The chemotherapy treatment regimen that is being used to work on my Mantle Cell Lymphoma is Rituxan and Hyper-CVAD.
The term ‘hyper’ refers to the hyperfractionated nature of the chemotherapy, which is given in smaller doses, more frequently, to minimize side-effects. ‘CVAD’ is the acronym of the some of the drugs used in courses A and B. Those drugs are:
C – Cyclophosphamide
Cyclophosphamide is an inactive cyclic phosphamide ester of mechlorethamine. It is transformed via hepatic and intracellular enzymes to active alkylating metabolites, 4-hydroxycyclophophosphamide, aldophosphamide, acrolein and phosphoramide mustard. Cyclophosphamide causes prevention of cell division primarily by cross-linking DNA strands. It is considered to be cell cycle phase-nonspecific.
Synonyms
Cyclo, CPA, CPM, CTX, CYC, CYT
Common Trade Names
Procytox® (Baxter), Cytoxan® (Bristol), Neosar® (USA)
Molecular and Chemical
Cyclophosphamide
Adverse Effects
Many people taking cyclophosphamide do not have serious side effects. Side-effects include chemotherapy-induced nausea and vomiting (CINV), bone marrow suppression, stomach ache, diarrhea, darkening of the skin/nails, alopecia (hair loss), changes in color and texture of the hair, and lethargy. Hemorrhagic cystitis is a frequent complication, but this is prevented by adequate fluid intake and Mesna (sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl donor and binds acrolein.
Cyclophosphamide is itself carcinogenic, potentially causing transitional cell carcinoma of the bladder as a long-term complication. It can lower the body’s ability to fight an infection. It can cause temporary or (rarely) permanent sterility. Although it is used to treat cancer, it may increase the risk of developing another form of cancer, sometimes months to years after treatment.
A more scientific description of adverse effects and methods to mitigate them follows – Dose-related chemical hemorrhagic cystitis occurs due to direct contact with bladder mucosa of active and toxic metabolites which accumulate in concentrated urine. This occurs in 10% of patients and may occur during or several months after treatment. Hemorrhagic cystitis may occur in >40% of patients receiving high-dose cyclophosphamide for bone marrow transplantation. Concurrent or previous radiation therapy to the pelvis may increase the risk of this complication. Cystitis appears to result in chronic inflammation leading to fibrosis, telangiectasis of the bladder epithelium and bladder cancer. Severe cases may be fatal. Prophylactic measures to reduce the incidence of cystitis include catheter bladder drainage, bladder irrigation, hyperhydration, forced diuresis and the administration of mesna. However, hyperhydration places the patient at risk for fluid overload and electrolyte imbalance, particularly given the antidiuretic effect of cyclophosphamide. It appears that mesna and hyperhydration are equally effective in preventing cyclophosphamide-induced cystitis in the BMT population. Cyclophosphamide should be administered as early in the day as possible to decrease the amount of drug remaining in the bladder overnight. The drug should be promptly discontinued and not re-instituted if possible in patients developing this complication.
Several methods of treatment for established hematuria are currently advocated, depending on the severity of bleeding. Mild cases can be controlled by simple measures such as bladder irrigation with water or normal saline. Intravesical instillations of astringents (alum, silver nitrate) or systemic administration of antifibrinolytics (aminocaproic acid, tranexamic acid) are also effective. For moderate bladder hemorrhage, cystoscopy should be undertaken to evacuate the bladder of clots and continuous bladder irrigation instituted to prevent recurrent clot formation. Treatment can then be attempted with astringents or antifibrinolytics. Intravesical prostaglandins have also been recommended in addition to the above treatments. Following cystoscopy for severe hematuria, treatment begins with intravesical formalin (the aqueous solution of formaldehyde), phenol or intravesical prostaglandin and may proceed to surgical intervention. Electrocautery, cryosurgery, diversion of urine flow, hypogastric artery ligation or cystectomy have been advocated.
Children appear to be more at risk than adults for the development of hemorrhagic cystitis, but this may be due to the relatively high doses given intravenously to children. Children should be hydrated for several hours prior to cyclophosphamide. Mesna is not routinely administered with cyclophosphamide in children; bladder toxicity can be avoided in most patients by adequate hydration and voiding. Co-administration of mesna is recommended for very high dose therapy >1000 mg/m2 (such as in bone marrow transplant preparation) or in those who experience persistent microscopic hematuria or transient gross hematuria. If persistent gross hematuria occurs cyclophosphamide therapy should be stopped permanently.
Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g., some leukemias and lymphomas), can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.
Interstitial pneumonitis and pulmonary fibrosis occur occasionally. This frequently fails to respond to cyclophosphamide withdrawal and corticosteroid therapy and is often fatal when advanced to the point that symptoms are clinically apparent. Signs and symptoms typically include tachycardia, dyspnea, nonproductive cough, basilar crepitant rales, interstitial bilateral infiltrates on chest x-ray, hypoxemia and ventilation/perfusion dysfunction. Lung biopsy is the only sure method of diagnosis. The drug should be stopped at the first hint of pulmonary toxicity; all other possible causes of pneumonitis should be ruled out. It is most frequently reported in patients with Hodgkin’s and non-Hodgkin’s lymphomas. There does not appear to be a duration, route, dose, or schedule relationship.
Administration of cyclophosphamide in doses higher than 30-40 mg/kg has been associated with water retention and dilutional hyponatremia. Decreased urine flow, decreased serum osmolarity and sodium and increased urine osmolarity occur 4 to 12 hours after cyclophosphamide and resolve within 20 to 24 hours after therapy. This is related to a direct toxic effect of alkylating metabolites on distal renal tubules and collecting ducts. SIADH (syndrome of inappropriate secretion of ADH) may also be a contributing factor. The condition is self-limiting although diuretic therapy may be helpful in the situation where the patient has stopped urinating (especially if this occurs during the first 24 hours of cyclophosphamide therapy), in order to minimize contact of the toxic metabolites with the bladder mucosa. Susceptible patients should be monitored for cardiac decompensation. If weight gain is excessive (1.5-2 kg) during hydration, the volume of IV fluid should be reduced.
Nasal stuffiness or facial discomfort can occur with rapid injection. If troublesome for the patient, slow the infusion rate or give as an intermittent infusion rather than as an IV bolus.
Cardiac toxicity and acute cardiac failure (hemorrhagic necrosis) can occur, especially with high doses used in preparing patients for marrow transplantation (>120 mg/kg) and concomitant doxorubicin or daunorubicin therapy or with radiation to cardiac vessels or heart. Cardiac tamponade has been observed in thalassemic patients given cyclophosphamide prior to bone marrow transplant. Special caution is advised for patients with pre-existing cardiac disease and prior cardiac radiation.
Cyclophosphamide has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with, or even after the administration of the cyclophosphamide. Recurrent injury to a previously radiated site may occur weeks to months following the radiation.
Secondary malignancies have developed in some treated patients, often several years after administration. Neoplasms most frequently have been urinary bladder cancer, non-lymphocytic leukemia and non-Hodgkin’s lymphoma. Patients who develop bladder cancer usually have a history of hemorrhagic cystitis.
History
Cyclophosphamide and the related nitrogen mustard-derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds. They converted the base nitrogen mustard into a non-toxic “transport form”. This transport form was a pro-drug, subsequently actively transported into the cancer cells. Once in the cells, the pro-drug was enzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s.
Sources
Cancer Care Ontario Drug Monographs for Health Professionals (Acrobat pdf document)
V – Vincristine
Vincristine, also known as leurocristine, is a vinca alkaloid from the Madagascar periwinkle (Catharanthus roseus, formerly Vinca rosea and hence its name). It is a mitotic inhibitor, and is used in cancer chemotherapy. Causes myelosuppression – decreased activity of the bone marrow.
Vincristine works by preventing mitosis in metaphase. This alkaloid binds to tubulin, thus preventing the cell from making the spindles it needs to be able to divide. This is different from the action of taxol which interferes with cell division by keeping the spindles from being broken down.
Synonyms
VCR, LCR, leurocristine
Common Trade Names
Vincristine Sulfate Injection (Mayne), (Novopharm), Oncovin® (USA)
Molecular and Chemical
Adverse Effects
Nausea, vomiting, weight loss, diarrhea, bloating, stomach/abdominal pain or cramps, mouth sores, dizziness, or headache may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.
Vincristine may also affect the nerves in the intestines, causing gut movement to slow down. This effect can result in constipation, which in some cases may become serious. Consult your doctor or pharmacist about how you can prevent constipation (e.g., maintain a diet adequate in fiber, drink plenty of water, exercise, choose the right type of laxative with a stool softener, avoid bulk-forming laxatives). Tell your doctor or pharmacist promptly if you develop constipation.
