Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

Thyroid Physiology

May 2, 2019May 2, 2019 Rodrigo Arrangoiz MS, MD, FACS, FSSO

The basic functional unit of the thyroid gland is the:
- Thyroid follicle:
  - The thyroid follicle is made up of a:
    - Single layer of cells that forms a sphere that surrounds a protein aggregate called colloid.
  - The thyroid follicular cells are polarized:
    - With the side toward the colloid called the:
      - Apical membrane
    - And the outer side of the cell in contact with capillaries called the:
      - Basal membrane (Figure)
The synthesis of thyroid hormone is activated after binding of:
- Thyrotropin-stimulating hormone (TSH) to the basal membrane surface receptor:
  - The TSH receptor
- TSH stimulates all the steps of thyroid hormone synthesis and secretion, including:
  - Iodide transport
  - Synthesis of thyroglobulin
  - Iodination of thyroglobulin
  - Secretion of thyroid hormones
- TSH binding of the TSH receptor on the basal membrane of the thyroid follicular cell activates adenylate cyclase:
  - To increase intracellular cAMP:
    - Which activates a cascade of numerous steps in the thyroid hormone synthetic pathway
The first step is transport of iodide across the basal membrane into the follicular cell in an energy-dependent manner by the Na⁺/I symporter:
- The iodide becomes covalently attached to the precursor thyroid hormone glycoprotein:
  - Thyroglobulin:
    - This occurs at the interface between the apical membrane and the colloid by the enzyme thyroperoxidase (TPO).
The iodide is attached to the tyrosine molecules in the thyroglobulin molecule to form:
- Monoiodotyrosines (MITs) and diiodotyrosines (DITs).
  - TPO enzymatically couples two iodotyrosines to create bioactive thyroid hormones:
    - Two diiodotyrosines (DITs) = L-thyroxine (T4)
    - One monoiodotyrosine (MIT) and diiodotyrosine (DIT) =triiodothyronine (T3).
  - The T4 and T3 remain part of the thyroglobulin molecule and is stored as colloid within the interior of the follicle.
- The thyroid gland is a unique endocrine organ:because it stores large amounts of thyroid hormones as colloid that is released as needed through TSH stimulation.
- In healthy and iodine-sufficient individuals:
  - The majority of thyroid hormone is stored as T4 with a small amount, less than 20%, stored as T3.
- TSH receptor stimulation leads to colloid uptake into the cytoplasm by pinocytosis to form a cytoplasmic vesicle:
  - The cytoplasmic vesicles fuse with lysosomes to from a phagolysosome and the proteases found within the lysosome hydrolyze the peptide bonds of thyroglobulin to release T4 and T3 into the cytoplasm where it diffuses into the bloodstream.
    - Approximately 90 mcg of T4 is secreted from the thyroid each day in adults.
    - T4 and T3 travel in the circulation bound 99.97% and 99.5%, respectively, to a group of serum thyroid hormone binding proteins synthesized in the liver, which include:
      - Thyroxine binding globulin (TBG), transthyretin (also known as prealbumin), and albumin.
        
        TBGhas the highest affinity to bind thyroid hormone and is clinically the most important member of this group:
        
        TBG carries about 68% of the circulating T4 and 80% of the T3.
        
        Transthyretin, formally named prealbumin binds with a lower affinity and carries 11% of the circulating T4 and 9% of T3.
        
        Albumin has the lowest affinity for thyroid hormone but the largest capacity, binding 20% of the T4 and 11% of the T3.
      - More than 99% of thyroid hormones circulate bound to these carrier proteinsand are biologically inactive.
      - The half time of T4 in the blood is 7 to 10 days.
      - The thyroid hormones not associated with protein, free T4 and free T3, can enter the cells and are biologically active.
      - T4 is made exclusively by the thyroid gland, whereas T3 is made primarily in peripheral tissues by deiodination of circulating T4 by a group of enzymes called deiodinases:
        
        Deiodinase enzyme activity is tightly regulated to maintain a normal T3 despite fluctuations in T4.
      - T3 binds with a much higher affinity to the thyroid hormone receptor and is more biologically active than T4.
      - The activity of a specific 5′-deiodinase and the resulting T3 level can be reduced by:
        
        Hyperthyroidism
        
        Drugs:
        
