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MEDICAL FOREFRONT
Information and Updates for Doctors in the Community
Spring 2008
Edited by Prof. Shmuel Shapira MD MPH
Deputy director-general, Hadassah Medical Organization
Director Hebrew university Hadassah School of public Health
Dear Colleagues,
The scope of reports that appear in this issue represents a defined area of accomplishment and innovation. For example, the benign but annoying condition of rhinosinusitis is described. Today, Hadassah offers relatively simple treatments that help solve the problem. At the other extreme, there are life-threatening and extreme conditions such as malignant tumors and stroke. In all these, Hadassah innovates at the micro-technical level. Here too, skills, experience and the tools make the difference (see, for example, the case of clot removal).
Hadassah also stands at the cutting edge of research and constantly updates itself. This is exemplified by the article dealing with the effects of bariatric surgery on recovery from diabetes. To implement this new finding, the public and doctors in the community must become aware of it.
In addition, we all know of situations between the routine and the rare in which the patient must be made aware of acute conditions such as a heart attack or cerebral event. It is vital for the patient to reach the hospital quickly to benefit from available treatment.
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Research, teaching and service infrastructures must be developed to take advantage of all these; in the background, suitable knowhow has to be disseminated among professionals and the general public.
This issue serves as an appetizer for the deepening of knowledge in the subjects being presented.
We will be happy to supply you with additional information and all experience that will be accumulated at Hadassah.
Yours,
Prof. Shmuel Shapira MD MPH
Content:
3. CLOT BUSTER
6. Catheterization of the Sinuses – A New Technique for Treating
Rhinosinusitis
9. A New Look at an Old Disease: The Potential to Cure Type 2
Diabetes Using Bariatric Surgery
15. Surgery for the Removal of Metastatic, Diffuse Large Intestine
Cancer in the Peritoneum, Combined with Inter-Peritoneal
Infusionof Heated Chemotherapy
25. Depression and the Thyroid Gland: the Use of the Trilodothyronine
Hormone (T3) to Augment Anti-Depressive Therapy
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CLOT BUSTER
Prof. Jose Cohen, director of the endovascular neurosurgery
and invasive neuroradiology unit,
Hadassah University Medical Center in Jerusalem’s Ein Kerem
An embolism in the brain is liable to strike out of nowhere – like thunder on a clear day – and leave severe functional damage. A new Hadassah development offers hope to some of these patients.
A., 57 years old, who suffers from high cholesterol and hypertension and has a family history of stroke, suddenly collapsed. He suddenly felt weak on the right side of his body and had difficulty speaking. The symptoms disappeared, but he went to his doctor and reported what had happened. On the following day, he collapsed against, and Magen David Adom medics evacuated him urgently to Hadassah’s stroke center.
An examination showed that a clot had halted blood circulation to a large part of the left side of his brain. This event immediately paralyzed his muscles on the right side and disrupted his speech. Inside his head, a biochemical storm occurred. If this process had continued without intervention, within a few hours, there would have been massive death of brain cells. If he were lucky, he would have survived and been permanently disabled.
According to statistics, such a thing happens to about 15,000 Israelis each year, two-thirds of them over the age of 60. The rest of stroke victims are younger, some of them in their 20s. Of those who survive the initial stroke, about 75% will remain with long-term disability involving movement, feeling, memory or cognition.
For treating these complex cases, Hadassah has a multidisciplinary system for urgent care of stroke victims. It has neurologists, neuroradiologists and neurosurgeons who base their diagnosis and principles of treatment on clinical findings and information obtained from advanced brain scanning.
The incidence of stroke is expected to rise during the coming years as a result of both the ageing of the population and the large number of people who survive heart attacks and
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are at a higher risk for stroke; these two phenomena result from shared risk factors, such as hypertension, hypercholesterolemia and diabetes.
The basic mechanism of arterial blockage is identical in both stroke and heart attack and based on the development in the vessels of atherosclerosis and clots. Surprisingly, the advances in treating heart attack victims did not translate into improved treatment of strokes until a few years ago. Today, only one drug – tPA – is recognized as useful in increasing blood flow in stroke victims. This important drug can boost the chances for maximal recovery from stroke in 33% of victims. But this medication has to be given within three hours of the appearance of the first stroke symptoms. After that, it is not effective.
The drug must be administered in the hospital to the stroke victim via a vein. Another way is to give it selectively and in a focused way via catheterization – and this extends the window of opportunity to six or eight hours after the cerebrovascular accident.
