Editorial
From Nagoya to the World
SHINYA TOYOKUNI
pg(s) 1-2
Invited Review Articles
Gastric Cancer with Minimal Peritoneal Metastasis: Is this a Sign to Give up or to Treat More Aggressively?
YASUHIRO KODERA
pg(s) 3-10
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Peritoneal metastasis from gastric cancer is often undetectable by routine imaging studies. Even a
microscopic metastasis detected only by cytologic examination of the peritoneal washes denotes a dismal
prognosis, and surgery is ruled out as futile for patients who turn out to be cytology-positive by staging
laparoscopy. On the other hand, recent developments in cancer chemotherapy have improved the outcome of
the cytology-positive population to the point where a certain proportion of these patients survive for 5 years
through a straightforward strategy of radical surgery followed by chemotherapy. Thus, there is certainly a
role for surgeons in patients with minimal peritoneal metastasis, both in clinical practice and in clinical
trials where multimodal treatment strategies including surgery are to be explored. Even in this category
of patients, surgery in combination with various types of chemotherapy remains the only hope for a cure.
What Happens in the Brain of Schizophrenia Patients?: An Investigation from the Viewpoint of
Neuropathology
SHUJI IRITANI
pg(s) 11-28
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Studies that seek to determine the etiology of schizophrenia through pathological images and morphological
abnormalities of the brain have been conducted since the era of E. Kraepelin, and pioneers in
neuropathology such as A. Alzheimer have also eagerly pursued such studies. However, there have been
no disease-specific findings, and there was a brief era in which it was said that “schizophrenia is the
graveyard of neuropathologists.” However, since the 1980s, neuroimaging studies with CT and MRI etc.,
have been used in many reports of cases of schizophrenia with abnormal brain morphology, thus generating
renewed interest in developments within brain tissue and leading to new neuropathological studies. There
are now many reports in which, in addition to morphological observations, cell distribution and the like are
image-processed and statistically processed through computers. Due to methodological problems in making
progress in the field of cerebral pathology, we have not yet been able to observe disease-specific findings,
although there are several findings with high certainty. However, the neurodevelopmental hypothesis has
been supported as being able to reasonably explain the accumulated findings of previous studies. At the
same time, results of recent molecular-biological studies have revealed the risk genes for this disease, and
because many of those genes are associated with functions related to nerve differentiation, development,
and plasticity, there is growing interest in their correlations with cerebral pathology. We are now on the
verge of uncovering the etiology of this disease by integrating cerebral neuroimaging, molecular genetics,
and cerebral neuropathology. In that sense, neuropathological studies of this disease from new viewpoints
have become essential.
The Regulation of Sleep and Wakefulness by the Hypothalamic Neuropeptide Orexin/Hypocretin
AYUMU INUTSUKA and AKIHIRO YAMANAKA
pg(s) 29-36
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Orexins, also known as hypocretins, are neuropeptides that are exclusively expressed by neurons in the
lateral hypothalamic area. Although originally recognized as regulators of feeding behavior, orexins are
now mainly regarded as key modulators of the sleep/wakefulness cycle. In addition, anatomical studies of
neural networks and analyses of transgenic mice have revealed integrated roles for orexin neurons in the
coordination of emotion, energy homeostasis, and the reward system. A functional link between the limbic
system and orexin neurons may be important for increasing vigilance in response to emotional stimuli.
These findings suggest that orexin neurons relay information about an organism’s environment to maintain
the proper amount of sleep and wakefulness in animals.
Original Papers
Cerebral Hemorrhage and Cerebral Infarction in 30 Cases of Adult Moyamoya Disease:
Comparison between Conservative Therapy and Superficial Temporal Artery-Middle Cerebral
Artery Anastomosis
HIROFUMI OYAMA, AKIRA KITO, HIDEKI MAKI,
KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 37-40
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To clarify the effect of surgery on the prevention cerebral hemorrhage in adult moyamoya disease, we
compared postoperative courses between superficial temporal artery-middle cerebral artery (STA-MCA)
anastomosis and conservative therapy. The study subjects were 30 adults with moyamoya disease. Unilateral
STA-MCA anastomosis was conducted in 7 of these 30 cases, and bilateral STA-MCA anastomosis was
conducted in 8 of these 30 cases. Therefore, anastomosis was performed in a total of 23 sides. The
postoperative clinical course was observed for more than 5 years after the STA-MCA anastomosis.
