Publications by authors named "Aviram Mizrachi"

57 Publications

Chemotherapy-induced acute vascular injury involves intracellular generation of ROS via activation of the acid sphingomyelinase pathway.

Cell Signal 2021 Jun 26;82:109969. Epub 2021 Feb 26.

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address:

Several categories of chemotherapy confer substantial risk for late-term vascular morbidity and mortality. In the present study, we aimed to investigate the mechanism of acute chemotherapy-induced vascular injury in normal tissues. Specifically, we looked at activation of the acid sphingomyelinase (ASMase)/ceramide pathway, which leads to generation of reactive oxygen species (ROS) and induction of oxidative stress that may result in vascular injury. In particular, we focused on two distinct drugs, doxorubicin (DOX) and cisplatin (CIS) and their effects on normal endothelial cells. In vitro, DOX resulted in increased ASMase activity, intra-cellular ROS production and induction of apoptosis. CIS treatment generated significantly reduced effects in endothelial cells. In-vivo, murine femoral arterial blood flow was measured in real-time, during and after DOX or CIS administration, using fluorescence optical imaging system. While DOX caused constriction of small vessels and disintegration of large vessels' wall, CIS induced minor vascular changes in arterial blood flow, correlating with the in vitro findings. These results demonstrate that DOX induces acute vascular injury by increased ROS production, via activation of ASMase/ceramide pathway, while CIS increases ROS production and its immediate extracellular translocation, without causing detectable acute vascular injury. Our findings may potentially lead to the development of new strategies to prevent long-term cardiovascular morbidity in cancer survivors.
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http://dx.doi.org/10.1016/j.cellsig.2021.109969DOI Listing
June 2021

Bioelectrical Impedance Analysis in Patients Undergoing Major Head and Neck Surgery: A Prospective Observational Pilot Study.

J Clin Med 2021 Feb 2;10(3). Epub 2021 Feb 2.

Department of Otorhinolaryngology Head and Neck Surgery, Rabin Medical Center-Beilinson Hospital, Petach Tikva 49100, Israel.

Background: Head and neck patients are prone to malnutrition. Perioperative fluids administration in this patient group may influence nutritional status. We aimed to investigate perioperative changes in patients undergoing major head and neck surgery and to examine the impact of perioperative fluid administration on body composition and metabolic changes using bioelectrical impedance. Furthermore, we sought to correlate these metabolic changes with postoperative complication rate. In this prospective observational pilot study, bioelectrical impedance analysis (BIA) was performed preoperatively and on postoperative days (POD) 2 and 10 on patients who underwent major head and neck surgeries. BIA was completed in 34/37 patients; mean total intraoperative and post-anesthesia fluid administration was 3682 ± 1910 mL and 1802 ± 1466 mL, respectively. Total perioperative fluid administration was associated with postoperative high extra-cellular water percentages ( = 0.038) and a low phase-angle score ( < 0.005), which indicates low nutritional status. Patients with phase angle below the 5th percentile at POD 2 had higher local complication rates ( = 0.035) and longer hospital length of stay (LOS) ( = 0.029). Multivariate analysis failed to demonstrate that high-volume fluid administration and phase angle are independent factors for postoperative complications. High-volume perioperative fluids administration impacts postoperative nutritional status with fluid shift toward the extra-cellular space and is associated with factors that increase the risk of postoperative complications and longer LOS. An adjusted, low-volume perioperative fluid regimen should be considered in patients with comorbidities in order to minimize postoperative morbidity.
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http://dx.doi.org/10.3390/jcm10030539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867235PMC
February 2021

Prophylactic central neck dissection has no advantage in patients with metastatic papillary thyroid cancer to the lateral neck.

J Surg Oncol 2021 Feb 1;123(2):456-461. Epub 2020 Dec 1.

Department of Otolaryngology, Head & Neck Surgery and Maxillofacial Surgery, Tel-Aviv Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Background: Papillary thyroid cancer (PTC) usually metastasizes via lymphatic channels in a sequential fashion, first to the central compartment, followed by the lateral neck. PTC patients diagnosed with lateral neck disease (N1b) without proof for central involvement traditionally undergo prophylactic central neck dissection (pCND). However, substantial evidence on outcomes to support this approach is lacking.

Materials And Methods: We conducted a dual center retrospective study to compare the rate of central neck recurrence between N1b PTC patients undergoing pCND and those spared pCND. All patients diagnosed with N1b PTC who underwent total thyroidectomy and lateral neck dissections with or without pCND between January 1998 and December 2015 were included in this study. The rates of central neck recurrences were compared between the groups.

Results: The 111 patients who met the inclusion criteria were 44 females (39.6%) and 67 males (60.4%), with a mean age of 50.2 ± 17.7 years, and a mean follow-up of 10.2 ± 5.3 years. Sixty patients (54.1%) underwent a pCND and 51 patients (45.9%) did not (non-pCND). During follow-up, 18 patients (16.2%) had level VI recurrences, 13 in the pCND group and 5 in the non-pCND group. Cox-regression models with propensity scoring did not reveal any inclination or an advantage for performing pCND.