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A few months ago, a group of American researchers reported preliminary results of the “Mercy” clot buster. It looks like a corkscrew device that pulls a cork out of a wine bottle. The clot remover found in a catheter can be navigated via the blood vessel to the blockage site. When it reaches the blockage, it exits the catheter and spikes the clot, and the catheter is used to pull it out. In attempts to do this on 114 patients, the device succeeded in opening the vessels of 61 patients. The condition of 20 improved dramatically. The US Food and Drug Administration approved this experimental device, thus enabling the “Mercy” to join the small group of implements developed in recent years for removing clots from cerebral arteries.
Brain cells are major consumers of oxygen and glucose. When the bloodstream is halted, these cells are irreversibly damaged in less than five minutes. The stroke usually causes a complete disconnection of blood circulation to a relatively small region, which is the center of the infarction where irreversible damage results. But around this region, there is an area that continues to be supplied with a small amount of blood. This is called a “twilight zone,” and everything is aimed at saving it. The main effort of stroke researchers in the last decade has focused on the search for materials and techniques to slow the peripheral damage until normal blood flow is resumed.
The new technique for removing clots has existed at Hadassah for a year. This can help groups of patients who are not suitable to other treatments. We are optimistic about this technology, and we will soon present our results.
For more information:
Prof. Jose Cohen
050-8573284
In emergencies, go to the Hadassah-Ein Kerem emergency department
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Catheterization of the Sinuses – A New Technique
for Treating Rhinosinusitis
Dr. Ron Eliashar, department of head and neck surgery, Hadassah University Medical Center, Ein Kerem
Rhinosinusitis is a condition of inflammation if the membranes in the nasal cavity and one or more of the sinuses. It is difficult to define it exactly, but according to what is accepted today, one can say rhinosinusitis is when two or more of the following symptoms occur (at least one of them has to the first or second most important symptoms):
1. nasal blockage, difficulty breathing through the nose or nasal congestion
2. post-nasal drip
3. pain or pressure on the face
4. Harm to the sense of smell
In addition:
a suitable endoscopic examination with findings of edema of the membranes, secretion of pus from the middle meatus, polyps and/or suitable changes in the CT of the sinuses
The condition is called acute rhinosinusitis when the symptoms are shorter than 12 weeks, followed by a complete recovery. Chronic rhinosinusitis is when the symptoms last for more than 12 weeks without recovery. It is liable to be expressed also by events of more serious symptoms and may appear with or without nasal polyposis. It can also result from a viral, bacterial or fungal disease or other factors such as anatomical blockage of the openings of the sinuses, allergy, edema of the nasal membranes,
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inflammatory disease such as Wegener’s granulomatosis and more. The number of rhinosinusitis cases in the US is around 37 million patients a year and its annual cost to that country’s economy is more than $6 billion!
The main treatment for it is local medication (including nasal rinses with saline, steroid nasal spray and/or anti-histamine spray), and sometimes systemic treatment (steroids, antibiotics, decongestants and anti-histamines). Patients who don’t respond to medications or those who develop complications are referred for surgery.
In the past, sinus operations were performed using open techniques that of course included morbidity and facial scars. During the last 20 years, most operations have been performed via Functional Endoscopic Sinus Surgery (FESS), with the resultant minimal morbidity and high success rates (about 85%). Despite this, these operations involve the removal of nasal tissue (which is liable on rare occasions to cause harm to nasal function and to create scarring), bleeding and a relatively long period of recovery for the nose and sinuses.
Recently, a new technique called balloon sinuplasty – developed as part of the minimally invasive surgery trend in general surgery and in sinus surgery in particular – was a big step forward. This technique takes advantage of technology used for a long time in coronary catheterization to treat the maximal, frontal and sphenoidal sinuses. During the surgery, which is currently performed under general anesthesia, a catheter is inserted into the nose and the diseased sinus (such as the frontal sinus), with help from an endoscope and imaging.
A balloon that can be filled with radio opaque material is placed on the end of the catheter. When the balloon reaches the opening of the sinus, the surgeon inflates it up to pressure of eight atmospheres, causing the radial expansion of the opening until it is five to seven millimeters in diameter. Damage to the tissue in the expanded area is minimal, so there is no significant bleeding and the nasal membranes are preserved maximally, which contributes to rapid recovery. One can also take cultures from the contents of the sinus and rinse it if needed. The operation takes advantage of the principle of “functionality” – that is, the creation of a wide opening in its natural location while preserving most of the natural anatomy, allowing the sinus to continue to recover by equalizing pressures, the draining of nasal secretions and recovered function of the cilia in the membranes.