Temporary hair loss may occur. Normal hair growth should return after treatment has ended.
Many people using this medication have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.
This medication commonly affects the nerves and muscles in your body. Most of these side effects go away after this medication is stopped, however some effects may persist for a long time. Tell your doctor immediately if any of these serious side effects occur: painful/difficult urination, change in the amount of urine, pain (e.g., in the joints, back, muscles, jaw), numbness/tingling/pain of the arms/legs, weakness, difficulty walking, loss of coordination/balance, inability to move your muscles (e.g., muscles of the face, other parts of your body), drooping eyelids, hoarseness, trouble speaking, mental/mood changes (e.g., depression, hallucinations, confusion).
Tell your doctor immediately if any of these rare but very serious side effects occur: vision/hearing changes, seizures, unusual bleeding/bruising.
This medication can lower the body’s ability to fight an infection. Tell your doctor promptly if you develop any signs of an infection such as fever, chills, or persistent sore throat.
Trouble breathing may infrequently occur with vincristine treatment, especially when it is given with another chemotherapy drug, mitomycin-C. Patients with lung problems may be more sensitive to this side effect. Long-term treatment of this side effect may be required if it worsens. This effect may occur within minutes to several hours after vincristine is given and up to 2 weeks after the dose of mitomycin-C. Seek immediate medical attention if you have shortness of breath or coughing. If you have this reaction, you should not receive vincristine again.
A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.
Peripheral neuropathy can be severe, and hence a reason to avoid, reduce, or stop the use of vincristine. This is due to the effect of vincristine on nerves. One of the first symptoms of peripheral neuropathy is foot drop: a person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) may benefit from genetic testing for CMT before taking vincristine. This usually improves slowly a few months after the treatment is finished. Very rarely other nerves may be affected (such as the neck nerves) which may cause pain in the jaw or double vision.
Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100%. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied by intractable pain, almost uniformly leading to death; a handful of survivors were left with devastating neurological damage with no hope of recovery. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.
If vincristine leaks out of the vein into the surrounding area, it may cause serious skin and tissue damage. Tell your health care professional immediately if you experience pain, irritation, redness, or swelling at the injection site. Prompt treatment of the leakage will help reduce discomfort and possible skin damage.
Not eating before your treatment may help relieve vomiting. Changes in diet such as eating several small meals or limiting activity may help lessen some of these effects. In some cases, drug therapy may be necessary to prevent or relieve nausea and vomiting. Contact your doctor, without delay, if you experience any of the following symptoms: constipation, stomach cramps, lack of sweating, painful or difficult urination, decrease or increase in urination, bed-wetting, joint pain, lower back or side pain, blurred or double vision, difficulty walking, headache, pain in jaw or testicles, pain or numbness in fingers or toes, nervousness, trouble sleeping, confusion, dizziness, fever or chills, hallucinations, loss of appetite, cough, unusual bleeding or bruising, black, tarry stools, blood in urine or stools, or small red spots on the skin.
History
Found in the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The natives of Madagascar traditionally used the vinca rosea to treat diabetes. In fact it has been used for centuries throughout the world to treat all kinds of ailments from wasp stings, in India, to eye infections in the Caribbean.
Studies in the 1950s revealed that C. roseus contained 70 alkaloids, many of which are biologically active. While initial studies for its use in diabetes mellitus were disappointing, the discovery that it caused myelosuppression led to its study in mice with leukemia, whose lifespan was prolonged by the use of a vinca preparation. Treatment of the ground plant with Skelly-B defatting agent and an acid benzene extract led to a fraction termed “fraction A”. This fraction was further treated with aluminium oxide, chromatography, trichloromethane, benz-dichloromethane and separation by pH to yield vincristine.
Vincristine was approved by the United States Food and Drug Administration (FDA) in July 1963 as Oncovin. The drug was initially marketed by Eli Lilly and Company.
Sources
A – Adriamycin
Adriamycin (generic name doxorubicin) is a common chemotherapy agent in the treatment of Hodgkin’s and Non-Hodgkin’s Lymphomas. It is more often than not used in conjunction with other chemotherapy agents in a multidrug regimen. It is is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. As such, it is an antineoplastic – adriamycin interferes with the growth of cancer cells. It is one of the older chemotherapy drugs, having been in use for decades for several types of cancer.