Conclusion: The present study demonstrated no advantage in performing pCND to prevent central neck recurrence among PTC patients with lateral neck involvement only. These findings question the need for pCND in patients without clinical evidence of central neck disease.
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http://dx.doi.org/10.1002/jso.26299DOI Listing
February 2021

Solid organ transplantation worsens the prognosis of patients with cutaneous squamous cell carcinoma of the head and neck region-Comparison between solid organ transplant recipients and immunocompetent patients.

Head Neck 2021 Mar 27;43(3):884-894. Epub 2020 Nov 27.

Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.

Background: Cutaneous squamous cell carcinoma of the head and neck (CSCC-HN) appears to behave more aggressively in immunosuppressed patients. We aimed to investigate this hypothesis by comparing solid organ transplant recipients (SOTR) with CSCC-HN to immunocompetent patients.

Methods: A retrospective comparative study was conducted for SOTR and immunocompetent patients who were treated for CSCC-HN.

Results: A total of 177 SOTR and 157 immunocompetent patients with CSCC-HN were included. Lymph node metastases were more common in the SOTR group (9% vs 3%), and distant metastases occurred only in SOTR (3% of patients). SOTR had a higher rate of recurrences (19% vs 10%), which were mostly regional (7%) and distant (3%). The 2-year disease-specific survival of SOTR was lower (93% vs 100%).

Conclusions: SOTR with CSCC-HN has significantly worse outcomes compared to immunocompetent patients. Solid-organ transplantation should be regarded as a negative prognostic factor in patients with CSCC-HN.
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http://dx.doi.org/10.1002/hed.26546DOI Listing
March 2021

Role of intraoperative recurrent laryngeal nerve monitoring for pediatric thyroid surgery: Comparative analysis.

Head Neck 2021 Mar 9;43(3):849-857. Epub 2020 Nov 9.

Department of Otolaryngology - Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.

Background: The data on the advantages of intraoperative nerve monitoring (IONM) during pediatric thyroid surgeries are limited. We aimed to study the role of IONM by comparing between children who underwent thyroid surgery with and without IONM.

Methods: A retrospective study of all children who underwent thyroid surgery between 2001 and 2019.

Results: The study included 113 patients with 183 recurrent laryngeal nerve (RLN) at risk. Transient paralysis rate was more than 5-fold lower in the IONM group compared to the control group (1.5% vs 8%; P = .114). Permanent paralysis was documented only in the control group (2.5% vs 0%; P = .552). Children <10 years and those who underwent central neck dissection had significantly higher rates of RLN injury.

Conclusions: IONM was associated with decreased rate of RLN injury during pediatric thyroid surgery and should be considered especially in children under 10 years of age and those undergoing concomitant central neck dissection.
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http://dx.doi.org/10.1002/hed.26544DOI Listing
March 2021

CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma.

J Clin Med 2020 Oct 7;9(10). Epub 2020 Oct 7.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.

Activating alterations in , the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular-based study using both HNSCC cell lines and patient-derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA-altered HNSCC treated with isoform-specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719-resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719-sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti-tumor effect when combined in human papillomavirus (HPV)-negative/PIK3CA-WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients.
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http://dx.doi.org/10.3390/jcm9103214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601167PMC
October 2020

Neck injuries - israel defense forces 20 years' experience.

Injury 2021 Feb 18;52(2):274-280. Epub 2020 Sep 18.

Israel Defense Forces, Medical Corps, Tel Hashomer, Ramat Gan, Israel.

Background: Neck injuries are an important cause of combat mortality and morbidity. This study's objective was to examine the characteristics and causes of neck injuries among Israel Defense Forces (IDF) and emphasize the best treatment protocols for the advanced life support providers in the prehospital combat environment.

Methods: The IDF Trauma Registry (IDF-TR) includes prehospital data regarding casualties treated by the IDF's medical forces. This study was a retrospective, observational study that included all casualties who were injured between January 2006 and December 2018.

Results: Between January 2016 and December 2018, 3294 casualties were recorded. During the study period, 1% (41/3,394) of all injury casualties in the registry were isolated neck injuries compared to 94% (3185/3,394) without neck injury. 42% (14/41) percent of the neck casualties were classified as urgent compared to 26% (830/3185, P = 0.09) in the no neck group. The most frequent type of injury mechanism in the neck casualties was penetrating injury (54% 22/41), mostly due to shrapnel (68% 15/22). 60% of neck injured personnel were injured during the 2nd Lebanon War and Operation Protective Edge in high-intensity conflicts. As for life-saving interventions, advanced airway interventions were performed in 12% of neck injured group (5/41) compared to 3% (104/3185, P = 0.02) in the no neck group. We revealed that cricothyroidotomy was performed in almost 10% (4/41) of neck injured casualties compared to only 1% (19/3185, P<0.0001) in no neck casualties. As for damage control resuscitation, neck injury casualties received higher amounts of Fresh Dried Plasma 7% (3/41) Vs. 1% (32/3185, P = 0.02) and Tranexamic acid 15% (6/41) Vs. 4% (124/3185, P = 0.01) compared to non-neck casualties.

