ISSN0535-1405

No. 507

September 30, 2021
Published by International Medical Society of Japan,
Chairman, Board of Directors: Kenichi Ishibashi, MD, PhD
Editors: K. Ito, MD, PhD, T. Kondo, MD, PhD,
K. Ichihashi, MD, PhD, T. Murakami, PhD, R.Nagai, MD, PhD,
I. Taniguchi, MD, PhD, and T. Yamazaki, MD, PhD
3F MK Sangenjaya Building, 1-15-3 Kamiuma, Setagaya-ku,Tokyo154-0011,Japan.
TEL 03(5486)0601 FAX 03(5486)0599 E-mail: imsj@imsj.or.jp https://www.imsj.or.jp/

The 450th International Symposium on Therapy
The 450th International Symposium on Therapy washeld by the Zoom Webinar on July 15, 2021. Dr. Koichi
Ito, Managing Director of the International Medical
Society of Japan (IMSJ), presided over the meeting.

The latest treatment of thyroid disease～ From the aspect of internal medicine and surgery ～Introductory Message from the Chair
Koichi Ito, MD, PhDManaging Director, IMSJ

Thank you for coming here today. Our hospital offers
the most advanced treatment for thyroid diseases.
Now, let me introduce our hospital staff to you.
Firstly, Dr. Ai Yoshihara is the medical directorof internal medicine. She will speak about"Hypothyroidism and Pregnancy." Hypothyroidism
is predominantly present among women. It often
coincides with childbearing age. Previously,
pregnancy complicated with hyperthyroidism wasa significant issue. But we have resolved it throughmany years of clinical experience. Nowadays,
established evidence suggests that childbirth
in a hypothyroid state is likely to impair brain
development in children. Therefore, it becomes
essential to call a thyroid doctor to cooperatewith a fertility specialist and a gynecologist. Our
specialists' mission, for now, is to fine-tune thethyroid-stimulating hormone flow while controlling
the TSH amount within the typical values. You willhear shortly how the team is trying to exploit theirexpertise.
Secondly, Dr. Chie Masaki, a staff member of thesurgery department, will talk about the "treatment
surgery of thyroid cancer." The overwhelming

majority of thyroid cancer is papillary carcinomas
with low biological malignancy. A single treatment
with surgery can produce an excellent prognosis.
Currently, micropapillary cancer with the 1 cm orless central axis is subject to a follow-up observation
under a secured medical care system. As toadvanced cancer, we have proactively performed
total thyroid surgery and internal radiotherapy.
But in some cases, additional treatment is
impossible due to insufficient isotope accumulation.
Under such circumstances, molecular-targeteddrugs have emerged as new cancer therapeutic
drugs. We use them aggressively. You will soonhear how we are racking our brains to provide thebest treatment.

LectureⅠ
Hypothyroidism and Pregnancy
Ai Yoshihara
Medical Director of Internal Medicine
Division of internal medicine, Ito Hospital
The reference value ranges of thyrotropin (TSH),
free triiodothyronine, and free thyroxin change
throughout pregnancy, mainly because ofincreases in estrogen, thyroid-binding globulin,
and human chorionic gonadotropin levels. In thefirst trimester, maternal hCG directly stimulates TSH
receptors, thereby increasing thyroid hormone
production and resulting in a subsequent reduction
in serum TSH concentration. Thus, women havelower serum TSH concentrations during pregnancy
than before pregnancy. TSH reference ranges
vary among racial and ethnic groups, and they