The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation. Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of the enzyme topoisomerase II, which unwinds DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.
The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures.
Diagram of two doxorubicin molecules intercalating DNA
The drug is administered by injection. It may be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex. Doxil is a liposome-encapsulated dosage form of doxorubicin made by Ben Venue Laboratories for Johnson & Johnson. The main benefits of this form are a reduction in cardiotoxicity. It is photosensitive and it is often covered by an aluminum bag to prevent light from affecting it.
Doxorubicin works by slowing or stopping the growth of cancer cells.
Synonyms
Doxorubicin, Rubex®
Common Trade Names
Doxorubicin Hydrochloride Injection
Molecular and Chemical
Adverse Effects
Acute side-effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. It can also cause neutropenia (a decrease in white blood cells), as well as complete alopecia (hair loss). When the cumulative dose of doxorubicin reaches 550 mg/m², the risks of developing cardiac side effects, including congestive heart failure, dilated cardiomyopathy, and death, dramatically increase. Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation. Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage the myocytes (heart cells), causing myofibrillar loss and cytoplasmic vacuolization. Additionally, some patients may develop Palmar plantar erythrodysesthesia, or, “Hand-Foot Syndrome,” characterized by skin eruptions on the palms of the hand or soles of the feet, characterized by swelling, pain and erythema.
Acute nausea and vomiting occurs frequently and may be severe. This may be alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may occur 5 to 10 days after administration. The effect may be severe leading to ulceration and represents a site of origin for severe infections. The dosage regimen consisting of administration of doxorubicin on three successive days results in greater incidence and severity of mucositis. Ulceration and necrosis of the colon, especially the cecum, may occur leading to bleeding or severe infections which can be fatal. This reaction has been reported in patients with acute non-lymphocytic leukemia treated with a 3-day course of doxorubicin combined with cytarabine. Anorexia and diarrhea have been occasionally reported.
Phlebosclerosis has been reported especially when small veins are used or a single vein is used for repeated administration. Facial flushing may occur if the injection is given too rapidly.
Due to these side effects and its red color, doxorubicin has earned the nickname “red devil.”
History
The history of doxorubicin can be traced back to the 1950s, when an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th century castle. A new strain of Streptomyces peucetius which produced a bright red pigment was isolated, and an antibiotic was produced from this bacterium that was found to have good activity against murine tumors. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin, combining the name Dauni, a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby, rubis, describing the color. Clinical trials began in the 1960s, and the drug saw success in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could produce fatal cardiac toxicity.
Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces was mutated using N-nitroso-N-methyl urethane and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention. Doxorubicin showed better activity than daunorubicin against murine tumors, and especially solid tumors. It also showed a relatively higher therapeutic index, yet the cardiotoxicity remained.
Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research by many investigators throughout the world has led to many other anthracycline antibiotics, or analogs, and today, it is estimated that there are over 2,000 known analogs of doxorubicin. By 1991, 553 of them have been evaluated in the screening program at the National Cancer Institute (NCI).
Sources
D – Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. It acts as an anti-inflammatory and immunosuppressant.
Dexamethasone is a strong anti-inflammatory agent. Its potency is about 20-30 times that of hydrocortisone and 4-5 times of prednisone. This drug works by preventing white blood cells from completing an inflammatory reaction. This drug can cause lymphocytes, a type of white blood cell, to break apart and die. Thus it is an important drug used in combination with chemotherapy for the treatment of lymphoma, leukemia, and multiple myeloma. The drug is sometimes given to reduce the likelihood that a person will have an allergic reaction to a chemotherapeutic agent, such as paclitaxel. Finally, this medicine is used to prevent nausea and vomiting from chemotherapy, in combination with other drugs.
Synonyms
Decadron, Dexamethasonum, DXM, Hexadecadrol, Methylfluorprednisolone
Common Trade Names
Aeroseb-Dex, Alba-Dex, Decaderm, Decadrol, Decadron, Decasone R.p., Decaspray, Deenar, Deronil, Dex-4, Dexace, Dexameth, Dezone, Gammacorten, Hexadrol, Maxidex, Sk-Dexamethasone
Molecular and Chemical
Adverse Effects
- Stomach upset, increased sensitivity to stomach acid to the point of ulceration of esophagus, stomach, and duodenum
- Increased appetite leading to significant weight gain
- A latent diabetes mellitus often becomes manifest. Glucose intolerance is worsened in patients with preexisting diabetes.