Conclusions: Military neck injuries are a significant cause of substantial disability and result in incompatibility with combat duties in previously healthy soldiers. Prompt medical care, especially urgent hemodynamic and airway management, is paramount in these injuries. Routine use of designated neck protection might lower the number of neck injuries, mitigate their severity, and even decrease mortality.

Level Of Evidence: Level III (Retrospective study with up to two negative criteria).
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http://dx.doi.org/10.1016/j.injury.2020.09.042DOI Listing
February 2021

Skull base chordomas review of current treatment paradigms.

World J Otorhinolaryngol Head Neck Surg 2020 Jun 18;6(2):125-131. Epub 2020 Apr 18.

Department of Otolaryngology- Head and Neck Surgery, Rabin Medical Center, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Chordomas are locally invasive neoplasms, arising from notochordal remnants and can appear anywhere along the axial skeleton. Local recurrences are common, and distant metastases may occur years after the initial presentation.

Methods: Literature review of current treatment strategies for chordomas of the skull base.

Results: Surgery is the mainstay of treatment and complete resection has paramount importance for prognosis.When complete resection is not achieved recurrent disease is common. The anatomical complexity of the skull base makes resection complex. Endonasal endoscopic approaches to the clivus has become increasingly favored in recent years although addressing reconstruction of the skull base to prevent CSF leak may be challenging.Evidence suggests that radiotherapy should not be considered as a primary single modality when trying to achieve cure of the disease. Nonetheless, immediate post-operative radiotherapy improves survival. Many strategies have been suggested to preserve sensitive vital structures in the skull base during treatment but as for survival there is no evidence of advantage when comparing adjuvant therapy with photon radiotherapy, gamma knife surgery, proton beam therapy, and carbon ion radiation therapy.There is no evidence to support cytotoxic chemotherapy in the treatment of chordomas but targeted therapies have started to show promise. Several optional molecular targets exist. Brachyury is overexpressed in 95% of chordomas but not in other mesenchymal neoplasms. However, its precise role in chordoma pathogenesis is currently unclear, and its cellular location in the nucleus makes it difficult to target. The inhibition of brachyury in chordoma cell lines induces growth arrest and apoptosis. This does not have clinical application to date. There are retrospective results with different molecular targeted therapies for advanced chordomas with some effectiveness.

Conclusion: Despite improvements made in the past 10 years in our knowledge of chordoma biology, available therapies still offer a limited benefit. There is an unmet need for new therapeutic options for patients with advanced disease. Therefore, patients with advanced disease should be encouraged to participate in clinical trials when and where available.
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http://dx.doi.org/10.1016/j.wjorl.2020.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296475PMC
June 2020

Manipulating Oxidative Stress Following Ionizing Radiation.

J Cell Signal 2020 ;1(1):8-13

Department of Medicine, Renal Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.33696/signaling.1.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299208PMC
January 2020

The prognostic value of lymph node ratio in Medullary thyroid carcinoma: A multi-center study.

Eur J Surg Oncol 2020 11 18;46(11):2023-2028. Epub 2020 Apr 18.

Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address:

Introduction: The lymph node ratio (LNR), which represents the proportion of metastatic lymph nodes resected, has been found to be a prognostic variable in several cancers, but data for Medullary thyroid carcinoma (MTC) are sparse. The aim of this study was to determine the value of the LNR in predicting outcome in patients with MTC.

Materials And Methods: A retrospective multicenter study design of 107 patients with MTC who underwent total thyroidectomy with neck dissection between 1984 and 2016. The association of LNR with patient and tumor characteristics and prognostic factors was evaluated.

Results: Study population consisted of 53.3% female, mean age at diagnosis was 50.3 ± 18.4 years; 16.8% had inherited MTC. LNR was positively correlated with tumor size (p = 0.018) and inversely correlated with age at diagnosis (p = 0.024). A higher LNR was associated with extrathyroidal extension (p < 0.001), multifocality (p = 0.001), bilateral tumor (p = 0.002), distant metastases (p < 0.001), and tumor recurrence (OR = 14.7, p < 0.001). LNR was also correlated to postoperative calcitonin levels (p < 0.001) and carcinoembryonic antigen (p = 0.011). LNR >0.1 was associated with shorter disease-specific survival in patients at risk: tumor larger than 20 mm at diagnosis (p = 0.013), sporadic MTC (p = 0.01), and age above 40 years at diagnosis (p = 0.004). Cox multivariate survival analysis revealed LNR as the only significant independent factor for disease free survival (p = 0.005).

Conclusions: This study showed that LNR correlates well with patient and tumor characteristics and prognostic variables. We suggest that LNR should be considered an important parameter for predicting outcome in MTC.
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http://dx.doi.org/10.1016/j.ejso.2020.04.016DOI Listing
November 2020

Squamous cell carcinoma of the oral tongue: Distinct epidemiological profile disease.

Head Neck 2020 09 22;42(9):2316-2320. Epub 2020 Apr 22.

