warfarin and Adenocarcinoma

We are presenting a rare case of a spontaneous extensive perirenal hematoma caused by ruptured renal adenocarcinoma in a patient who was on warfarin therapy because she had atrial fibrillation and three myocardial infarctions. A 77-year-old woman was admitted to our department with acute right flank pain and hemorrhagic shock. The anamnestic data revealed no trauma and hematuria. Abdominal ultrasonography and computed tomography scan showed large retroperitoneal hematoma. The patient underwent urgent surgery and radical nephrectomy was performed. A large retroperitoneal hematoma was found originating from a ruptured renal neoplasm in the upper pole of the right kidney. The pathohistological diagnosis was chromophobe renal cell carcinoma. The clinical, diagnostic and therapeutic peculiarities of this rare condition are presented, along with the literature review on the topic.

Topics: Adenocarcinoma; Aged; Anticoagulants; Atrial Fibrillation; Carcinoma, Renal Cell; Diagnosis, Differential; Female; Hematoma; Humans; Kidney Neoplasms; Warfarin

Cancer cells may promote fibrin formation in the tumor microenvironment through availability of procoagulant activities which are mainly of two types: tissue thromboplastin-like or direct activator of coagulation factor X. The pharmacological modulation of these activities could be potentially important in the control of metastasis growth. However, very limited information is available so far on this issue; it has recently been shown that the direct activator of coagulation factor X is a vitamin K-dependent activity which is depressed by warfarin treatment, not by anticoagulation with heparin or defibrinating enzymes. Whether the inhibition of this peculiar cancer procoagulant is involved in the antimetastatic activity of warfarin is a stimulating hypothesis which needs to be further substantiated.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Blood Coagulation Factors; Cell Membrane; Cysteine Endopeptidases; Endopeptidases; Humans; Leukemia, Myeloid, Acute; Mice; Mucins; Neoplasm Metastasis; Neoplasm Proteins; Thromboplastin; Warfarin

The purpose of The Cancer and Leukemia Group B (CALGB) 90203 trial is to determine which of 2 treatment strategies is superior in treating men with high-risk, clinically localized adenocarcinoma of the prostate (stage T1 to T3a NX M0), defined as a predicted probability < or =60% of remaining free from disease recurrence for 5 years after surgery. Patients with a > or =10-year life expectancy will be randomized to either radical prostatectomy (RP) alone versus estramustine and docetaxel before RP. Participants will be excluded if they have received prior therapy for prostate cancer (except transurethral resection of the prostate) or are judged not to be appropriate candidates for RP. Eligible patients will be stratified according to their predicted probability of remaining free from disease recurrence at 5 years after surgery (0% to 20%, 21% to 40%, and 41% to 60%) and randomized. Neoadjuvant chemotherapy will be 6 cycles (1 cycle = 21 days) of estramustine (280 mg tid, days 1 to 5) and docetaxel (70 mg/m2 on day 2). Warfarin (2 mg/day orally) will be given for prophylaxis against deep venous thrombosis. Bilateral pelvic lymph node dissection and RP will be performed within 60 days of registration/randomization for men randomized to the surgery-alone arm. For men randomized to receive preoperative chemotherapy, the surgical procedure will be performed within 60 days of completion of chemotherapy. Patients will be monitored with history review, physical examination, and serum prostate-specific antigen (PSA) levels every 3 months for the first 3 years after surgery, every 6 months for the next 3 years, and annually thereafter. Biochemical disease recurrence will be defined as a serum PSA level >0.4 ng/mL on 2 consecutive occasions > or =3 months apart after RP. The time of biochemical failure is measured from the date of randomization to the time of the first PSA level <0.4 ng/mL that is confirmed on the second serial PSA. The primary study end point is to determine if early systemic treatment with neoadjuvant estramustine and docetaxel before RP in patients with high-risk prostate cancer will decrease 5-year recurrence rates when compared with RP alone. Secondary outcomes will include (1) the safety and tolerability of neoadjuvant estramustine and docetaxel before RP; (2) the impact of this neoadjuvant strategy on pathologic tumor stage, including lymph node and surgical margin status; (3) time to clinically apparent disease recurrence; and (4) overall sur