Cerebral hemorrhage occurred after operation in 2 sides (8.7%) among the 23 sides that received STAMCA
anastomosis. On the contrary, hemorrhage occurred during conservative therapy in 5 sides (13.5%)
among 37 non-operation sides (no significance in χ2 test). Cerebral infarction occurred in 3 sides (13%)
among 23 sides treated with STA-MCA anastomosis. However, the infarction occurred in 2 sides (5.4%)
among the 37 non-operation sides (no significance in χ2 test).
Cerebral hemorrhage tended to occur less frequently after STA-MCA anastomosis, and bypass surgery
was suggested to have some beneficial effect in preventing cerebral hemorrhage in adult moyamoya disease.
However, it was revealed that STA-MCA anastomosis exacerbated the brain ischemia. Therefore, strict
management is mandatory in the perioperative period.
Atherothrombotic Lesion of the Middle Cerebral Artery: Report of 21 Cases with Stenotic and
Obstructive Lesions
HIROFUMI OYAMA, AKIRA KITO, HIDEKI MAKI,
KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 41-46
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This was a retrospective analysis of 12 consecutive cases of middle cerebral artery stenosis and 9
consecutive cases of middle cerebral artery occlusion that presented to our hospital with acute cerebral
ischemia. The degree and area of the cerebral infarctions were assessed with the Alberta Stroke Program
Early CT Score (ASPECTS) and ASPECTS-DWI (APSECTS with assessment of white matter lesion
using diffusion-weighted image). As for cerebral infarctions in the region of the perforating artery, lesions
that were more than 20 mm long in the caudal-cranial direction were diagnosed as branch atheromatous
disease (BAD).
Activities of daily living (ADL) were poorer in the cases with lower ASPECTS and ASPECTS-DWI.
ADL tended to be worse in cases with BAD than in those without. The prognosis was significantly poorer
in the group with ASPECTS≤7 points. ASPECTS tended to be lower in cases with BAD than in those
without. ADL, ASPECTS and the presence of BAD were not significantly different between the stenosis
and obstruction groups.
In summary, the neurological prognosis was dependent on the extent of the cerebral infarction and was
related to BAD to some extent. These findings will be important when considering medical treatment at
the outpatient clinic setting.
Impact of Back Muscle Strength and Aging on Locomotive Syndrome in Community Living Japanese
Women
KENICHI HIRANO, SHIRO IMAGAMA, YUKIHARU HASEGAWA,
NORIMITSU WAKAO, AKIO MURAMOTO and NAOKI ISHIGURO
pg(s) 47-56
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The Japanese Orthopaedic Association has proposed the term locomotive syndrome (LS) to designate
a condition of individuals in high-risk groups with musculoskeletal disease who are highly likely to
require nursing care. This study investigates the influence of spinal factors on LS in Japanese females.
A total of 187 women >50 years old were enrolled in the study. Those answering yes to least one of
the 7 categories in the self-assessment checklist for LS were defined as having LS. We evaluated lateral
lumbar radiographs, sagittal parameters, sagittal balance using the spinal inclination angle (SIA) as an
index, spinal range of motion (ROM) as determined with SpinalMouse®, back muscle strength (BMS),
and body mass index (BMI). Age, BMI, BMS, SIA, sacral slope angle (SSA), and lumbar spinal ROM
showed significant correlations with LS. Multiple logistic regression analysis indicated that an increase in
age (OR 1.054, p<0.05) and a decrease in BMS (OR 0.968, p<0.01) were significantly associated with
LS. Age had significant negative correlations with BMS, SSA, thoracic and lumbar spinal ROM, and it
had positive correlations with BMI, SIA, and lumbar kyphosis. BMS had significant negative correlations
with age, SIA, thoracic and lumbar kyphosis, and it had positive correlations with SSA, lumbar and total
spinal ROM. An increase in age and a decrease in BMS may be the most important risk factors for LS
in Japanese women. Back muscle strengthening and spinal ROM exercises could be useful for improving
the status of an individual suffering from LS.