Department of Otolaryngology-Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.

Background: Oral squamous cell carcinoma (OSCC) occurs in different subsites within the oral cavity. Our goal was to investigate the epidemiological features of OSCC with relation to age and subsite.

Methods: Retrospective review of all patients treated for OSCC in a tertiary care center between 2000 and 2018.

Results: A total of 360 patients were included. Five age groups were defined: 0 to 30, 31 to 45, 46 to 60, 61 to 75, and 76+. In the 0 to 30 and 31 to 45 groups, 94.6% of tumors originated in the oral tongue compared to 87%, 66%, and 61% in the 46 to 60, 61 to 75, and 76+ groups, respectively (P < .001). A higher proportion of oral tongue SCC (OTSCC) was found in nonsmokers (76% vs 62%, P = .02). In nonsmokers aged 0 to 60, 97.9% had OTSCC compared to 67.5% in the 61+ groups (P < .001).

Conclusions: OSCC in young nonsmokers originates primarily in the tongue. The etiology of OTSCC in young patients may be different than other OSCC subsites and not related to smoking.
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http://dx.doi.org/10.1002/hed.26177DOI Listing
September 2020

Detecting Recurrence Following Lobectomy for Thyroid Cancer: Role of Thyroglobulin and Thyroglobulin Antibodies.

J Clin Endocrinol Metab 2020 06;105(6)

Endocrinology & Metabolism Institute, Rabin Medical Center, Petach Tikva, Israel.

Background: The use of thyroglobulin (Tg) and thyroglobulin antibodies (TgAb) for detecting disease recurrence is well validated following total thyroidectomy and radioiodine ablation. However, limited data are available for patients treated with thyroid lobectomy.

Methods: Patients who had lobectomy for papillary thyroid cancer followed for >1 year, with sufficient data on Tg and TgAb, including subgroup analysis for Hashimoto's thyroiditis and contralateral nodules.

Results: One-hundred sixty-seven patients met the inclusion criteria. Average tumor size was 9.5 ± 6 mm. Following lobectomy, Tg was 12.1 ± 14.8 ng/mL. Of 52 patients with Hashimoto's thyroiditis, 38% had positive TgAb with titers of 438 ± 528 IU/mL, and in patients without TgAb the mean Tg level was 14.7 ± 19.0 ng/mL. In 34 patients with contralateral nodules ≥1 cm, Tg was 15.3 ± 17 ng/mL. During the first 2 years of follow-up, Tg declined ≥1 ng/mL in 42% of patients (by 5.1 ± 3.7 ng/mL), remained stable in 22%, and increased in 36% (by 4.9 ± 5.7 ng/mL). During a mean follow-up of 6.5 years (78 ± 43.5 months), 18 patients had completion thyroidectomy and 12 were diagnosed with contralateral cancer (n = 8) or lymph node metastases (n = 4). In patients with recurrence followed for >2 years, there was a rise in Tg in 3 cases, Tg was stable in 2 cases, and in 1 TgAb decreased from 1534 to 276 IU/mL despite metastatic lymph nodes. Basal Tg and Tg dynamics did not predict disease recurrence.

Conclusions: Serum thyroglobulin used independently is of limited value for predicting or detecting disease recurrence following thyroid lobectomy. Other potential roles of Tg, such as detecting distant metastases following lobectomy, should be further studied.
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http://dx.doi.org/10.1210/clinem/dgaa152DOI Listing
June 2020

[THE USE OF ROBOTICS IN HEAD AND NECK SURGERY - THE EXPERIENCE OF RABIN MEDICAL CENTER].

Harefuah 2020 Feb;159(1):142-145

Department of Otorhinolaryngology -- Head and Neck Surgery, Rabin Medical Center, Beilinson Hospital, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Introduction: In recent years, minimally invasive surgeries have been undergoing a revolution with the development of robotic assisted surgery. Due to the anatomical region in which many operations are carried out, in small spaces through natural orifices in the body such as the mouth, the nose or the ear, as well as the esthetic discomfort caused by external scars in the head and neck, the use of robotic assisted surgery in the field of head and neck surgery is gaining momentum and is being implemented more and more in Israel and around the globe. Most of the operations currently performed in otolaryngology are carried out through the oral cavity or through distant and camouflaged skin cuts. In this article we will review the new applications and technologies in the field of surgical robotics in otolaryngology - head and neck surgeries, as well as summarize the experience of the Department of Otorhinolaryngology and Head and Neck Surgery at the Rabin Medical Center in robot assisted surgeries.
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February 2020

Intraoperative nerve monitoring is used routinely by a significant majority of head and neck surgeons in thyroid surgery and impacts on extent of surgery-Survey of the American Head and Neck Society.

Head Neck 2020 08 6;42(8):1757-1764. Epub 2020 Feb 6.

Department of Otolaryngology-Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.

Background: The data on the advantages of intraoperative nerve monitoring (IONM) during thyroid surgeries is inconsistent. Our objective was to study the patterns of use of IONM in thyroid surgery among American Head and Neck Society (AHNS) members.

