Oct 11, Cannabinoids such as THC and CBD have been found to display impressive anti -tumour, anti-anxiety, anti-inflammatory, neuroprotective, and. Thyroid cancer is the most common endocrine malignancy and Ligresti et al.  demonstrated that CBD exerted. Apr 23, We report a rare case of neuroendocrine tumor (NET) in the common bile duct ( CBD). The patient is a year-old female who presented to our.
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The preoperative diagnosis was that of cholangiocarcinoma or other intraperitoneal tumor compression of the bile duct. We conducted an exploratory laparotomy and found a tough tumor located in the CBD, protruding from the wall of the bile duct to the right abdominal. The tumor was not completely blocking the bile duct lumen and there were no other tissues encroaching on the surrounding tissues, including the portal vein, hepatic artery, inferior vena cava, and pancreas. We excised the CBD 2 cm above and below the tumor with a hepatoduodenal ligament lymph node dissection.
The Roux-en-Y anastomosis was conducted for the proximal bile duct and jejunum. The intraoperative pathology of the bile duct showed no tumor cells. The surgical resection specimen is shown in Figure 2. After resection, we observed that the mass was located on the right wall of the common bile duct. The left wall of the common bile duct was incised.
The black arrow shows the left side of the common bile duct, the red arrow shows the right side of common bile duct, the white arrow shows the hepatic margin of the common bile duct, and the blue arrow shows the tumor. The pathology is shown in Figure 3: The patient has demonstrated tumor-free survival for 8 months after the operation to date without chemotherapy.
The patient provided written informed consent and gave permission for the use of biopsies and publication of case details, including publication of the images. The gastrointestinal tissues are the most common site for NETs. At present, the etiology of bile duct NETs is unclear. Some studies indicate that NETs are linked with cholelithiasis and congenital malformation of the biliary tract, both of which lead to chronic inflammation.
According to previous literature, 9 , 10 cholangiocarcinoma is often located in the upper third of the bile duct and demonstrates invasive growth behavior. The degree of differentiation of NETs is usually determined through immunohistochemistry. Surgical radical resection is the main treatment for choledochus NETs. The operation is classified into three types according to the position of the mass: The National Comprehensive Cancer Network guidelines for gastrointestinal and pancreatic NETs indicate that lymph node dissection is advocated, but there is no uniform standard for the extent of specific dissection.
Furthermore, there was no uniform standard before the operation in the current study, and chemotherapy could not be performed because of the difficulty in diagnosis before the operation. Currently, cisplatin and etoposide are often used for chemotherapy after surgery. In a study consisting of 21 patients with biliary duct and pancreatic NEC, who were treated with platinum-based chemotherapy after surgery, three were sensitive to the chemotherapy; the median progression-free survival was 1.
The bile duct NET G3 patients without postoperative chemotherapy died sooner, whereas patients who underwent postoperative chemotherapy and those who did not undergo chemotherapy had all survived at the reported follow-up time. Therefore, we believe that postoperative prophylactic intravenous chemotherapy is beneficial for NETs, especially for patients in G3. Many more clinical trials are ongoing, and these results will clarify this point. In this case, the patient presented to our ward with fever.
The ultrasound analysis found a tumor in the extrahepatic bile duct without the symptom of jaundice we speculate that the bile duct was not blocked completely by the exophytic tumor. We first considered the possibility of cholangiocarcinoma.
However, when we considered the uncommon symptoms and CT results the enhancement degree of CT in the arterial phase for cholangiocarcinoma is lower than for the liver, and it is often a delayed enhancement. In this case, the enhancement was early. In addition, the tumor demonstrated exophytic growth, which is unusual in bile duct cholangiocarcinoma. We had doubts about the diagnosis of bile duct cancer before surgery.
Some clinicians consider that a biopsy of an endoscopic retrograde cholangiopancreatography ERCP for a bile duct mass is a reasonable diagnostic method, which helps to characterize a tumor and guide subsequent surgery. However, we did not consider ERCP, as the bile duct biopsy may cause complications such as bile leakage. Such patients must undergo surgery to remove the tumor and so we conducted an exploratory laparotomy preparing for radical resection of bile duct cancer.
The postoperative pathologic diagnosis was NET G2. NETs G1—G3, except for any other pathologic types in extrahepatic bile ducts are rare. We found no more than cases on PubMed. PubMed contains just 45 cases of NETs in the CBD except for NETs in the gallbladder and cystic duct, ampulla, hail bile duct, and left or right hepatic ducts in the liver and also except for any other pathology, such as adenocarcinoma-NET.
Michalopoulos et al reported approximately 38 cases from to We found that bile duct NETs do not have an endocrine function. Patients with non-functional NETs in the CBD often have the symptom of jaundice first, with or without the symptom of fever and abdominal discomfort.
Because of the absence of a specific symptom, NETs in the CBD are often considered to be cholangiocarcinoma, leading to a misdiagnosis. The WHO has made a classification for extrahepatic and gallbladder tumors, including the bile duct and gallbladder NETs.