In multicenter trials in the US and Australia performed on 115 patients (with 358 sinuses) who underwent the new operation, the surgeons succeeded in catheterizing and expanding the sinuses in 96.9% of attempts. A followup after 24 weeks after 95 of the patients (with 304 sinuses), using endoscopy showed that 80.5% of the sinuses were well
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opened; 1.6% were blocked, and in 17.9%, it was impossible to know if the sinus was open or not, because the opening could not be viewed (one must remember that the anatomical structure around the opening does not change during expansion, which may prevent the insertion of the endoscope). There were no complications from the procedure or the anesthesia, and a significant statistical improvement was achieved in all of the patients who did not need a repeat operation (97%).
Only three sinuses in three patients needed a repeated expansion in a subsequent operation. The results at followup of those patients a year later have still not been officially published, but they are similar to those found after 24 weeks.
The new technology is suitable especially for patients suffering from chronic rhinosinusitis without nasal polyposis, in whom the problem is located in one or two sinuses as mentioned above. It is not meant to replace completely the current endoscopic technique and it cannot treat ethmoidal sinuses. The technique is approved by the FDA and the Health Ministry, and it is covered by national health insurance. Hadassah is one of the first and leading centers in the country in implementing this new and promising technology.
For more information:
Dr. Ron Eliashar
050-7874164
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A New Look at an Old Disease: The Potential to Cure Type 2 Diabetes Using Bariatric Surgery
Dr. ANDREI KEIDAR, general surgery department,
and CHAYA SCHWEIGER, clinical dietitian
Hadassah University Medical Center, Ein Kerem
The number of Type 2 diabetes patients is constantly rising and reaching epidemic proportions. This metabolic disease contributes to the significant rise in cardiovascular
diseases, renal insufficiency, retinopathy, neuropathy, peripheral artery disease and others. The risk of mortality linked to diabetes is up to 5% for each year of followup. The prevalence of the disease reaches 7.5% in European countries. In 2002 alone, 150 million new cases were diagnosed around the world. The significant rise in diabetes is explained
at least in part by the increase in the prevalence of overweight and obesity.
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Less than 10% of diabetes patients achieve the treatment targets for blood sugar/insulin homeostasis as a result of various treatments. The factors that stymie such attempts for
homeostasis are patient compliance and the cost of treatment, side effects of drugs, interference with the way of life as a result of treatment and weight gain.
For more than a decade, it has been know that bariatric surgery for treating morbid obesity causes diabetes to disappear or improve. In addition, mortality from diabetes complications significantly decline in such patients, as shown by research published in the prestigious New England Journal of Medicine (NEJM). For this study, the researchers followed for over seven years some 10,000 stomach-bypass surgery patients who were treated for morbid obesity and compared the causes and mortality rates with a control group of people of the same ages, sexes and weights whose obesity was treated conservatively. It became clear that the mortality risk from complications of diabetes dropped among the bariatric surgery group by 92% (a risk of death of 0.4 per 10,000 man-years compared to 3.4).
In addition, the improvement in diabetes persevered in the long term. The positive influence on sugar and HbA1C levels was well documented in followup over 16 years.
The improvement was found in all the operations, but the pace and rate of the disappearance of diabetes varied among the various procedures. The most efficient operations for improving diabetes are the Roux-en-Y Gastric Bypass (RYGB) technique, Scopinaro’s biliopancreatic Diversion (BPD) and its new version, Scopinaro’s Biliopancreatic Diversion with Duodenal Switch (PBD+DS).
These operations cause a return to normal levels of sugar, insulin and HbA1C in between 80% and 100% of patients who underwent surgery. The surprising improvement of diabetes occurs even before the patients lose a significant amount of weight – a fact that can point to the existence of hidden mechanisms in sugar homeostasis that are active in these operations.
What is the cause for the difference in rates of diabetes disappearance among the various surgical techniques?
In a number of studies, the influence of bariatric surgery on diabetes was examined. In a meta-analysis of 136 studies comprising 22,094 patients, the rate of disappearance was reported according to the type of surgery. (See Table 1).
It can be asked whether the improvement in diabetes is the direct result of the operation or only an accompanying phenomenon as a result of weight loss, and thus an improvement of insulin resistance.
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Possible Mechanisms of Improvement in Diabetes
Homeostasis After Bariatric Surgery
1. A reduction in the amount of food
Immediately after the operation, there is a significant decline in the amount of food that the patient consumes, and this can be the reason for the disappearance of their diabetic condition. Against this thesis as the main mechanism for improvement are a number of facts: There is an observation that diabetic patients treated with a very-low-calorie diet were not cured of diabetes, and after they underwent stomach-bypass bariatric surgery, high percentages of them recovered. In addition to patients who undergo Scopinaro’s Biliopancreatic Diversion, there is only a temporary restriction in the amount of food consumed, and a short time after surgery, they return to a similar amount of calories to what they ate before the surgery. Despite this, their sugar metabolism homeostasis remains normal.