Method: A web-based survey was e-mailed to all members of the AHNS.

Results: A total of 275 surgeons completed the survey. Seventy-two percent reported using IONM routinely. Routine use of IONM was associated with longer period in practice. Twenty-one percent only used IONM selectively in high-risk cases. Most surgeons would consider aborting the procedure in cases of loss of signal without continuing to the contralateral side. Finally, only 19% of surgeons attempt to identify the external branch of the superior laryngeal nerve (EBSLN).

Conclusions: The majority of AHNS surgeons routinely use IONM during thyroid surgery as a real-time decision-making tool. However, IONM for preservation of the EBSLN is underutilized.
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http://dx.doi.org/10.1002/hed.26093DOI Listing
August 2020

Recurrence predictability by various staging systems in 283 patients after thyroidectomy and radioactive iodine treated for papillary thyroid carcinoma.

Clin Otolaryngol 2019 11 13;44(6):1147-1152. Epub 2019 Sep 13.

Department of Otolaryngology-Head and Neck Surgery, Rabin Medical Center, Petach Tikva, Israel.

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http://dx.doi.org/10.1111/coa.13420DOI Listing
November 2019

Long-term outcomes of tonsillectomy for recurrent tonsillitis in adults.

Laryngoscope 2020 02 25;130(2):328-331. Epub 2019 Mar 25.

Department of Otorhinolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: There is uncertainty regarding the effectiveness of tonsillectomy for recurrent tonsillitis in the adult population. Several studies have described a reduced number and severity of tonsillitis episodes; however, the impact of tonsillectomy on healthcare burden has yet to be studied. The aim of the present study was to evaluate the long-term outcomes of tonsillectomy in the adult population.

Methods: A retrospective review of the central database of Clalit Health Services, Tel Aviv, Israel, between 2003 and 2009 was performed. The study included all adult patients (>18 years) who underwent tonsillectomy due to recurrent tonsillitis. Clinical and epidemiological data from 3 years before and after surgery were collected and analyzed.

Results: A total of 3,701 patients were included in the study. Mean age was 37.4 years, and 42.9% were males. Following surgery, there was a significant decrease in the total number of tonsillitis episodes, otolaryngologist clinic visits, consumption of pertinent antibiotics, and respiratory complaints. Moreover, a reduced number of hospitalizations to the otolaryngology department and shorter hospitalization duration were also noted. Although the total number of hospitalizations was unaffected, there was an increase in the number of primary care office visits. Finally, a break-even time analysis revealed an average of 2.7 years following tonsillectomy.

Conclusion: Tonsillectomy for recurrent tonsillitis is effective in decreasing the number and severity of tonsillitis episodes and might also have an economic benefit. The impact of tonsillectomy on general health needs to be further evaluated; however, it appears that there is no increase in overall morbidity.

Level Of Evidence: NA Laryngoscope, 130:328-331, 2020.
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http://dx.doi.org/10.1002/lary.27928DOI Listing
February 2020

Tumor Tissue Explant Culture of Patient-Derived Xenograft as Potential Prioritization Tool for Targeted Therapy.

Front Oncol 2019 22;9:17. Epub 2019 Jan 22.

The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

Despite of remarkable progress made in the head and neck cancer (HNC) therapy, the survival rate of this metastatic disease remain low. Tailoring the appropriate therapy to patients is a major challenge and highlights the unmet need to have a good preclinical model that will predict clinical response. Hence, we developed an accurate and time efficient drug screening method of tumor analysis (TEVA) system, which can predict patient-specific drug responses. In this study, we generated six patient derived xenografts (PDXs) which were utilized for TEVA. Briefly, PDXs were cut into 2 × 2 × 2 mm explants and treated with clinically relevant drugs for 24 h. Tumor cell proliferation and death were evaluated by immunohistochemistry and TEVA score was calculated. and drug efficacy studies were performed on four PDXs and three drugs side-by-side to explore correlation between TEVA and PDX treatment . Efficacy of drug combinations was also ventured. Optimization of the culture timings dictated 24 h to be the time frame to detect drug responses and drug penetrates 2 × 2 × 2 mm explants as signaling pathways were significantly altered. Tumor responses to drugs in TEVA, significantly corresponds with the drug efficacy in mice. Overall, this low cost, robust, relatively simple and efficient 3D tissue-based method, employing material from one PDX, can bypass the necessity of drug validation in immune-incompetent PDX-bearing mice. Our data provides a potential rationale for utilizing TEVA to predict tumor response to targeted and chemo therapies when multiple targets are proposed.
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http://dx.doi.org/10.3389/fonc.2019.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350270PMC
January 2019

Single Stage Transoral Laser Microsurgery for Early Glottic Cancer.

Front Oncol 2018 14;8:298. Epub 2018 Aug 14.

Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petach Tikva, Israel.