Simple and Rapid Quantitation of 21 Bile Acids in Rat Serum and Liver by UPLC-MS-MS: Effect
of High Fat Diet on Glycine Conjugates of Rat Bile Acids
YUDAI SUZUKI, RINA KANEKO, MINA NOMURA, HISAO NAITO, KAZUYA KITAMORI,
TAMIE NAKAJIMA, TADASHI OGAWA, HIDEKI HATTORI, HIROSHI SENO and AKIRA ISHII
pg(s) 57-72
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In this report, we present a simple and rapid method for analysis of 21 kinds of bile acids and the
conjugates in rat serum and liver samples by ultra-performance liquid chromatography-tandem mass
spectrometry (UPLC-MS-MS) in the negative ionization mode, using cholic-2, 2, 4, 4-d4 acid as internal
standard. After liquid-liguid extraction from serum and liver samples, specimens were analyzed by UPLC
equipped with an Acquity TQD tandem quadrupole mass spectrometer. All of the 21 bile acids were
sufficiently separated within 5 min. For most bile acids, calibration curves showed good linearities in the
range of 0.25 to 5000 ng/mL for serum samples, 2.5 ng/g to 50 mg/g for liver samples. The limits of
detection (LOD) were estimated to be less than 0.25 to 7.5 ng/mL in serum, less than 2.5 to 10 ng/g in
liver samples. The present method was validated with respect to repeatability; the coefficient of variation
(CV) values were less than 26.7% in the serum and 25.9% in the liver. In the animal study, we compared
21 bile acids in the serum and liver samples of the stroke-prone spontaneously hypertensive (SHRSP)
rats fed with control (SP) diet or high-fat and high-cholesterol-containing (HFC) diet. By feeding with
HFC diet, the glycine conjugates of some bile acids significantly increased and the taurine conjugate of
ulsodeoxicolate (TUDC) decreased in serum and liver samples. Our results suggest that the change of bile
acid profiles could be applied for the diagnosis of non-alcoholic fatty liver disease (NAFLD).
DPP4 Genetic Variants Influence Baseline Prostate-Specific Antigen Levels: The J-MICC Studyg
TAKAHIRO HIGASHIBATA, MARIKO NAITO, ATSUYOSHI MORI, NORIYO OZAWA,
MASATOSHI FURUTA, RUMI TSUCHIYA, ERINA KOYAMA, EMI MORITA, SAYO KAWAI,
RIEKO OKADA, GUANG YIN, KENJI WAKAI and NOBUYUKI HAMAJIMA
pg(s) 73-80
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Prostate specific antigen (PSA) testing plays a major role in prostate cancer screening; however, the
low positive predictive value of PSA testing leads to many unnecessary biopsies. Genetic background is
one of factors that could cause it. That’s why an association between genetic background and PSA levels
should be elucidated. This study aimed to investigate whether DPP4 genetic variants are associated with
baseline PSA levels. A cross-sectional study was performed on 2,074 Japanese men aged between 35 and
69 in the Shizuoka area from the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. Three
DPP4 tagging single nucleotide polymorphisms (SNPs) were selected for genotyping: rs3788979 (A/G),
rs7608798 (T/C), and rs2268889 (A/G). Higher mean serum PSA levels were significantly associated with
an increase in the number of the rs7608798 C allele (p for trend = 0.02). A stratified analysis by age
groups demonstrated that PSA levels had positive significant trends with the numbers of the minor alleles
of rs3788979 or rs7608798 in the oldest group (men aged between 60 and 69) (p for trend=0.004 for
rs3788979 and p for trend=0.001 for rs7608798). Haplotype analysis showed that the C-A (rs7608798-
rs2268889) haplotype was significantly associated with increased PSA levels (p=0.006), compared with
the most common haplotype, T-A. In summary, our study suggests that DPP4 genetic variants influence
baseline PSA levels, especially in men aged between 60 and 69.