However, there are no uniform guidelines for NET treatment, especially for radiotherapy and chemoradiotherapy postoperatively. It is useful to report this uncommon tumor.
National Center for Biotechnology Information , U. Journal List Onco Targets Ther v. Published online Apr Author information Copyright and License information Disclaimer. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https: By accessing the work you hereby accept the Terms.
Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Loss of appetite and tumor cachexia is a common problem in oncology. A few clinical trials included the change of body weight with THC, but gave mixed results in cancer patients.
An increase in weight was also observed in a crossover, placebo-controlled study with much higher doses 0. In Table 1 , results of studies with THC in cancer patients are summarized.
A case series with 6 patients who received THC showed, however, a loss of effect in 3 of the subjects after several weeks, 19 which may be related to a desensitization of CB1 receptors. It has been hypothesized that weight gain is due to an increase of fat mass as a result of the lipogenic action of THC via CB1 receptors. In contrast, CBD has no orexigenic effect; high doses 2. Chronic pain is another common symptom and not confined only to tumor patients. A recent review that included THC, nabilone, and nabiximols found moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity.
However, there was no difference in average quality-of-life scores as measured by the EQ-5D health status index between nabiximols and placebo.
In a cancer trial, oral THC 20 mg was thought to be comparable to codeine mg, but with more marked psychological effects. However the dose of CBD—each substance was given as sublingual spray containing 2. Details of some representative studies are given in Table 2.
Other notable findings include the reduction in the dose of opioid pain medications with cannabinoids and the blockade of opiate-dependence in rats. As morphine induces upregulation of CB2 with inflammatory responses in activated microglia and potentially abnormal immune function , cannabinoids are also counteracting this unwanted effect. Mechanisms of CBD seem to be rather complex: Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay; thus, the opioid-saving effect of a combination may depend on the pain type.
To note, a dysfunction of TRP channels has been implicated in chronic pain. During the last decades many studies reported that numerous other cancer-related or treatment-related symptoms were also significantly improved by cannabinoids, such as depression, anxiety, fatigue, constipation, sexual function, sleep disorders, and itching.
The only cannabinoid likely having a role in depression is CBD as may be concluded from animal experiments. More generally, cancer patients using cannabis uniformly report better influence from the plant extract than from pure or synthetic products. In a recent review, mixed and somewhat inconsistent results have been reported about effects on sleep with cannabinoids, including nabilone and nabiximols. Differences between cannabinoids may exist as well.
THC seems to decrease the time to sleep latency and to improve sleep quality over a wide dose range of 2. In rats, very low doses of about 0. RBD is a sleep disorder that causes people to act out their dreams. Common symptoms include talking, shouting, and complex movements associated with nightmares. Three of the patients received 75 mg of CBD per day and 1 received mg per day.
All 4 patients experienced a significant reduction in symptoms following treatment. Probably the most exciting property of cannabis, scientific evidence for anticancer effects, goes back to at the Medical College of Virginia at the behest of the US government, about 2 decades before the endocannabinoid system and mechanism of its actions had been detected.
Funded by the National Institutes of Health to find evidence that marijuana damages the immune system, the study found instead that THC slowed the growth of 3 kinds of cancer in mice—lung and breast cancer, and a virus-induced leukemia. Astrocytomas and in particular glioblastomas are the most frequent brain tumors among approximately different types.
Malignant glioma remains one of the most aggressive forms of brain cancer, with a median survival after resection, radiotherapy and chemotherapy of 12 to 15 months. In children, brain tumors constitute the second-most-common malignancy. When cells become malignant, they develop more cannabinoid receptors and become more susceptible to endocannabinoids, thus enabling an efficient intervention. In most brain tumors the endocannabinoid system is upregulated and seems to be under epigenetic control.
Interestingly, some benign pediatric astrocytic tumors, such as subependymal giant cell astrocytoma, which may only occasionally cause mortality owing to progressive growth, also display high CB2 immunoreactivity.
Cannabinoids decrease tumor progression by at least 2 mechanisms: Initial studies showed that THC and other cannabinoids induce the apoptotic death of glioma cells by CB1- and CB2-dependent stimulation of the de novo synthesis of the proapoptotic sphingolipid ceramide. Therefore, additional, nonreceptor mechanisms such as induction of reactive oxygen species seem to be plausible.
The first and only published clinical study aimed at assessing antitumoral action of THC in humans was a pilot phase 1 trial in 9 patients with recurrent glioblastoma multiforme. All of them had previously failed standard therapy surgery and radiotherapy and had clear evidence of tumor progression at the time they received THC. The median duration of an administration cycle was 10 days; 5 patients received more than 1 cycle. In 3 of these 5 patients, a temporary reduction of tumor proliferation was observed.
THC administration was safe without overt psychoactive effects. In 2 patients who received THC for 30 and 26 days, respectively, and in whom CB receptor expression had been determined after THC treatment, a slight decrease in CB1 receptor expression but no change in CB2 receptor expression was observed, which might reflect a predominant binding of THC to the former protein or its higher susceptibility to desensitization.