- Immunsuppressant action, particularly if given together with other immunosuppressants such as ciclosporine. Bacterial, viral, and fungal disease may progress more easily and can become life-threatening. Fever as a warning symptom is often suppressed.
- Psychiatric disturbances, including personality changes, irritability, euphoria, mania
- Osteoporosis under long term treatment, pathologic fractures (e.g., hip)
- Muscle atrophy, negative protein balance (catabolism)
- Elevated liver enzymes, fatty liver degeneration (usually reversible)
- Cushingoid (syndrome resembling hyperactive adrenal cortex with increase in adiposity, hypertension, bone demineralization, etc.)
- Depression of the adrenal gland is usually seen, if more than 1.5 mg daily are given for more than three weeks to a month.
- Hypertension, fluid and sodium retention, edema, worsening of heart insufficiency (due to mineral corticoid activity)
- Dependence with withdrawal syndrome is frequently seen.
- Increased intraocular pressure, certain types of glaucoma, cataract (serious clouding of eye lenses)
- Dermatologic: Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, erythema, impaired wound-healing, increased sweating, rash, striae, suppression of reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.
- Allergic reactions (though infrequently): Anaphylactoid reaction, anaphylaxis, angioedema. (Highly unlikely, since dexamethasone is given to prevent anaphylactoid reactions.)
In addition to the CVAD drugs, the following drugs are part of the regimen:
Mesna
Mesna (INN) is an adjuvant used in cancer chemotherapy involving cyclophosphamide and ifosfamide. It is currently marketed by Baxter as Uromitexan and Mesnex.
Mesna is used therapeutically to reduce the incidence of haemorrhagic cystitis and haematuria when a patient receives ifosfamide or cyclophosphamide for cancer chemotherapy. These two anticancer agents, in vivo, may be converted to urotoxic metabolites such as acrolein and other urotoxic metabolites of oxazaphosphorines (cyclophosphamide or ifosfamide) to form stable, non-urotoxic compounds. Mesna does not have any antitumour activity, nor does it appear to interfere with the antitumour activity of
antineoplastic drugs. Mesna assists to neutralise these metabolites by binding through its sulfhydryl-moieties, and also increases urinary excretion of cysteine.
Mesna .pdf document (click here)
Some people who are given ifosfamide chemotherapy may get blood in their urine (haematuria). This can also happen with higher doses of cyclophosphamide chemotherapy, but is less common. Both drugs can cause irritation and bleeding from the lining of the bladder and the kidneys. Mesna helps to protect your bladder and kidneys, to prevent this.
Mesna is always given with ifosfamide, and normally only given with higher doses of cyclophosphamide (as with HyperCVAD regimen). While you are having this treatment, your urine is closely monitored and tested for any signs of blood. If you have blood in your urine, you will be given extra mesna. Drinking as much water as possible can help to flush through the chemotherapy.
Synonyms
Sodium 2-mercaptoethane sulfonate
Common Trade Names
Uromitexan® (Baxter), Mesna for Injection (Pharmaceutical Partners of Canada)
Molecular and Chemical
Adverse Effects
Feeling or being sick (nausea and vomiting) There are now very effective anti-sickness drugs (anti-emetics) to prevent or reduce nausea and vomiting. These are normally given both in the drip with the treatment, and as tablets. If the sickness is not controlled, or continues, tell your doctor. They can give you other anti‑sickness drugs which may be more effective. Some anti‑sickness drugs may cause constipation. Let your doctor or nurse know if this is a problem.
Taste changes This is common. You may notice that your food tastes different. Normal taste will come back after your treatment has finished.
Headache Your doctor or nurse can give you tablets to help relieve this.
Diarrhoea or soft stools that may cause discomfort or colic (wind) Diarrhoea can normally be easily controlled with medicine, but let your doctor know if it is severe or continues. Try to drink as much as 2–3 litres of fluid a day, to replace the fluid you are losing.
Tiredness and a general feeling of weakness Fatigue is also a common side effect of chemotherapy. It is important to allow yourself plenty of time to rest.
Limb and joint pain Your doctor can give you painkillers to help relieve this pain.
Skin changes Mesna can cause a rash, which may be itchy. Your doctor can give you medicine to help with this.
Irritability and mood changes Occasionally, mesna can make you feel irritable and to have mood swings. Let your doctor know if there are any changes in your behaviour that concern you.
more drug information to come
[...] Drugs [...]
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