Glucocorticoid-Induced Hypertension and Cardiac Injury: Effects of Mineralocorticoid and
Glucocorticoid Receptor Antagonism
TAKUYA HATTORI, TAMAYO MURASE,
ERIKA IWASE, KEIJI TAKAHASHI, MASAFUMI OHTAKE, KOJI TSUBOI,
MAYUKO OHTAKE, MASAAKI MIYACHI, TOYOAKI MUROHARA and KOHZO NAGATA
pg(s) 81-92
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Glucocorticoids are widely administered for the treatment of various disorders, although their long-term
use results in adverse effects associated with glucocorticoid excess. We investigated the pathophysiological
roles of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the cardiac changes
induced by exogenous corticosterone in rats. Corticosterone or vehicle was injected twice daily in rats from
8 to 12 weeks of age. The effects of the GR antagonist RU 486, the MR antagonist spironolactone, or both
agents on corticosterone action were also determined. Corticosterone induced hypertension, left ventricular
(LV) fibrosis, and LV diastolic dysfunction. Neither RU 486 nor spironolactone affected corticosteroneinduced
hypertension, whereas spironolactone, but not RU 486, attenuated the effects of corticosterone on
LV fibrosis and diastolic function. Corticosterone also increased cardiac oxidative stress and inflammation
in a manner sensitive to spironolactone but not to RU 486. The corticosterone-induced LV atrophy was not
affected by either RU 486 or spironolactone. Our results implicate MRs in the cardiac fibrosis and diastolic
dysfunction, but not MRs or GRs in the cardiac atrophy, induced by corticosterone. Neither MRs nor GRs
appear to contribute to corticosterone-induced hypertension.
No Association between MTHFR C677T and Serum Uric Acid Levels among Japanese with ABCG2
126QQ and SLC22A12 258WW
YUKAKO HINOHARA,
MARIKO NAITO, RIEKO OKADA, GUAN YIN, TAKAHIRO HIGASHIBATA,
TAKASHI TAMURA, SAYO KAWAI, EMI MORITA, KENJI WAKAI,
HIROTAKA MATSUO, ATSUYOSHI MORI and NOBUYUKI HAMAJIMA
pg(s) 93-100
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Several genome-wide association studies (GWAS) have revealed that single nucleotide polymorphisms
(SNPs) of ABCG2 and SLC22A12 were strongly associated with serum uric acid (SUA), but those of
methylene tetrahydrofolate reductase (MTHFR) were not. However, there were several studies indicating
the association with MTHFR C677T polymorphism. This study examined the association with the
polymorphism, taking into account the genotypes of ABCG2 Q126X and SLC22A12 W258X. Subjects
were 5,028 health checkup examinees of Seirei Preventive Health Care Center (3,416 males and 1,612
females) aged 35 to 69 years, who participated in the Japan Multi-Institutional Collaborative Cohort Study
(J-MICC Study). Hyperuricemia was defined as SUA equal to 7 mg/dL or over. The genotype frequency
was 35.9% for CC, 48.1% for CT, and 16.0% for TT, being in Hardy-Weinberg equilibrium (p=0.90).
Among 4,425 participants with ABCG2 126QQ and SLC22A12 258WW who were not under medication
for hyperuricemia, the mean SUA was 5.6 mg/dL, 5.6 mg/dL, and 5.7 mg/dL, respectively. When 114
participants with ABCG2 126QQ and SLC22A12 258WW under medication for hyperuricemia were included
in hyperuricemia cases, the sex-age adjusted odds ratio (OR) of hyperuricemia was not significant; OR=1.00
(95% confidence interval, 0.89–1.24) for CT genotype and OR=0.98 (0.84–1.32) for TT genotype, relative
to CC genotype. The present study indicated no association between SUA and MTHFR C677T genotype,
after the influences of ABCG2 Q126X and SLC22A12 W258X were removed.