2. Weight loss
In patients who underwent Gastric Banding (LAGB), the rate of diabetes disappearance is lower at about 50% compared to 80% to 100% in BPD or BPD+DS. Diabetes disappearance in restrictive surgery occurs gradually as weight is lost. In contrast to that, in bypass surgery, most studies show an improvement in sugar-insulin homeostasis already a few days after the surgery – well before the patient has lost significant weight. Scopinaro reported normal sugar levels without need for medication a month after surgery when excess weight was still over 80%.
There are those who think the drastic amount of consumed food after surgery is what causes the drop in blood sugar levels, and that these levels are preserved due to the fact that the patient continues to lose weight. In order to counter this belief, Rubino and colleagues conducted a study in Goto-Kakizaki rats that underwent Duodenal Jejunal Bypass (DJB). They compared them to diabetic mice that had non-functional surgery. In DJB, a full bypass of the duodenum and a small part of the beginning of the small intestine is performed by gastrojejunostomy and the closing of the passage to the duodenum.
In the surgery, there is no reduction in the volume of the stomach, so it does not limit calories – that is, it serves as a research model for a gastric bypass performed in mortally obese patients but without any limitation on their ability to eat excessively. Rodents that had DJB completely recovered from diabetes, while those that had the non-functional surgery did not. From this comparison, one can conclude that the disappearance of
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diabetes after surgeon occurs not only because of changes in food consumption and weight loss.
That is, the operation with a bypass of the upper digestive tract not only indirectly causes sugar homeostasis but actually cures the diabetes. These findings raise the question whether diabetes is a disease whose solution is surgery.
3. Sub-absorption of food
There is another possibility that explains sugar homeostasis after bariatric surgery, in operations that integrate the mechanism of sub-absorption of food (especially by BPD). Sub-absorption of food can improve sugar homeostasis in many ways. Sub-absorption of fat and glucose can cause an increase in sensitivity to insulin and a reduction in insulin resistance.
Lab studies on diabetic animals did not show a decrease in glucose and fat absorption in animals who underwent DJB, but they did show an improvement in diabetes. It is important to note that DJB surgery imitates RYGB in humans. There are various studies in humans that support the claim that the element of sub-absorption in RYGB is not significant. Nevertheless, one can expect a significant improvement in diabetes after RYGB.
4. Hormonal changes
There are studies showing changes in hormonal excretion of the digestive system after bariatric surgery (RYGB and BPD) changes in the structure and passage of food in the new intestine. The main changes that were observed were reduction in the secretion of gherlin, a drop in the level of leptin and insulin in the plasma, an increase in adiponectin and a rise in PPY. There was evidence supporting the possibility that these operations have an effect on hormones, plus evidence that is not clear cut or a rise of GLP-1 after RYGB. A rise in GLP-1 is significant to hunger and sugar homeostasis after RYGB.
5. Influence of the new anatomical structure on the digestive system and sugar homeostasis
It’s important to understand which of the structural changes that occur during the surgery are responsible for the improvement in diabetes. There are two main theories – the hindgut hypothesis (in which the homeostasis comes from the move from faster movement of the food to the small intestine, which causes a change in GLP-1 levels and additional distal peptides that help homeostasis sugar levels); and the foregut hypothesis, (which claims the lack of movement of food in the duodenum and proximal jejunum following the digestive system’s anatomical change causes a decline in potent factors that does away with insulin resistance).
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Rubino and his group compared Goto-Kakizaki rats that underwent DJB and diabetic rats that had gastrojejunostomy without blocking it (so there is movement of food directly both to the jejunum and the duodenum). It was found that in rats whose passage to the duodenum was shut, there was significant improvement in sugar homeostasis, while rats with only a gastrojejunostomy did not show improvement.
In addition, in those rats that had JDB so that the movement of food via the duodenum, sugar levels rose again. In addition, rats that had only gastrojejunostomy and then were operated on again to block the passage to the duodenum were shown to have improved sugar levels only after the second operation. Since in these two experiments the change in the anatomy of the foregut was what caused the changes in reaction to the sugar, Rubino argues that the correct theory is the foregut hypothesis.
The incretin effect was first defined during the early 1970s after observations showed that giving oral glucose causes increased release of insulin compared to giving glucose via infusion. Today it is known that the effect occurs under the influence of hormones of the incretin system.
GIP (Gastric Inhibitory Polypeptide/Glucose Dependent Insulinotropic Polypeptide)
This peptide released by the K cells in the duodenum as a reaction to absorption of carbohydrates and fats. Its half-life is three to seven minutes.