The purpose of the study was to present the outcome of our management protocol of a single stage transoral laser microsurgery (SSTLM), with the intention of complete removal of a lesion, considered to be an early glottic cancer. Between January 2015 to February 2017 patients with the clinical appearance of an early glottic cancer, who were candidates for (SSTLM) management protocol, were included in this study. Type of cordectomy was determined by pre- and intra-operative evaluation of the extent of lesion in cord layers. Thirty patients (6 females, 24 males; mean age 65 years) underwent SSTLM. Twenty-two patients had malignant histopathological diagnosis of severe dysplasia or Cis in 4 patients, microinvasice carcinoma in 3 patients and invasive carcinoma in 15 patients (T1a tumor in 14 and T1b tumor in 1). Eight patients had a nonmalignant histological diagnosis of keratosis without atypia in 2 patients, mild dysplasia in 2 patients and moderate dysplasia in 3 patients. Based on pre- and intra-operative evaluation, 14 subepithelial (type I), 10 subligamental (type II), and 6 transmuscular (type III) cordectomies were performed. Comparison of cordectomies types with postoperative histopathologic diagnosis showed an adequate extent of resection in 26 out of 30 patients (87%). Considering only patients without recent background of direct laryngoscopy and biopsy, an adequate resection was performed in 90% of patients. None of the patients was further treated by external beam radiation. At average follow-up of 21 months, none of the patients developed local recurrence. In selected cases, a SSTLM for clinical appearance of an early glottic cancer, allows a reliable histopathologic diagnosis and a high local control rate with favorable cost effectiveness. A careful pre- and intraoperative evaluation for selecting the appropriate cases for this management is required in order to avoid under- or over-treatment.
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http://dx.doi.org/10.3389/fonc.2018.00298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102390PMC
August 2018

Accuracy of Neck Ultrasonography in Predicting the Size and Location of Parathyroid Adenomas.

Otolaryngol Head Neck Surg 2018 12 14;159(6):968-972. Epub 2018 Aug 14.

1 Department of Otorhinolaryngology-Head and Neck Surgery, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.

Objectives: Ultrasonography (US) is a reliable tool for the preoperative localization of parathyroid adenomas (PTAs). The aim of this study was to evaluate the accuracy of US for estimating both the size and the location of PTAs and the effect of operator expertise.

Study Design: Retrospective cohort study.

Setting: A single tertiary medical center.

Subjects And Methods: All patients who underwent parathyroidectomy for primary hyperparathyroidism between 1996 and 2012 were included. The estimated PTA localization and size by preoperative ultrasound were compared with the intraoperative findings and pathology report.

Results: The cohort included 410 patients. US correctly localized the adenoma in 76% of cases with a sensitivity of 76.2% and a positive predictive value of 86.8%. Measurements were least accurate for adenomas measuring <1 cm in diameter (24%). Scans made by a single senior operator specializing in the neck had a higher accuracy rate than scans made by multiple operators, with a significant difference for small adenomas ( P < .001).

Conclusions: US is an accurate and sensitive tool for evaluating PTA size and location. Neck US is less accurate for small adenomas (<1 cm). In these cases particularly, the experience and expertise of the US operator may play an important role.
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http://dx.doi.org/10.1177/0194599818792236DOI Listing
December 2018

Neck recurrence in clinically node-negative oral cancer: 27-year experience at a single institution.

Oral Oncol 2018 03 20;78:94-101. Epub 2018 Feb 20.

Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address:

Objectives: Neck failure in patients with oral squamous cell carcinoma (OSCC) carries a poor outcome, yet the management of patients who initially present with clinically node-negative (cN0) neck is not clearly defined.

Patients And Methods: Retrospective review of patients with cN0 OSCC treated at Memorial Sloan Kettering Cancer Center from 1985 to 2012, focusing on rate, pattern and predictors of neck failure, salvage treatment, and survival outcomes.

Results: Of 1,302 patients, 806 (62%) underwent elective neck dissection (END) and 496 (38%) had observation. 190 patients (15%) developed neck recurrence. Median follow-up was 58.5 months (range 1-343); 5-year neck recurrence-free survival (NRFS) was 85% and 80% for the END and observation group respectively (p = .06). Patients with neck failure had poorer outcomes than patients without neck failure (5-year overall survival, 37% vs. 74% [p < .001]; disease-specific survival [DSS], 41% vs. 91% [p < .001]). Independent predictors of neck failure were smoking, primary tumor subsite (hard palate and upper gum), and extranodal extension. 87% of patients underwent salvage treatment (END: 81.1%; observation: 94%). Salvage surgery with adjuvant (chemo) radiation had better DSS than surgery alone or nonsurgical salvage.

Conclusions: In our cohort of patients with initially cN0 OSCC triaged to END vs. observation using clinical parameters, 15% developed neck failure. Salvage treatment was feasible in most cases but survival was poorer compared to patients without neck failure. Surgery followed by adjuvant (chemo) radiation resulted in the best outcome.
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http://dx.doi.org/10.1016/j.oraloncology.2018.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836807PMC
March 2018

Quantitative self-assembly prediction yields targeted nanomedicines.