Surface Markers and Gene Expression to Characterize the Differentiation of Monolayer Expanded
Human Articular Chondrocytes
TAKASHI HAMADA,
TADAHIRO SAKAI, HIDEKI HIRAIWA, MOTOSHIGE NAKASHIMA,
YOHEI ONO, HIROHITO MITSUYAMA and NAOKI ISHIGURO
pg(s) 101-112
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Autologous chondrocyte implantation (ACI) is a method of cartilage repair. To improve the quality
of regenerated tissue by ACI, it is essential to identify surface marker expression correlated with the
differentiation status of monolayer expanded human articular chondrocytes and to define the index for
discriminating dedifferentiated cells from monolayer expanded human articular chondrocytes. Normal human
articular chondrocytes were cultured in monolayer until passage 4. At each passage, mRNA expression of
collagen type I, II, and X and aggrecan was analyzed by real-time quantitative PCR, and the surface marker
expression of CD14, CD26, CD44, CD49a, CD49c, CD54, and CD151 was analyzed by fluorescenceactivated
cell sorting (FACS). The ratios of mRNA levels of collagen type II to I (Col II/Col I) represented
the differentiation status of chondrocytes more appropriately during monolayer culture. The surface marker
expression of CD44, CD49c, and CD151 was upregulated according to the dedifferentiation status, whereas
that of CD14, CD49a, and CD54 was downregulated. The most appropriate combination of the ratio of Col
II/Col I was CD54 and CD44. Cell sorting was performed using a magnetic cell sorting system (MACS)
according to CD54 and CD44, and real-time quantitative PCR was performed for the cell subpopulations
before and after cell sorting. The expression of collagen type II and aggrecan of the chondrocytes after
MACS was higher than that before sorting, but not significantly. The mean fluorescence intensity (MFI)
ratio of CD54 to CD44 could be an adequate candidate as the index of the differentiation status.
Note
Reappraisal of Importance of the Left Internal Mammary Artery to the Left Anterior Descending
Artery in Improving Mid-Term Outcome in Patients with Severe Left Ventricular Dysfunction
MIN-HO SONG
pg(s) 113-120
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We sought to investigate the effects of the left internal mammary artery anastomosed to the left anterior
descending artery for improving mid-term outcome in patients with severe left ventricular dysfunction.
Twenty consecutive coronary artery bypass grafts performed by a single surgeon for less than 35% ejection
fraction patients were reviewed retrospectively from April 2000 to November 2008. There was one
perioperative death (5.0% mortality). The mean survival was 55 months with an actual 5-year survival rate
of 75%. Echocardiography showed the ejection fraction improved to 10.7±0.32% (p < 0.01). The strongest
correlation was observed between both the flow and the pulsatile index of the left internal mammary artery
measured intraoperatively by transit time flow meter and the postoperative ejection fraction improvement
(R2=0.737 and 0.639, respectively). We reappraised the mid-term beneficial effects of the internal mammary
artery anastomosed to the left anterior descending artery in patients with severe left ventricular function.
Case Reports
Advantage of a More Central Incision onto Left Atrium by Using Ultrasonic Scalpel
MIN-HO SONG
pg(s)121-124
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Exposure of the mitral valve is of critical importance in mitral valve surgery. The mitral valve is located
near the interatrial groove. As we accumulated experience and learned from embryology, we found that
a more central left atriotomy was advantageous, and was made possible by interatrial groove dissection
using an ultrasonic scalpel. This crucial finding prompted us to report the technique.
A Surface-Based Hemangioma of the Radius Which Posed Radiological Diagnostic Difficulties
TAKAAKI SHINOHARA, MASAHIRO TATEBE, MICHIRO YAMAMOTO,
SHIGERU KURIMOTO and HITOSHI HIRATA
pg(s) 125-130
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Surface-based bone hemangiomas are uncommon, mostly occurring in long bones of the lower extremities.
Radiographic surface-based bone hemangioma images may present various features that provide a
diagnostic challenge. We report a case of surface-based hemangioma of the radius that posed radiological
diagnostic difficulties. The tumor size was small and the cortical reaction was subtle. MRI findings were
nonspecific and angiography was useful in the assessment of painful but less obvious surface-based bone
hemangioma. The patient’s pain improved following surgery and no tumor recurrence was observed at 3
years after surgery.