GLP-1(Glucagon-Like Polypeptide 1)
A peptide secreted by the alpha cells in the pancreas and L-cells in the intestinal mucosa (primarily in the ileum and the colon. Its half-life is four to five minutes.
The two hormones are broken down by the enzyme DPP-IV (dipeptidly peptidase IV).
The incretin effect is responsible for the secretion of about half of the insulin released after eating. It has been found that obese people and diabetics have a low level of incretin hormones secreted after eating.
Attempt to treat diabetes by surgery on patients
Few studies carried out in the field have been on patients. There are reports on surgical treatment in diabetics whose weight is normal or who are moderately overweight (average BMI 33.2) who underwent BPD and whose diabetes disappeared in most cases.
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Today, the indication for surgery to treat overweight in diabetics is based on the arbitrary number of 35 kg/m, and it does not leave room for judgment about the presence of diabetes or its severity. It may be that the decision has to be based on the relative risk and benefit in a specific candidate and to decide on an individual basis.
It is clear that there is not yet enough knowledge in this field, and the latest discoveries about the influences of surgery on homeostasis of diabetes are only the beginning of understanding the mechanisms involved in the disease. It is for this reason that innovative treatment of diabetes is based on the mechanisms we have described – the inhibition of the DPP enzyme.
For more information:
Dr. Andrei Keidar
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Surgery for the Removal of Metastatic, Diffuse Large Intestine Cancer in the Peritoneum, Combined with Inter-Peritoneal Infusion of Heated
Chemotherapy
Dr. Aviram Nissan, surgical department, Hadassah-Ein Kerem
In the operating room
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System is ready
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Tumors of the peritoneum constitute a medical challenge. The dissemination of the cancer over a large surface in the abdominal cavity and the pelvis and tiny foci of tumors, the accumulation of liquid ascites and the proximity to vital organs make the detection and treatment of these diseases especially difficult.
Malignancies in the peritoneal cavity result from primary and secondary sources. The primary tumors of the peritoneal cavity are of two kinds:
Primary peritoneal carcinoma, which is similar in its behavior to ovarian cancer and mesothelioma that develop from cells that cover the abdominal membrane of the peritoneum or the chest cavity
Secondary malignancies that come from a number of sources –
1. colorectal cancer
2. ovarian cancer
3. cancer from the appendix
4. stomach cancer
5. pancreatic cancer
6. a tumor that releases mucus (pseudomyxoma peritoneii)
Survival from this group of diseases is connected to a number of factors, but the most important is the course from which the primary tumor developed.
The highest rate of survival is connected to pseudomyxoma peritoneii, and the least chance of survival is connected to peritoneal malignancies originating in the pancreas.
Administering chemotherapy in the accepted way (systemic infusion to the vein) is not able to bring about recovery of this group of diseases.
The pioneer in this field was an American surgeon named Paul Sugerbaker, who developed a surgical technique for the removal of cancer foci from the peritoneal cavity in combination with infusion of heated chemotherapy during the surgery, while using a pump usually used for open-heart surgery.
As a result of his work, a small number of medical centers in the world adopted this technique for treating peritoneal cancers. In recent years, following the development of unique pumps equipped with efficient and exact heating mechanism and following much basic and clinical research, this technique has become widespread, especially against metastases in the peritoneal cavity whose source is the colon, a common tumor.
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The logic in removing metastases from the peritoneal cavity
Even though colon cancer, except in its earliest stages, is a systemic disease that affects the whole body, surgical treatment for removing the primary tumor is an important treatment for the disease. When it spreads to the regional lymph glands that are also removed in the operation, it is common to add chemotherapy to prevent the return of the disease. When metastases are found in the liver or lungs, there is cause for removing them in some of the patients. In those patients whose metastases have been completely removed and treated with systemic chemotherapy, there is a chance for a cure in a third of the patients. In those colon cancer patients in whom the disease has spread beyond that organ, the spread to the peritoneal cavity will occur in 15% of patients. For them, as well as those with metastases in the liver, if those in the peritoneal cavity can be removed, survival rates will reach 20% to 30%, as in those patients whose metastases to the liver or lungs have been surgically removed.
Unlike patients who suffer from metastases in the liver or any other solid organ with masses that can be seen clearly using imaging techniques such as CT, ultrasound or PET – in patients with a spread to the peritoneal cavity, the metastases have a small volume and are disseminated over a wide area. Thus it is very difficult to determine with scans whether these metastases can be resectioned and how to plan the operation. To do a complete resection, one must perform not only a focused removal of a single organ but also remove many peritoneal surfaces and a number of affected organs. It is very important to open secondary cavities in the abdomen that are hidden from view and where metastases may develop. These facts make such operations very complicated ones that take many hours and are liable involve a high rate of complications.