Page 7

greatly depend on iodine intake. Serum TSH
measurements remain the principal means ofassessing maternal thyroid status, and reference
ranges should be based on values obtained inhealthy thyroid-antibody-negative pregnant
women with optimal iodine intake and no thyroid
illness. It is recommended that local population
data be used to assess population-based trimesterspecific TSH reference value ranges. The upper limitof the normal range of TSH values measured in thefirst trimester in our hospital is 2.56 μIU/ml.
Overt hypothyroidism during pregnancy has
consistently been shown to be associated with anincreased risk of adverse pregnancy complications,
including pregnancy loss, gestational hypertension,and placental abruption. Thyroid hormone isessential for fetal brain development, which
begins early in gestation and is totally dependent
on the maternal thyroid hormone that crosses
the placenta. One study conducted on
pregnant hypothyroid women showed impaired
neurocognitive development in their offspring incomparison with the offspring of pregnant euthyroid
women. Adequate thyroid replacement withlevothyroxine (LT4) prevents the adverse outcomesof pregnant hypothyroid women and their offspring.
Subclinical hypothyroidism (SCH) is a condition inwhich thyroid hormone levels remain within theirnormal ranges, but the TSH level is above theupper limit of the reference range. SCH during thefirst trimester has been reported to be associatedwith increased maternal and fetal complications,
including increased rates of fetal loss, pre-eclampsia,
placental abruption, and preterm delivery.
A prospective study conducted in Italy reported
finding that euthyroid pregnant women who
were TPOAb-positive developed impaired thyroid
function that was associated with an increased
risk of miscarriage and premature delivery., andthat LT4 replacement therapy reduced the rateof miscarriage and premature delivery. The samegroup of investigators conducted a study on TPOAbnegative pregnant women and found a significantly
higher rate of spontaneous fetal loss in the womenwhose TSH levels were between 2.5 and 5 mIU/L in
the first trimester compared with those whose TSHlevels were <2.5 mIU/L. Based on these findings, theAmerican Thyroid Association and the European
Thyroid Association made the goal of LT4 treatment
the normalization of maternal serum TSH values towithin their trimester-specific pregnancy reference
ranges: first trimester, 0.1–2.5 mIU/L; second trimester,
0.2–3.0 mIU/L; third trimester, 0.3–3.0 mIU/L. In 2017,
the American Thyroid Association recommended LT4
replacement for TPOAb-positive women with a TSHlevel greater than the pregnancy-specific reference
range, or a TSH level >2.5 μIU/ml when no local
specific range is available, and for TPOAb-negative
women with a TSH level greater than the pregnancyspecific reference range, or a TSH level >4.0 μIU/ml

International Medical News

when no local specific reference range is available.
In addition, the American Thyroid Association
recommended LT4 therapy for SCH women seeking
pregnancy by means of artificial reproduction
technology who had a TSH level elevation to >2.5
mU/L and stated that the goal of treatment is toachieve a TSH concentration <2.5 mU/L.
Thyroid autoimmunity has also been reported to
be associated with fetal loss and preterm delivery,
and one of the hypotheses proposed to explainthese complications is that mothers with thyroid
autoimmunity tend to have an impaired thyroid
response to human chorionic gonadotropin.
Theoretically, treating SCH by LT4 supplementation
should reduce the risk of adverse pregnancy
outcomes, but there have been discrepancies
among the results of studies on the effect of LT4
supplementation. Some studies have reported
beneficial effects of LT4 supplementation,
while others have shown no significant effects
on miscarriage rates. The Japanese Thyroid
Association is currently attempting to develop
clinical guidelines for the treatment for SCH before
conception and during pregnancy. Further large
randomized controlled trials are needed to beable to draw definite conclusions in regard to thetreatment of SCH before and during pregnancy.

LectureⅡ
Treatment Strategy of Thyroid Cancer～ Now and beyond focused on Molecular
Targeting Drugs ～Chie Masaki MD,
Medical Staff
Department of Surgery, Ito Hospital
Thyroid cancer is well known to have low causespecific mortality, but morbidity has recently been
increasing despite stable mortality worldwide. The
problem of “overdiagnosis and overtreatment”
has been raised, and restriction of diagnosis byfine needle aspiration cytology and of surgicaltreatment has been proposed worldwide. “Active
surveillance (AS) for low-risk T1aN0M0 papillary
thyroid carcinoma”, first advocated in Japan, is
now spreading globally.
On the other hand, there are certainly patientswith advanced cancer who progress to fatal
outcomes, though in limited numbers. Patientswith distant metastases have had no other choicethan to receive total thyroidectomy followedby radioactive iodine (RAI) therapy until now.
The long-awaited molecular-targeted therapy
for thyroid cancer started with sorafenib in 2014,
followed by lenvatinib and vandetanib, whichwere approved in 2015. They all are classified