        Beta-blockers
        
        Ipodate
        
        Amiodarone
        
        Dexamethasone
        
        Propylthiouracil,
        
        Malnutrition
        
        Severe illness.
      - Conversely, during hypothyroidism, the 5′ deiodinase is activated to ensure that T4 is converted to the more bioactive T3.
    - Normally, 20% of the daily T3 requirement is directly synthesized and secreted by the thyroid gland:
    - During starvation and illness:
      - The 5′ deiodinase converts the bioactive T4 and T3 to biologically inactive molecules:
        
        Reverse T3 (rT3) and 3, 3′ diiodothyronine
    - The small quantity of free T3 binds to its intranuclear thyroid hormone receptor to alter gene expression:
      - Which in turn alters cellular function and determines the thyroidal status.
      - The thyroid hormone receptor (TR) is a nuclear protein that is a member of a superfamily of receptors that bind steroid hormone such as retinoic acid, vitamin D, and estrogen.

Presentation1

Rodrigo Arrangoiz MS, MD, FACS a head and neck surgeon / endocrine surgeon / surgical oncologist and is a member of Sociedad Quirúrgica S.C at the America British Cowdray Medical Center in Mexico City:

He is an expert in the management of thyroid and parathyroid diseases.

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

#Arrangoiz

#Teacher

#Surgeon

#Cirujano

#SurgicalOncologist

#CirujanoOncologo

#CancerSurgeon

#CirujanodeCancer

#HeadandNeckSurgeon

#CirugiaEndocrina

#EndocrineSurgery

#CirujanodeCabezayCuello

#ParathyroidExpert

#ExpertoenParatiroides

#Hyperparathyroidismo

#Hiperparatiroidismo

#ThyroidExpert

#ExpertoenTiroides

http://www.cirugiatiroides.com

http://www.hiperparatiroidismo.info

http://www.sociedadquirurigca.com

Breast Cancer Screening – When to Start?

April 9, 2019 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Women with no symptoms for breast cancer should undergo mammography screening every other year:
- According to a new evidence-based guidance statement from the American College of Physicians (ACP):
  - The largest medical specialty organization in the United States.
The guidance applies to women between the ages of 50 and 74 who are at average-risk:
- The statement was published online April 9 in the Annals of Internal Medicine:
  - “The evidence shows that the best balance of benefits and harms for these women, which represents the great majority of women, is to undergo breast cancer screening with mammography every other year.”
    - This approach is also endorsed by the US Preventive Services Task Force (USPSTF).
The new guidance drew immediate fire from:
- The American College of Radiology (ACR) and Society of Breast Imaging (SBI):
  - These two radiology groups recommend women have annual mammograms starting at age 40 years and that they continue “as long as they are in good health.”:
  - The American Cancer Society (ACS) also recommends starting screening mammography at age 40.

The new ACP guideline recommends:
- Mammography starting every other year:
  - Starting at 50 years and stopping at 74 years
    - This may result in up to 10,000 additional, and unnecessary, breast cancer deaths in the United States each year:
    - This approach would also do little to nothing to address over-diagnosis or the harms of screening:
      - The ACR and SBI comment in a joint press statement.

New ACP Recommendations:
- The new ACP document is an assessment of the quality and content of seven English-language guidelines for breast cancer screening:
  - Including those from USPSTF, ACS, ACR, American College of Obstetricians and Gynecologists, Canadian Task Force on Preventive Health Care, National Comprehensive Cancer Network, and World Health Organization.
- The new ACP recommendations are for women at average risk of breast cancer:
  - This includes women:
    - Without a history of breast cancer
    - Previous diagnosis of a high-risk lesion
    - Without genetic mutations such as BRCA1/2 or another familial breast cancer syndrome
    - Without a history of radiation therapy to the chest in childhood

- In average-risk women aged 40 to 49 years:
  - Clinicians should discuss whether to screen for breast cancer with mammography before age 50 years:
    - Discussion should include the potential benefits and harms and a woman’s preferences:
      - Potential harms outweigh benefits in most women aged 40 to 49 years according to the ACP guidelines.
- In average-risk women aged 50 to 74 years:
  - Clinicians should offer screening for breast cancer with biennial mammography.The ACP guidance consists of four statements about mammography screening, as follows:
- In average-risk women aged 75 years or older or in women with a life expectancy of 10 years or less:
  - Clinicians should discontinue screening for breast cancer.
- In average-risk women of all ages:
  - Clinicians should not use clinical breast examination to screen for breast cancer.