The logic of giving chemotherapy directly to the peritoneal cavity
In recent years, there has been much progress in the development of effective drugs for treating colon cancer patients. The progress has been in the development of cytotoxic drugs like Oxaliplatin (CPT11) and Irinotecan, as well as biological drugs such as Avastin and Erbitux. These have doubled the average lifespan of metastastic colon cancer patients and significantly reduced the rate of recurrence in patients whose whole tumors have been removed.
The metastases that develop in solid organs such as the liver or lung creates around them new blood vessels that develop in a process called angiogenesis, thus they can grow and turn into tumor masses with a large volume. This fact also works to harm them, as the concentration of chemotherapeutic drugs that reaches them is high, so these blood vessels can be destroyed via drugs, such as Avastin, that halt the process of angiogenesis.
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Metastases in the peritoneal cavity have less of an ability to create blood vessels, so they usually do not develop into large masses. Instead, they tend to spread as seeds or thin surfaces over organs in the abdominal cavity. Chemotherapy concentrations given via a vein are lower than in the peritoneum, and the effects of the drugs are weaker. By comparison, drugs given directly to the peritoneal cavity can penetrate the tissue to the depth of one millimeter (depending on the molecular weight of the drug) ad even be absorbed into the bloodstream. Theoretically, one can reach very high concentrations of chemotherapeutic drugs in the peritoneal cavity with very few side effects.
The logic of using heated solutions for treating peritoneal cavity malignancies
Much research has been performed in the field of the influence of heat (hyperthermia) on cancer cells. It has been proven that heat has an inhibitory effect on cancer cells. In order to kill 100% of cancer cells on a culture medium in the lab, one must heat them to 46 degrees Celsius for 20 minutes. This heating will cause irreversible damage also to healthy tissues, so it is not practical. But researchers have found that heating cells in culture to between 42 and 44 degrees C. for 90 minutes will cause much damage to tumor cells at the cost of minimal damage to normal tissue. Other research has shown that when a number of chemotherapy drugs are given together with heating, there is an even better effect in killing the cancer cells.
The attempt to give heated chemotherapy drugs within these temperature ranges via a vein in a patient who is awake will cause brain damage, thus it is not practical. An additional fact that makes heated chemotherapy treatment difficult is that the temperature drops quickly as the solution penetrates the tissue, and the optimal temperature can be preserved only to a depth of one millimeter in the malignant tissue.
Therefore, there is much logic in using heated chemotherapy in metastases with a low volume and spread over a large surface area. If all the metastases with a diameter of over one millimeter can be resected, one can theoretically treat the remaining diseases tissue with heated chemotherapy.
Clinical research on resection of metastases in the peritoneal
cavity and infusion of heated chemotherapy
A number of studies published in recent years have shown that there is truth in the assumption that there is an advantage to resectioning metastases from the peritoneal cavity while using infusion of chemotherapeutic drugs.
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A number of studies by European and American researchers showed in a followup of years after colon cancer patients were treated using this technique that one can have survival for more than five years in a fifth of patients. The most important factor for success is the surgeon’s ability to perform a full removal of all the visible metastases.
Yan and colleagues from the group of Dr. Paul Sugerbaker published a meta-analysis of large studies dealing with the resection of metastases originating in the peritoneal cavity. In their work, they found 14 major studies, of which two are prospective and randomized. The results of all these studies showed that 11% to 19% of patients survived for at least five years. In the group of patients in which all underwent resection of all metastases without any visible remaining disease, the five-year survival rate was achieved by between 22% and 49%. The rate of morbidity connected with these complicated operations ranged between 23% and 44%, and the mortality rate ranged between 0% and 12%.
Two randomized prospective studies compared giving conventional systemic chemotherapy to the vein versus surgery that integrates infusion with heated chemotherapy to the peritoneal cavity. The first, which was carried out in France, was halted at an early stage because of the inability to enlist patients to the control group (chemotherapy via a vein). The second, in Holland, was stopped at an advanced stage by the ethics committee after a primary examination proved a significant advantage in those who were treated during surgery. A three-year followup in patients who received an infusion to the vein showed that not a single patient survived that long, compared to 20% of patients who had surgery. In those patients who complete removal of all the visible metastases, the rate of return was especially low – in only one patient.
It should be noted that the chemotherapy with which patients in the control group were treated was the conventional type when the study was carried out, but today, there are much more effective chemotherapy drugs.
Choice of patients for surgery
Since the surgery – involving the infusion of heated chemotherapy for 90 minutes – is very long and complicated, it is clear that the choice of patients is vital. Only those with a high rate of functioning and lacking significant heart or lung disease can be considered suitable for this treatment.