Page 8International Medical Newsas tyrosine kinase inhibitors (TKIs), with effects on
multiple sites of the molecular pathway. These
three drugs are now indicated for “unresectableadvanced thyroid cancer (RAI refractory in thecases of differentiated cancer)”.
Along with this, postoperative surveillance methods
for thyroid cancer patients in the high-risk groupare also changing. More frequent morphologicalevaluation by CT and PET-CT examinations has
been performed, and multidisciplinary treatment
including surgery and radiation therapy for
distant metastases has been actively provided.
Pharmacotherapy for thyroid cancer is notindicated only because of the presence of distantmetastases, unlike many other malignancies,
because of the relatively long survival after theappearance of distant metastasis. Therefore, theoptimal timing for starting TKIs remains unresolved,
despite repeated discussions.
Our hospital specializes in the full spectrum of
thyroid cancer treatment, from diagnosis andsurgery to radioiodine internal therapy andpharmacotherapy. TKI treatment has been given
to more than 100 patients so far, with a 2-year
survival rate of 51% and progression-free survival of
13.8 months in patients treated with lenvatinib. The
factors associated with prognosis have been foundto be performance status at treatment initiation,
tumor-related symptoms, and tumor diameter.
Long-term continuation of each TKI is important toobtain long-term survival due to the high frequencyof adverse events and the limited number ofavailable drugs.
In addition to the cancer-specific drugs describedabove, the number of available drugs that are
not restricted to cancer-derived tissues is also
expanding. Thyroid cancer is well known to have arelatively high frequency of actionable genes that
can access therapeutic targets. Promising target
molecules include NTRK, RET, and BRAF. Some drugs
such as NTRK inhibitors, RET inhibitors, combination
BRAF inhibitors and MEK inhibitors, and combination
BRAF inhibitors and immune checkpoint inhibitors
are now being developed. The possibility of cure,safe use for advanced cancer patients, and low
frequency of side effects are the ideals for anticancer drugs. Some reports have shown the safety
and efficacy of drugs that meet these conditions.
Furthermore, cancer multi-gene panel testing has
been covered by insurance since 2019 in Japan.
The testing can be performed in only a limited
number of facilities, and only a limited number ofpatients have access to available drugs basedon the testing at the moment. However, greater
proliferation of precision medicine is expected in
the future as experience accumulates.
The treatment strategy for thyroid cancers involves
understanding that the prognosis is good after theappearance of distant metastases and that RAI
is available. Therefore, the next issue is when to

consider cancer multi-gene panel testing. There
are also unique characteristics of thyroid cancer.
For instance, there can be a time delay between
the first surgery and when tissue samples for genetic
testing need to be obtained, and even when
genetic information is actually desired, it is often
difficult to sample metastatic lesion sites becauseof the anatomical features.
Thus, in considering the strategy for thyroid cancer
treatment, it will be necessary to find answers to
the issues that we face now and in the future.

Discourse
Introduction of the speaker of discourse
Koichi Ito, MD, PhD
Managing Director, IMSJ
We have the honor to invite Mr. Masato Mizuno asa speaker today.
Mr. Mizuno graduated from Konan University's
Economics Department and finished Science at
Carthage College, Wisconsin, USA. He served
as the third president and chairman of Mizuno
Corporation, a sports equipment manufacturer.
Notably, he spends a lot of time on social services,
including sports, the Olympics, the Boy Scouts, andthe Rotary Club.
Mr. Mizuno has been a member of the International
Olympic Committee in the sections of sports and theenvironment for 20 years since 1996. He will deliver alecture about his long-standing research theme.