Maximal doses of THC and CBD in these 2 trials are about 5- to times lower than doses that were effective in animal studies see below. In contrast to THC, CBD does not interact directly with CB1 and CB2 receptors but produces nonetheless a remarkable antitumor effect in glioma as well in a number of other animal models of cancer, including reduction of invasiveness and metastasis.
The mechanisms by which CBD kills glioma cells, independently of cannabinoid receptor stimulation, both in vivo and in vitro, has not as yet been completely clarified. It seems to rely—at least in part—on its ability to inhibit the transcription of tumor-related genes eg, midkine, MDK and enhance the production of reactive oxygen species in cancer cells.
CBD also decreases the activity and content of 5-lipoxygenase. It is therefore of particular interest that CBD significantly downregulates Id-1 gene expression and associated glioma-cell invasiveness and self-renewal at concentrations that can be achieved in vivo.
A number of reports on treatment of various brain tumors with cannabis exist in the internet but are unfortunately restricted to inconclusive or poorly documented anecdotal testimonials on various cannabis extracts eg, hemp oil used by patients or their relatives 63 ; this includes also a report on spontaneous regression of pilocytic astrocytoma after incomplete resection in 2 children.
A recent review article emphasized that all 16 in vivo studies that evaluated cannabinoid action on glioma so far showed statistically significant reductions of tumor volumes when comparing to controls.
Duration of treatment was between 7 and 28 days. Results are summarized in Table 3 and also include publications since the data lock date of AM review, December Combinations with temozolomide, X-rays, or cannabinoids enhanced the activity further.
One study demonstrated that higher doses of THC were more effective, thus confirming a dose-dependency observed already in vitro; differences in sensitivity of glioma cells to cannabinoids exist. In short, a number of experiments, in vitro and in vivo, have demonstrated that cannabinoids act synergistically, which is of great importance for the development of future anticancer therapies. The treatment of glioblastoma cells with both compounds, THC and CBD, led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities.
These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique.
A steadily increasing number of publications demonstrate the high potential of cannabinoids in palliative care. They can be combined with other therapies and seem to be devoid of any significant toxicity. Effects differ, however, between cannabinoids and change also with increasing doses whereby many aspects remain unsolved. However, CB1 stimulation is necessary for improving mood and appetite and many other effects.
At present, it is hard to imagine a better approach than adjusting THC doses individually to balance wanted versus unwanted effects. Generally, higher doses are needed to achieve analgesic and antiemetic effects. Such high doses preclude an oral use of THC as single substance in humans due to side effects. Many questions are also unsolved when it comes to chronic treatment with cannabinoids, a particularly important point in palliative care.
Full recovery of CB1 receptors after stopping THC for example may take up to several weeks, with regional differences. Is a daily treatment, as commonly practiced, necessary or is a pulse-dosing concept with intermittent dosages given as short cycles a better alternative?
How long last effects? CBD and possibly other non-psychotropic cannabinoids, may be a promising alternative for many indications, likely to include nausea, vomiting and improvement of sleep, although more studies in humans are necessary. Combinations were synergistic under many circumstances such as in pain and antitumor studies. Cannabinoids differ in their antitumor activities and probably in their mechanisms and targets, which is a rationale for combinations.
However, for many pharmacological effects except against tumors roughly times higher daily doses are needed for CBD compared to THC. This leaves some doubts as to whether a 1: A further, unsolved question is whether the common intervention strategy of 1 to 3 applications of cannabinoids per day can be optimized.
More recent findings demonstrate that the activity of the ECS is profoundly modulated by circadian rhythmicity. As an example, CB1 receptor protein is at its highest concentration when AEA levels are lowest and vice versa, whereas the expression of CB2 did not show striking diurnal differences, at least in the rat cerebral cortex.
In contrast, levels of 2-AG, a full agonist to CB1 receptors and about times more abundant in brain than AEA, follow an opposite course. Concentrations are lowest around In rats, an AEA injection before experimentally induced traumatic brain injury significantly increased survival when traumatic brain injury was induced at This suggests that the time of administration of cannabinoids could also modulate effects. Last but not least, nutrition also plays an important role in palliative care.
Some pathways of their degradation produce, among others, proinflammatory compounds. A recent study found that 2-AG plasma levels were significantly reduced by a diet high in omega-3 and low in omega-6 fatty acids H3-L6 intervention , which in turn significantly decreased severity of headaches.
In summary, the endocannabinoid system is likely playing a crucial role in palliative care. The future will show whether an optimized treatment strategy with cannabinoids can also prolong life of brain tumor patients by their virtue to combat cancer cells. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
Sign In or Create an Account. Close mobile search navigation Article navigation. Cannabinoids Reduce Nausea and Vomiting. Cannabinoids Improve Other Cancer-related Symptoms. Anticancer Effects of Cannabinoids may be able to Prolong Life.
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Neuroendocrine tumor of the common bile duct: a case report and review of the literature
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