Stabilizing Incomplete Reduction of the Radial Head Using a Hinged Splint: Conservative Treatment
for a Monteggia Equivalent Lesion
TAKAAKI SHINOHARA, EMIKO HORII,
MASAHIRO TATEBE, MICHIRO YAMAMOTO, SHIGERU KURIMOTO and HITOSHI HIRATA
pg(s) 131-138
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Radial head dislocation associated with plastic bowing of the ulna is classified as a Monteggia equivalent
lesion. This injury in children can be treated by closed reduction, but manipulative reduction may not
completely correct plastic bowing of the ulna. We encountered two cases of incomplete reduction in which
the radial head was reduced in a supination position, but redislocated during rotation from neutral to a
pronation position. The patients were treated conservatively using an adjustable hinged elbow splint. Plain
radiography at 6 weeks after incomplete closed reduction showed that the radial head was reduced in all
positions from supination to pronation; thus, both patients had good outcomes. Our method is non-invasive
and may be an option for treatment of incomplete reduction of radial head dislocation with acute plastic
bowing of the ulna.
Selective IgA Deficiency Mimicking Churg-Strauss Syndrome and Hypereosinophilic Syndrome: A
Case Report
NORIYUKI TAKAHASHI, TAKESHI KONDO,
MAMIKO FUKUTA, AYUMU TAKEMOTO, YUICHIRO TAKAMI, MOTOKI SATO,
TAKAFUMI ANDO, NAOZUMI HASHIMOTO, TOMIO SUZUKI, JUICHI SATO,
MASAHIRO YAMAMURA and NOBUTARO BAN
pg(s) 139-146
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Selective IgA deficiency (SIgAD) is the most common type of primary immunoglobulin deficiency. Most
individuals with SIgAD are asymptomatic. However, some patients are associated with allergic and autoimmune
disease. SIgAD is included in the list of differential diagnoses of eosinophilia. We experienced a
patient who initially presented with abdominal pain and eosinophilia. A >1-year follow-up revealed SIgAD,
and we had difficulty differentiating it from Churg-Strauss syndrome (CSS) or hypereosinophilic syndrome
(HES). A 66-year-old Japanese male presented with a history of recurrent abdominal pain. A diagnostic
work-up revealed eosinophilia, eosinophilic gastritis, eosinophilic pneumonia, and SIgAD over 1 year of
clinical observation. He also suffered from asthma and sinusitis. Anti-neutrophil cytoplasmic antibody was
negative and vasculitis was not detected in the obtained tissue specimens of stomach, lung, nose and skin.
The patient showed no evidence of drug ingestion, parasitic infections, or malignant neoplasms. Although
we cannot rule out prevasculitic CSS and idiopathic HES, the whole clinical picture in this patient can
be explained most consistently by SIgAD.
Impalement Injury to the Left Buttock with Massive Bleeding: A Case Report
SHINGO OYA, KANJI MIYATA, NORIHIRO YUASA, EIJI TAKEUCHI,
YASUTOMO GOTO, HIDEO MIYAKE, KEIICHI NAGASAWA and YOICHIRO KOBAYASHI
pg(s) 147-152
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A 67-year-old man fell from the second floor of his home and was impaled on an iron pipe used
for a garden stake. The pipe was 2 cm in diameter and had entered his left buttock to his anus. A plain
abdominal X-ray film showed that the tip of the pipe was located in front of the 4th lumbar vertebra, so the
penetration distance was 30 cm. An emergency operation was performed for hemorrhagic shock. Laparotomy
revealed massive intra-abdominal bleeding, injuries of the sigmoid and transverse mesocolon, superior rectal
artery, and the first part of the duodenum. Because of suspected lower rectal injury, division of the upper
rectum, closure of the rectal stump, and sigmoidostomy were performed. Gauze packing into the pelvic
cavity was performed for uncontrollable bleeding. All the gauze was postoperatively removed from the
drain wound without laparotomy. Six months after the operation, he underwent a second operation including
anastomosis of the descending colon and lower rectum, which allowed him to live a normal daily life.
Hypothesis Paper
New Hypothesis on the Origin of Metastases
NICOLA SCHISCHMANOV
pg(s) 153-159
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A new hypothesis for the origin of metastases is presented. It assumes that a cancer-transformed gene
in a primary tumour is incorporated in its identical form via a virus-vector function into biologically potent
recipient cells in other organs, such as stem cells, multipotent cells or cells in an early phase of division.
The origin of metastases may thus possibly occur via a genetic pathway.