Clarity Amid Chaos:
- The new guidance from the ACP provides “clarity and simplicity amidst the chaos of diverging guidelines,” write Joann Elmore, MD, MPH, University of California, Los Angeles, and Christoph Lee, MD, MS, University of Washington, Seattle, in an accompanying editorial.
- The editorialists congratulate the ACP for their effort to clarify the multitude of breast cancer screening guidelines:
  - However, they emphasize it is not a perfect product:
    - These guidance statements…do not clearly illuminate the full path ahead for every woman:
      - For example, the issue of breast cancer density:
        
        The ACP considers women with dense breast tissue on mammography — and no other risk factors — to be at average risk:
        
        Because just under half of all women have dense tissue on mammography, this would seem reasonable,” the editorialists opine:
        
        When the average risk of dense breast tissue is combined with other risk factors that also indicate average risk in isolation (such as early menarche, late menopausal onset, oral contraceptive or menopausal hormone therapy, or a single family member with a history of postmenopausal breast cancer), a woman may no longer be at average risk.
        
        Physicians can expect that more women will inquire about breast density as a factor that increases risk beyond the average.
- The editorialists emphasize that breast cancer screening guidelines are an ongoing project:
  - Physicians are left to use their best judgment based on available research and expert recommendations.

Major Disservice:
- Reacting to the news, Laurie Margolies, MD, radiologist, Mount Sinai Health System, New York City, said the new ACP guidance statements “are based on no new evidence…[and] are a major disservice to American women.”
  - The majority of women who are diagnosed with breast cancer are at average risk and delaying screening until age 50 will significantly delay diagnosis for many.
  - Hopefully, women are smart enough to make the decision to continue yearly screening mammography.
- The ACR and SBI also take issue with the idea of screening every other year:
  - In their joint press statement, the societies say that the ACP claims that “every other year mammography screening results in no significant difference in breast cancer mortality.”
    - “This is incorrect,” the societies say in their press statement.
    - “There have been no randomized controlled trials to test this ACP claim.
      - In fact, the NCI/CISNET models that were used by the USPSTF and the ACS actually show a major decline in deaths among women screened annually vs every other year.

Effect on Mortality
- The ACP guidance notes that pooled results from meta-analyses of randomized clinical trials:
  - Demonstrated that mammography was not associated with a reduction in all-cause mortality:
    - In their press statement, the ACR and SBI do not address that issue of overall survival:
      - Instead, they discuss breast cancer-associated mortality:
        
        They cite a recent study that showed women screened regularly for breast cancer have a 47% lower relative risk of dying from the disease within 20 years of diagnosis than those not regularly screened:
        
        Cancer. 2019;125:515-523.
        
        They also cite two large studies that showed regular mammography use “cuts the risk of dying from breast cancer nearly in half.

Ann Intern Med. Published online April 9, 2019

Rodrigo Arrangoiz MS, MD, FACS a surgical oncologist and is a member of Sociedad Quirúrgica S.C at the America British Cowdray Medical Center in Mexico City:

He is an expert in the management of breast cancer.
- If you have any questions about the screening for breast cancer please fill free to contact Dr. Arrangoiz.

20d943b1-6f20-49c3-9754-2f3756051c93

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

#Arrangoiz

#Surgeon

#Cirujano

#SurgicalOncologist

#CirujanoOncologo

#BreastSurgeon

#CirujanodeMama

#CancerSurgeon

#CirujanodeCancer

http://www.sociedadquirurigca.com

img_0832-2 img_0833-2 img_0834-2 img_0835-2 img_0836-2 img_0837-2

Recombinant Human Parathyroid Hormone 1-84 is Safe for Long-Term Use

April 8, 2019 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Natpara_R_Logo_CMYK_US_FNL_D

Recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) (Natpara):

New research has shown that Natpara is safe and effective:
- Based on data were patients used Natpara for over 6 years of continuous use for the treatment of adults with chronic hypoparathyroidism:
  - Findings from the long-term, open-label RACE extension study were presented March 26, 2019 at ENDO 2019: The Endocrine Society Annual Meeting by:
    - John P. Bilezikian, MD, professor of medicine at Columbia University, New York City.

