of enlarged nodes, and other imaging findings. Seventy-two enlarged nodes were identified. The maximum diameter of enlarged nodes ranged from 1.0 to 2.5 cm (mean, 1.5 cm). Lymphadenopathy was unilateral in 8 patients (67%) and located at level IB in 2 patients, II in 50 patients, III in 10 patients, IV in 1 patient, and V in 9 patients. Perinodal infiltration was found in 10 patients (83%), and 3 patients (25%) had focal low attenuation within nodes. Retropharyngeal hypodense area was present in 4 patients (33%), peritonsilar hypodense area in 3 patients (25%), and enlarged tonsils in 4 patients (33%). Cervical lymphadenopathy in Kawasaki disease usually showed unilateral distribution predominantly at levels II, III, and V with perinodal infiltration occasionally accompanied by retropharyngeal hypodense area, peritonsilar hypodense area, and enlarged tonsils.

Relationships between insulin sensitivity measured with the oral minimal model and blood rheology

In studies using the intravenous glucose tolerance test with minimal model analysis we reported that low insulin sensitivity (SI) is associated with increased erythrocyte aggregability and plasma viscosity, that appeared to be markers of insulin resistance. Recently, development of modelling has made available a new approach of insulin sensitivity from oral glucose tolerance test data (oral minimal model). We aimed at determining in 111 subjects (51 men, 62 women, age 11-77 yr), insulin sensitivity with this approach together with blood viscosity parameters. With this approach the Myrenne indexes of red cell aggregation were negatively correlated to SI (M; r = -0.456; p = 0.0007; M1; r = -0.397; p = 0.004) while plasma viscosity was not. Correlations with fasting insulin levels (Ib) were weaker (M; r = 0.2711; p = 0.05; M1; r = 0.373; p = 0.007). Accordingly, a stepwise regression analysis selects M as the best correlate of SI and M1 as the best correlate of Ib. With this approach plasma viscosity does not exhibit any clear relationship with SI. This study supports the concept that RBC hyperaggregability is the prominent hemorheologic symptom of insulin resistance.

Is gene array testing to be considered routine now?

There are five multi-gene expression based prognostic tests for breast cancer offered as reference lab tests - Mammaprint, MapQuant Dx, OncotypeDx, PAM50 Breast Cancer Intrinsic Subtype Classifier, and Theros Breast Cancer Index. Each claims to provide additional prognostic information beyond conventional prognostic markers and to aid in determining who should receive systemic therapy. Evidence for their clinical utility was reviewed to determine whether any of them should be considered as routine clinical test. Peer reviewed publications, meeting abstracts, and information provided by company web sites have been reviewed to compile information regarding their clinical utility according to the following criteria; (1) Analytical validity and regulatory approval of the reference lab test. (2) Level of evidence for clinical utility. (3) Whether published evidences support prognostic and/or predictive claim. While published evidences for clinical claims for OncotypeDx and Mammaprint used reference lab tests, and the supporting evidences for other tests come from academic assays before being converted to reference lab tests, results from two large randomized clinical trials testing the clinical utility of OncotypeDx and Mammaprint are still several years away and until that time none of the markers would reach level I evidence by Marker Utility Grading System. However Oncotype Dx has reached a level IB evidence according to Simon modification to Marker Utility Grading System. Therefore OncotypeDx may be considered for routine clinical use as an adjunct to clinical and pathological information and has been incorporated into clinical guidelines in USA. While Mammaprint, MapQuantDx, and PAM50 have been repeatedly demonstrated to provide robust prognostic information, evidence for its worth as a predictive marker for chemotherapy benefit is yet to come from randomize clinical trials and therefore its utility is limited to prognostication. Meta-analysis of publicly available microarray based gene expression studies demonstrated that gene expression assays provide similar information and the most important information they provide is the proliferation activity. In untreated population, the prognostic impact of proliferation genes is limited to ER+HER2- subset since HER2+ or ER-HER2- subsets are associated with high proliferation activity. Therefore the clinical utility of these gene expression based tests is mainly for ER+HER2- subset. Since they are usually treated with adjuvant anti-estrogen therapies, for their clinical utility, demonstration of the interaction between the gene expression markers and chemotherapy in anti-estrogen treated cohort in a randomized clinical trial would be required. While OncoytpeDx is the only test supported by studies in a randomized clinical trial for adjuvant chemotherapy, other gene expression based tests are expected to provide similar information. Gene expression profiling assays as more reproducible and precise surrogates for tumor grade (MapQauntDx and Theros Breast Cancer Index) are very promising assays. However, absence of definitive predefined cut-off for defining the subset that benefit from chemotherapy validated in cohorts from randomized trials limit their clinical application.

Multitarget Helical IMRT: Accelerated Treatment With Dynamic Jaw/Dynamic Couch Technique

Multitarget Helical IMRT: Accelerated Treatment With Dynamic Jaw/Dynamic Couch Technique