Nat Mater 2018 04 5;17(4):361-368. Epub 2018 Feb 5.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Development of targeted nanoparticle drug carriers often requires complex synthetic schemes involving both supramolecular self-assembly and chemical modification. These processes are generally difficult to predict, execute, and control. We describe herein a targeted drug delivery system that is accurately and quantitatively predicted to self-assemble into nanoparticles based on the molecular structures of precursor molecules, which are the drugs themselves. The drugs assemble with the aid of sulfated indocyanines into particles with ultrahigh drug loadings of up to 90%. We devised quantitative structure-nanoparticle assembly prediction (QSNAP) models to identify and validate electrotopological molecular descriptors as highly predictive indicators of nano-assembly and nanoparticle size. The resulting nanoparticles selectively targeted kinase inhibitors to caveolin-1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeutic effects while avoiding pERK inhibition in healthy skin. This finding enables the computational design of nanomedicines based on quantitative models for drug payload selection.
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http://dx.doi.org/10.1038/s41563-017-0007-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930166PMC
April 2018

Can molecular profiling enhance radiotherapy? Impact of personalized targeted gold nanoparticles on radiosensitivity and imaging of adenoid cystic carcinoma.

Theranostics 2017 14;7(16):3962-3971. Epub 2017 Sep 14.

Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.

Personalized molecular profiling has an established role in selection of treatment for metastatic disease; however, its role in improving radiosensitivity and functional imaging has not been evaluated. In the current study, we examined molecular profiling as a tool for designing personalized targeted gold nanoparticles (GNP) to serve as dual-modal tumor radiosensitizers and functional imaging enhancers. To this end, molecular profiling of a patient's salivary gland adenoid cystic carcinoma (ACC) was performed, and anaplastic lymphoma kinase (ALK) mutation was detected. The extracted tumor was subcutaneously injected into mice, which were then treated either with radiation, the specific ALK inhibitor crizotinib, or a combination of therapies. One of these combinations, namely, ALK-targeted GNP (via crizotinib coating), was found to enhance radiation treatment, as demonstrated by a significant decrease in tumor volume over 24 days. In parallel, ALK-targeted GNP substantially augmented tumor visualization via computed tomography. The mechanism of radiosensitivity enhancement was mostly related to a diminished cell repair mechanism in tumors, as demonstrated by proliferating cell nuclear antigen staining. These findings indicate that personalized molecular profiling is an effective technique for enhancing cancer theranostics.
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http://dx.doi.org/10.7150/thno.19615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667418PMC
June 2018

Submandibular salivary gland tumors: Clinical course and outcome of a 20-year multicenter study.

Ear Nose Throat J 2017 Mar;96(3):E17-E20

Department of Otorhinolaryngology-Head and Neck Surgery, Rabin Medical Center, Petah Tikva 49100, Israel.

The purpose of this retrospective chart review study was to review the nature and clinical course of benign and malignant submandibular gland tumors at 2 major university-affiliated tertiary medical centers. All patients who underwent submandibular salivary gland excision between 1990 and 2010 were included. Clinical and disease-related data were collected from the medical charts. One hundred ninety-three patients were identified, of whom 108 (56%) had non-neoplastic disorders (sialolithiasis and sialadenitis). The remaining 85 patients (44%) had a submandibular salivary gland tumor. The most common benign neoplasm was pleomorphic adenoma (53 patients). Twenty tumors (24%) were malignant: adenoid cystic carcinoma in 11 patients, mucoepidermoid carcinoma in 6 patients, and adenocarcinoma in 3 patients. Recurrence was noted in 7 patients with submandibular gland malignancy and in 2 patients with pleomorphic adenoma. The 5-year disease-free survival rate was 63%. Tumors of the submandibular gland are infrequently malignant. Recurrent submandibular salivary gland pleomorphic adenoma is rare compared with recurrences in the parotid gland.
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http://dx.doi.org/10.1177/014556131709600320DOI Listing
March 2017

Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma.

Nat Commun 2017 02 13;8:14292. Epub 2017 Feb 13.

Human Oncology &Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Alterations in PIK3CA, the gene encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3Kα), are frequent in head and neck squamous cell carcinomas. Inhibitors of PI3Kα show promising activity in various cancer types, but their use is curtailed by dose-limiting side effects such as hyperglycaemia. In the present study, we explore the efficacy, specificity and safety of the targeted delivery of BYL719, a PI3Kα inhibitor currently in clinical development in solid tumours. By encapsulating BYL719 into P-selectin-targeted nanoparticles, we achieve specific accumulation of BYL719 in the tumour milieu. This results in tumour growth inhibition and radiosensitization despite the use of a sevenfold lower dose of BYL719 compared with oral administration. Furthermore, the nanoparticles abrogate acute and chronic metabolic side effects normally observed after BYL719 treatment. These findings offer a novel strategy that could potentially enhance the efficacy of PI3Kα inhibitors while mitigating dose-limiting toxicity in patients with head and neck squamous cell carcinomas.
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http://dx.doi.org/10.1038/ncomms14292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316830PMC
February 2017

Lymph Node Dissection for Differentiated Thyroid Cancer.