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As the disease is diffused in the abdominal cavity, it is very important to assess the extent of the disease before surgery and set criteria for choosing patients who have a good chance for a complete resection of the metastatic disease. It is very difficult to assess the extent of the disease using even the most advanced imaging techniques. Most surgeons use CT for this. In order to create a worldwide system for ranking the extent of disease before, during and after the surgery, doctors from around the globe who treat peritoneal cavity malignancies wrote a document of agreement that defines a uniform technique for assessing the extend of disease. It is used today by all physicians in this field. It is called the Peritoneal Cancer Index (PCI) and is accompanied by criteria for choosing patients and guidelines for carrying out the surgery.
Suitable patients are those with disease limited to the peritoneal cavity (up to three metastases in the liver makes it possible to resection them), without blockage of the small intestine, the urinary tract or the entry to the liver. Involvement of the small intestine must be limited to isolated regions, and the superior mesenteric artery must be disease free.
Surgical principles
The operation is carried out under general anesthesia because of the length, complexity and high temperatures at which the infused chemotherapy is delivered. The surgery demands great skill by the anesthesiology team. Coping with difficult problems such as blood loss, preserving the body temperature over long hours and surgical procedures carried out in various parts of the abdomen and pelvis require deep understanding of details of the surgery. It is vital to manage the anesthetic materials, the pace of the infused solutions and the use of various drugs depending on changing situations, while preparing for and during each step in the operation and acting to prevent a drop in blood pressure and kidney damage.
The stage of giving heated chemotherapy needs special preparation by the anesthesiology team; body temperature must be lower at the beginning of the infusion, and during the infusion, the team must ensure that the body temperature does not rise above 39 degrees C. The operations in our institution are carried out under the responsibility of a senior anesthesiologist who was specially trained in a medical center abroad and has much experience in such an operation.
The surgery begins with the removal of the previous operation’s scar (if such exists). Then, there is the process of cutting the peritoneal membrane from the front and sides of the abdomen until it meets the back muscles. First, the abdominal organs are examined and the surgeon makes sure that there is no disease involvement in organs that would prevent full resection. Then begins the process of releasing the liver from the bands that
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anchor it and peeling away the metastases from the capsule that encloses it. After the peritoneal membrane is peeled from the diaphragm (sometimes, partial removal of the diaphragm or the spleen is needed), the stomach is released, and the space around it and next to the liver is checked for metastases. All diseased tissue is removed. The pelvis – which often has metastases – is examined, and the peritoneal membrane is removed from the bladder. Sometimes some of it must be removed, along with the uterus and ovaries in women. Then the upper rectum is removed if necessary.
Reconstruction is a complicated process of attached parts of the intestine to each other so the digestive system is continuous. This stage, according to the surgeon’s considerations, takes place before or after the stage of chemotherapy infusion.
The infusion stage is very complicated. The surgeon attaches tubes that will send chemotherapy to the area and pump it out and heat sensors that check the temperature of the flowing liquids. After the abdomen is closed, the surgeon attaches the tubes to those of the pump.
Initially, three liters of physiological solution are infused until a good flow rate is achieved. The nurse who operates the machine starts the heating process. The liquid’s temperatures in the tubes that enter and exit from the body appear on a computerized monitor. To prevent harm to the tissues, the computerized system warns and stops the function of the pump immediately when the temperature rises above that designated by the surgeon. After the temperature reaches the optimal 40 to 42 degrees C. in the exit tube (42 to 44 degrees C. in the peritoneal cavity), the surgeon adds chemotherapy liquid to the special container in the pump that distributes the drug uniformly in the infusion liquid. The flow of the chemotherapy at high temperatures continues for 90 minutes; at 45 minutes, an additional dose is introduced for preserving the necessary concentration of the drug in the peritoneal cavity. After the infusion ends, the patient is disconnected from the device, and drains are left in the abdominal cavity to remove secretions, blood and accumulated liquids. In patients whose diaphragm has been opened or cut, the drains are left also in the chest cavity.
At the end of the surgery, the patient is moved to an intensive care unit for two to three days until full recovery and from there to a regular department. Additional details, including photos and diagrams, can be found at this Web site:
www.surgicaloncology.com
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Assimilation of the technique at
Hadassah University Medical Center on Mount Scopus
After a senior surgeon from the department studied the technique in a number of centers in the US and Europe, several infusion systems for heated chemotherapy were checked. After examining the systems and consulting with hospitals abroad that use various types, it was decided to purchase the most efficient and reliable among them. An operating team that included surgeons, a senior anesthesiologist and nurses underwent training in a German medical center that specializes in this procedure, including lectures, demonstrations and a number of operations, including the use of the equipment in the operating theater.