Blood Pressure Targets for Patients with Diabetes or Kidney Disease

The most recent scientific guideline statements from foundations and societies dealing with diabetes and kidney disease argue for blood pressure (BP) goals lower than 130/80mmHg, but whether the evidence from properly done clinical trials supports this BP level remains questionable. A review of all the evidence suggests that almost all of the data come from retrospective data analyses of randomized cardiovascular and chronic kidney disease (CKD) trials. Meta-analyses of all clinical trials to date demonstrate that reducing BP reduces risk for stroke and coronary heart disease, but none have achieved a mean BP goal of less than 130/80mmHg. In fact, only two prospective trials achieved a BP lower than 130/80mmHg in people with type 2 diabetes, as did three trials in advanced proteinuric CKD. Of these, one of the two diabetes trials showed a benefit for overall cardiovascular risk reduction, and two of the three kidney disease trials showed a benefit on slowing of advanced CKD. Of note, however, these two trials in CKD had baseline average proteinuria rates of more than 500mg/day. No benefit of a lower BP was seen in microalbuminuric CKD. Therefore, the totality of the prospective randomized trial evidence indicates that a BP less than 130/80mmHg is not defensible to slow nephropathy progression unless proteinuria levels are at least 500mg/day, and it does not reduce overall cardiovascular events in diabetes. Stroke benefit was uniformly seen at BP levels less than 130/80mmHg, however. Therefore, newer guidelines are emerging that state that the BP goal for most people is lower than 140/90mmHg with level IA or IB evidence, and that levels lower than 130/80mmHg are defensible only if advanced proteinuric CKD is present or stroke risk is very high (i.e., history of prior stroke or several risk factors for stroke, including hypertension, smoking, diabetes mellitus, dyslipidemia).

Dominant lymph drainage in the facial region: evaluation of lymph nodes of facial melanoma patients

The purpose of this study was to evaluate the superficial lymph drainage patterns from primary lesions, with the primary focus on cheek/eyelid and lip melanomas. We conducted a retrospective study of 22 patients with facial melanomas who had undergone neck dissection or sentinel lymph node biopsy at the hospital from 1981 to April 2011. We then analyzed the dominant lymph drainage patterns from the cheek/eyelid and lip regions. The cheek/eyelid regions have two lymph drainage patterns: one is to the parotid nodes and the other is to level IB. The lymph drainage patterns in the lip region are to level IA or IB. The lymph drainage patterns to superficial lymph nodes from the primary sites were determined in both regions. Cheek/eyelid and lip melanomas have lymph drainage patterns different from those of malignant tumors of the oropharyngeal and larynx regions. Superficial lymph node groups also play an important role in facial melanomas.

From rehabilitation to remission in ankylosing spondylitis

During the past years, exercise and non-steroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of symptom control for Ankylosing Spondylitis (AS), a chronic, inflammatory rheumatic disease characterized by inflammatory back pain due to sacroiliitis and spondylitis. The ASsessment in AS (ASAS) international working group has constructed evidence based recommendations to guide the physician in the management of AS (1). Among the major recommendations for the management of AS, the ASAS group stated that there is a level Ib evidence that NSAIDs improve spinal pain, peripheral joint pain, and function, but comparative studies (1) or population-based survey (2) of different NSAIDs/coxib have not demonstrated one preparation to be clearly better than the others. Wanders et al (3) showed that the clinical efficacy of continuous NSAIDs/coxib treatment for AS was similar to intermittent ‘‘on demand’’ use and they suggested that the continuous treatment with NSAIDs/coxib could slow the radiographic disease progression over 2 years...

Is it oncologically safe to leave the ipsilateral submandibular gland during neck dissection for head and neck squamous cell carcinoma?

To investigate the incidence of metastasis to the submandibular gland in patients with head and neck squamous cell carcinoma. We retrospectively evaluated histological reports of neck dissections for upper respiratory tract carcinoma (performed 2002-2009), recording: primary tumour site, tumour-node-metastasis stage, level Ib involvement, previous radiotherapy, perineural invasion, lymphovascular invasion, extracapsular spread, and the presence of malignant disease in the submandibular gland. We evaluated 107 cases. The most common primary site was the oral cavity (49 per cent) followed by the supraglottis (21 per cent), glottis (14 per cent), oropharynx (9 per cent) and hypopharynx (6 per cent). Forty-eight per cent of patients had advanced local disease, with 21 per cent at tumour stage 3 and 27 per cent at tumour stage 4. Fifty-six per cent had cervical lymph node metastasis, and 8 per cent received pre-operative radiotherapy. Forty-eight per cent had perineural invasion, 46 per cent lymphovascular spread, 27 per cent extracapsular spread and 8 per cent level Ib metastasis. Only one patient had submandibular gland involvement, due to direct spread (a case with prior radiotherapy and macroscopic submandibular gland involvement evident peri-operatively). Submandibular gland metastasis from head and neck primary squamous cell carcinoma is extremely rare. Preservation of the ipsilateral submandibular gland during neck dissection is oncologically safe, except in patients with prior surgery or radiotherapy, or a primary tumour in close relation to the gland.

P03-123 - Is escitalopram exchangeable by citalopram? A systematic survey

ObjectiveEfficacy differences between antidepressants have only been detected exceptionally (Bauer et al., 2009). Due to the fact that escitalopram is the enantiomer of the racemate citalopram the question arose whether this compound possesses besides pharmacodynamic differences (e.g. Sánchez, 2006) also clinical relevant advantages.MethodsIn order to investigate this issue thoroughly the relevant studies of evidence level Ia (systematic surveys of randomized controlled studies) and Ib (randomized controlled trials) were summarized regarding three main outcome parameters: response (decrease of the depressive symptomatology of at least 50% on a depression scale), remission (reduction of the depressive symptomatology below a certain threshold on a depression scale) and change in depression symptomatology (point difference on a depression scale during the treatment period).ResultsOverall, approximately 20% more patients responded under escitalopram than under Citalopram. Regarding remission, this difference is approximately 30%. The point difference on the Montgomery-Åsberg depression scale was between 1 and 2 (statistically significant). In a subanalysis it was found that the superiority of escitalopram increased with increasing initial depression severity.ConclusionThese very robust data are discussed regarding their clinical implications.