Mol Imaging Radionucl Ther 2017 02;26(Suppl 1):10-15

Memorial Sloan-Kettering Cancer Center, Head and Neck Service, New York, USA, Phone: +90 347-449-3137, E-mail:

Lymph node metastases in differentiated thyroid cancer (DTC) have a wide spectrum of clinical significance. Several variables are taken under consideration when trying to decide on the optimal management of patients with DTC. Routine prophylactic central and/or lateral lymph node dissection is not advocated with exception of central neck dissection for locally advanced tumors. When regarding recurrent disease, foundations have been laid for clinicians to make accurate decisions as to when to perform surgery and when to continue maintaining the patient's disease under observation. These complex decisions are determined based upon multiple factors, not only regarding the patient's disease but also the patient's comprehension of the procedure and apprehension levels. Nevertheless if the patient and/or clinician are emotionally keen to surgically remove the disease then the procedure should be considered.
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http://dx.doi.org/10.4274/2017.26.suppl.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283708PMC
February 2017

Targeting acid sphingomyelinase with anti-angiogenic chemotherapy.

Cell Signal 2017 01 1;29:52-61. Epub 2016 Oct 1.

Department of Radiation Oncology, USA. Electronic address:

Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase, but not in asmase, hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1-2h before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials.
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http://dx.doi.org/10.1016/j.cellsig.2016.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138150PMC
January 2017

Prognostic factors in metastatic cutaneous squamous cell carcinoma of the head and neck.

Ear Nose Throat J 2016 Oct-Nov;95(10-11):E32-E36

Department of Otolaryngology-Head and Neck Surgery, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.

Metastatic cutaneous squamous cell carcinoma (SCC) of the head and neck poses a significant therapeutic challenge due to its aggressive biologic behavior. We conducted a retrospective study of 71 patients-58 men and 13 women, aged 28 to 88 years (mean: 71)-who had been treated at our university-affiliated tertiary care medical center for metastatic cutaneous SCC over a 15-year period. In addition to demographic data, we compiled and analyzed information on tumor characteristics, the site and extent of metastasis, treatment, follow-up, and outcome. Among the tumor factors, poorly differentiated carcinoma was an independent predictor of poorer disease-free survival, and older age was found to be an independent predictor of poorer overall survival. We found no significant difference in disease-free or disease-specific survival among patients with parotid involvement, neck involvement, or both. In our series, the site of nodal involvement appeared to have no prognostic significance in patients with metastatic cutaneous SCC of the head and neck.
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April 2017

Recurrent pleomorphic adenoma of the parotid gland: Institutional experience and review of the literature.

J Surg Oncol 2016 Nov 29;114(6):714-718. Epub 2016 Jul 29.

Department of Otorhinolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.

Background: Recurrent pleomorphic adenoma (PA) of the parotid gland is a challenging surgical issue with controversy regarding management and long term outcome.

Methods: All patients who were operated for recurrent PA of the parotid gland between the years 1991 and 2013 were reviewed. Patient demographics, clinicopathologic variables, and operative details were collected retrospectively.

Results: A total of 22 patients were operated for recurrent PA of the parotid gland. Mean interval between recurrences was 7 and 6 years for first recurrence and second recurrence, accordingly. Second recurrence was significantly influenced by younger age at initial treatment (P = 0.009). Only two patients (9%) with a recurrence developed facial nerve paralysis following surgery. Adjuvant radiotherapy was given to nine patients with no evidence of disease progression or recurrence. There were no cases of malignant transformation.

Conclusions: Recurrent PA of the parotid gland tends to occur in long intervals in a multifocal pattern. Adjuvant radiotherapy could be suggested as an alternative for surgery. J. Surg. Oncol. 2016;114:714-718. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jso.24392DOI Listing
November 2016

The predictive value of dendritic cells in early squamous cell carcinoma of the tongue.

Pathol Res Pract 2016 Dec 23;212(12):1138-1143. Epub 2016 Sep 23.

Departments of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Petach Tikva, Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objectives: The aim of this study was to evaluate the relationship between dendritic cell density in early squamous cell carcinoma (SCC) of the tongue and patients' clinical outcome.

Methods: Representative samples of low-risk SCC of the tongue (T1-2,N0,M0) from a homogeneous group of 18 patients following local complete excision and elective selective neck dissection, were immunostained with antibodies against S100 and CD1a. Dendritic cell density was analyzed by outcome.

Results: Mean dendritic cell densities were 17 cells/HPF for tumoral S100 and CD1a counts, and 10 cells/HPF for peritumoral S100 and CD1a counts. Better disease-free survival was associated with low peritumoral S100- and CD1a- positive cell counts (p=0.006 and p=0.004, respectively), and with low tumoral S100- and CD1a- positive cell counts (p=0.037 and p=0.04, respectively). Lymphocytic response was decreased in tumors with high dendritic cell density (p=NS). There was no association of dendritic cell density with patient age, tumor size and depth of invasion.

Conclusions: These results may suggest an association between dendritic cell accumulation and functional immunologic impairment.
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http://dx.doi.org/10.1016/j.prp.2016.09.011DOI Listing
December 2016