After undergoing training, the Hadassah operating room, intensive care unit and surgical departments for treating complex patients and the handling of cytotoxic drugs were prepared according to guidelines of the Hadassah Medical Organization and the Health Ministry. In cooperation with oncology department physicians and the pharmacy for cytotoxic drugs at Hadassah’s Sharett Institute of Oncology, all preparations were made while ensuring the safety of the patients and medical team.
So far, two patients in our department have undergone this technique. Both had uneventful surgery and were discharged to their homes between three and four weeks later. Both had full and successful infusion of heated chemotherapy according to the protocol and without any problems.
We are convinced that the technique constitutes an important tool for the successful treatment of such patients.
For more information:
Olga Simhoni
Tel (02) 5845045
050-8946305
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Depression and the Thyroid Gland: the Use of the Trilodothyronine Hormone (T3) to Augment Anti-Depressive Therapy
Dr. Rena Cooper-Kazaz and Dr. Aviva Cohen, the Biological Psychiatriy Unit and Psychiatric Clinic
Depression is a common psychiatric disorder in the population and especially among women. Today, treatment for depression puts more stress than the past on achieving a full remission, which means better functioning and an improved prognosis.
The most commonly used drug therapy for depression are anti-depressives from the family of SSRIs (selective serotonin reuptake inhibitors), but even with optimal treatment, only 30% of patients achieve full remission. Those who remain with the burden of significant symptoms need one of the following changes:
1. Replacement of their anti-depressant by another
2. Augmentation of an anti-depressant, such as the addition of lithium or Trilodothyronine Hormone (T3) or another anti-depressant in addition to the first type.
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The physiology of the thyroid gland has been studied a lot in connection with various affective disorders. A two-way connection between depression and hypothyroidism has been found. There is a greater incidence of depressive symptoms among patients with primary hypothyroidism and vice versa. Clinical or sub-clinical disorders in the thyroid are found in 5% to 10% of primary depressive patients. This condition can disrupt the quality of life and neurocognitive function. The connection between hypothyroidism (both clinical and sub-clinical) and a reduced reaction to anti-depressives has been shown.
The use of Trilodothyronine Hormone (T3) focuses today on augmentation of anti-depressive drugs. Most of the old studies assess the addition of T3 to treatments with tricyclic anti-depressives (TCA). In recent years, a number of new studies have been carried out that proved the efficacy of adding T3 to the anti-depressive Proxatin (SSRI).
A significant study performed in the psychiatric clinic of Hadassah University Medical Center in Ein Kerem aimed at examining the efficacy of T3 for augmentation to SSRI. It included 103 depressive patients with normal thyroid functioning who underwent comprehensive assessments and were enlisted for an eight-week study. All the patients were treated with a SSRI anti-depressant. When the patients were assembled, they underwent randomization to one of two T3 treatment groups or (N=53) or placebo (N=50), in addition to the SSRI.
The results showed the rate of patients who reacted to the treatment and were called respondents was 69 % among those who received augmentation of T3, compared to 50% among the placebo group. As for remission, we found that 58.5% of those treated with T3 and only 38% of those receiving the placebo achieved full remission.
The results point to an almost triple chance to react favorably to the addition of T3 compared to the placebo. In the attached diagram, we see the drop along the timeline in the Hamilton assessment questionnaire for depression. The diagram reflects the efficacy over time of the added T3 compared to the placebo.
The study also aimed at finding a correlation between the reaction to the addition of T3 and the thyroid function of patients: Among those who received T3, patients who reacted with remission from the addition of T3 had lower basic levels of T3 and a significant decline in TSH levels after treatment, compared to those patients who received T3 but did not go into remission. It’s important to note that in our study, there was a high rate of tolerance to T3, and only a minority suffered from undesirable side effects.
In our clinic, we are now conducting a continuing study that aims at examining more deeply the connection between thyroid functioning and the reaction to T3 among patients with depression majeure. We are also trying to examine a possible genetic connection
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between the addition of T3 and polymorphism in genes coded for receptors to thyroid hormones and receptors for TSH, as well as polymorphism in enzymes that participate in the production and breakdown of thyroid deiodinase hormones.
The target population is patients suffering from depression majeure, aged 18 to 70, without primary thyroid disease and without a contraindication for hormone treatment. The participants get close psychiatric supervision, a supply of drugs during the study and continued and organized followup in our clinic.
For more information:
Dr. Rena Cooper-Kazaz and Dr. Aviva Cohen
(02) 6416571 (messages only)
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