Hypoparathyroidism is a disorder of mineral homeostasis characterized by deficient or absent parathyroid hormone:
- The associated clinical findings are:
  - Hypocalcemia, hyperphosphatemia, and reduced tubular reabsorption of calcium, often leading to hypercalciuria.
Conventional treatment with:
- Oral calcium and activated vitamin D (calcitriol):
  - Doesn’t always maintain normal serum calcium levels and also doesn’t restore other physiologic actions of the missing parathyroid hormone.
The once-daily subcutaneous injectable drug:
- Was approved by the US Food and Drug Administration in 2015 and European Medicines Agency (Natpar) in 2017:
  - The new follow-up data is important because the original phase three trial lasted only 26 weeks:
    - These patients have a lifelong disease:
      - Physician who prescribe his drug like to have long-term safety and efficacy data:
        
        It still continues to demonstrate efficacy and no safety concerns have surfaced since the original study.
  - One new finding did arise in the 6-year data that was not seen in the original phase 3 REPLACE trial:
    - Urine calcium levels eventually went down among the patients who received rhPTH(1-84):
      - Whereas those levels hadn’t previously changed significantly over 26 weeks:
        
        One of the main shortfalls of conventional therapy is that you get hypercalciuria and that can be damaging to the kidneys:
        
        So if this data indeed holds up that the urine calcium concentration will eventually fall, that will mean this is a good way to go in those individuals in whom you can’t control the urine calcium by conventional therapy and other adjunctive therapy that we use to try and bring the urine calcium down.

natpara4

Relentless Reduction in Urine Calcium Excretion Over 6-Years:
- The RACE study, an open-label extension of REPLACE and another phase 3 trial:
  - Enrolled 49 patients from 12 US centers
    - 82% were women
    - Mean age 48 years
    - Hypoparathyroidism duration of about 16 years
  - Bilezikian reported findings for 34 of those patients who had completed 72 months of the study:
    - They were started on 25 or 50 µg/day of rhPTH(1-84) and titrated up or down to a maximum of 100 µg/day depending on serum calcium:
      - The goal was to maintain the albumin-corrected serum calcium between 8 mg/dl to 9 mg/dL.
      - Oral calcium and calcitriol supplementation doses were continued and also adjusted up or down to help achieve that target.
    - The composite efficacy endpoint was:
      - The proportion of patients who achieved at least:
        
        A 50% reduction from baseline in oral calcium dose (or calcium ≤ 500 mg/day) and at least a 50% reduction from baseline in calcitriol dose (or calcitriol ≤ 0.25 µg/day):
        
        While normalizing or maintaining albumin-corrected serum calcium compared with baseline and not exceeding the upper limit of normal for the central laboratory.
    - After the first year:
      - 76% of patients had achieved the primary composite endpoint.
    - By 72 months:
      - 65% of the 34 patients who reached that timepoint met the primary endpoint:
        
        Among the 34 patients, there was a 40% reduction in oral calcium supplementation doses and a 72% reduction in calcitriol dose, while albumin-corrected serum calcium levels were maintained within the target range (mean 8.4 mg/dL at baseline and 6 years).
    - And there was a “very interesting, progressive, if not relentless,” reduction in urinary calcium excretion:
      - From hypercalciuric values (mean 357 mg/24 hours) at baseline to normal levels (213 mg/24 hours) at 6 years.
    - At the same time, there were no significant changes in serum creatinine concentrations or estimated glomerular filtration rate.
  - Average serum phosphorus levels also declined rapidly and significantly:
    - From 4.8 mg/dL at baseline and was maintained at about 4.0 mg/dL through the 6 years.
  - Calcium phosphate product also dropped quickly:
    - By an average of 9.5 mg²/dL² lower than baseline at 6 years.

No Unexpected Adverse Events:
- Adverse events were reported by most patients:
  - The most common drug-related adverse events were:
    - Nausea, hypercalcemia, and hypocalcemia.
- A quarter of the patients experienced serious adverse events:
  - But none where believed to be because of the drug.
Conclusions:
- Continuous use of rhPTH(1-84) over 6 years resulted in a:
  - Favorable safety profil
  - Was effective
  - Improved key measurements of mineral homeostasis:
    - Notably normalization of urinary calcium.

ENDO 2019. Presented March 26, 2019. Abstract OR30-1.