Discourse: The measures for the SDGs.
Masato MIZUNO
Senior Corporate Adviser
Mizuno Corporation
I would like to talk with you today requested
by Dr. Koichi Ito, the director of the Thyroid
Disease Hospital and a fellow of the Tokyo RotaryClub.  Humankind is in danger of extinction
due to climate change caused by global
warming.  Today's talk is about the United Nationsled SDGs, the Sustainable Development Goals.
Ecosystems on Earth are expected to become
extinct in the near future.  The United Nations has
set 17 items as sustainable development goals
from 2015 to 2030 in order to systematize and put
into practice what humankind can do to extend
extinction as much as possible.  We are requesting
governments, organizations, and companies ineach country to scrutinize what they can do, set
numerical targets, and implement them.
From the middle of the 18th century to the 19th

Page 9century, mass production due to the Industrial
Revolution and convenience of life due to many
inventions progressed at an accelerating rate.
The population of the earth at the beginning of
the 20th century was 1.6 billion, 100 years later,
6.4 billion at the beginning of the 21st century,
the population has quadrupled in the last 100
years, and the world population has continued
to grow in the next 20 years, food, water andhealth. , Medical care, education, energy sources,
ecosystems, social systems, etc.  While enjoying
a very convenient era with advanced scientificcivilization, global warming has occurred due tothe large amount of carbon dioxide generated
by using fossil fuels as an energy source, and theglobal ecosystem and humankind have become
extinct due to major climate change.
Even now, global warming due to the large
consumption of fossil fuels has caused remarkableclimate change beyond imagination andhas become a major threat to the extinctionof humankind.  The glaciers in the world are
disappearing, and the permafrost in Siberia
is melting and methane gas, which has agreenhouse effect 23 times that of CO2, is blowing
up from below.  Rising sea surface temperaturesgenerate a large amount of water vapor, causing
huge typhoons, localized heavy rains, breaking
the food chain of marine resources, and drasticallyreducing fishery resources.  American tornadoes
have become bigger than ever, and tornado
damage has been reported even in Japan, where
there were no tornadoes.  It causes heavy rains,
floods, landslides, and damage to agriculture suchas forest fires and droughts.
The United Nations has been holding the United
Nations Framework Convention on Climate
Change (COP) every year since the Earth Summit
in Rio in 1992.  I planned the Millennium Golds from2000 to 2015, but it didn't go as expected.  TheUnited Nations is strongly working on the SDGs from2015 to 2030, as the damage caused by global
warming and climate change is becoming more
prominent worldwide.  
These 17 items
1. Eliminate poverty
2. Zero hunger
3. Health and welfare for all
4. High quality education for everyone
5. Achieve gender equality
6. Safe water and toilets around the world
7. Energy for everyone
8. Both job satisfaction and economic growth
9. Foundation of industry and innovation
10. Eliminate inequalities in people and countries
11. Creating a town where you can continue to live
12. Responsibility to make, responsibility to use
13. Take concrete measures against climate changeInternational Medical News

14. Protect the abundance of fish
15. Protect the richness of the land
16. Peace and justice for all
17. Achieve goals through partnership
In addition to global warming countermeasures,
there are basically a list of measures to live a healthy
life. Currently, there are 87 democracies and 92
non-democratic countries on the planet, and there
are challenges to be solved such as human rights
issues and the gap between rich and poor.
In any case, we must do our best as we are indanger of extinction.  It is time for social activities andcorporate activities to change from greedy capitalism
to public interest ethical capitalism, democraticnational governance in which all nations decidesoundly by voting by the people, and corporate
governance that does not tolerate injustice.
Let's solve many difficult problems with ingenuity
and continuity, and cooperate so that the earth
can be sustained for as long as one day.
We want to keep planting apple trees cheerfullyeven when the last day of the earth comes.