Topics: Adenocarcinoma; Anticoagulants; Clinical Trials, Phase III as Topic; Disease-Free Survival; Docetaxel; Estramustine; Feasibility Studies; Humans; Lymph Node Excision; Male; Multicenter Studies as Topic; Neoadjuvant Therapy; Patient Selection; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk; Taxoids; Thromboembolism; Treatment Outcome; Warfarin

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Drug Interactions; Female; Humans; Hypoprothrombinemias; Lung Neoplasms; Middle Aged; Ovarian Neoplasms; Sulfonylurea Compounds; Warfarin

VA Cooperative Study #75 was established to test in a controlled, randomized trial the hypothesis that warfarin anticoagulation would favorably affect the course of certain types of malignancy. No differences in survival were observed between warfarin-treated and control groups for advanced non-small cell lung, colorectal, head and neck and prostate cancers. However, warfarin therapy was associated with a significant prolongation in the time to first evidence of disease progression (P = 0.016) and a significant improvement in survival (P = 0.018) for patients with small cell carcinoma of the lung, including the subgroup of patients with disseminated disease at the time of randomization (P = 0.013). A trend toward improved survival with warfarin treatment was observed for the few patients admitted to this study with non-small cell lung cancer who had minimal disease at randomization. These results suggest that warfarin, as a single anticoagulant agent, may favorably modify the course of some, but not all, types of human malignancy, among which is small cell carcinoma of the lung. Further trials of warfarin may be indicated in patients with limited disease who have cell types that failed to respond when advanced disease was present.

Topics: Adenocarcinoma; Blood Coagulation; Carcinoma, Small Cell; Clinical Trials as Topic; Colonic Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Prostatic Neoplasms; Random Allocation; Warfarin

The value of the oral anticoagulant warfarin sodium and fibrinolytic agents is discussed in relation to cancer surgery. A controlled trial of 128 patients showed that in a variety of recurrent cases the addition of warfarin to chemotherapy doubled the 2-year survival rate. The best results were obtained in postmenopausal patients with breast cancer. Warfarin depresses cellular immune responses which might militate against its use for cases undergoing "curative" surgery. Instead, induction of fibrinolysis by streptokinase or Brinase is suggested, because it increases the activity of the cellular immune mechanism. The results to date of an ongoing controlled randomized trial of streptokinase with surgery of tumors of the large bowel are presented, showing that the trends are in favor of streptokinase therapy; however, insufficient time has elapsed to make it, as yet, statistically significant. The action of streptokinase-induced plasmin and Brinase on lymphocytes is described.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Agents; Aspergillus; Breast Neoplasms; Colonic Neoplasms; Drug Evaluation; Female; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity, Cellular; Lymphoma, Non-Hodgkin; Male; Neoplasms; Ovarian Neoplasms; Peptide Hydrolases; Rectal Neoplasms; Streptokinase; Warfarin

Mistletoe, Viscum album, is a medicinal plant used in complementary medicine in oncology. Patients do not necessarily mention to their oncologist this phytotherapeutic treatment which may be responsible for unsuspected drug interactions. Some patients are adept at taking medicinal plants, a practice often unknown to health professionals who take care of them. This case reports drug interactions leading to bleeding secondary to warfarin overdose. A patient over 75 years of age was treated with nab-paclitaxel and gemcitabine as a first course for metastatic pancreatic adenocarcinoma (day 0). He was also treated with warfarin for atrial fibrillation. At day 3, he reported faintness and melena. At day 5, the biological assessment revealed anemia with hemoglobinemia of 5.1 g/dL and an international normalized ratio of 7.3, indicating vitamin K antagonist (VKA) overdose. Warfarin was discontinued and the patient received vitamin K supplementation and transfusions. The final diagnosis was an anemic syndrome due to gastrointestinal bleeding secondary to VKA overdose. Based on the chronology, a drug interaction between chemotherapy and warfarin was first suspected. Then, the patient interview found out that he self-medicated with subcutaneous injections of mistletoe extracts: 10 mg on day 0 and on day 2. Nab-paclitaxel can displace warfarin from its albumin binding sites and increase the free and active concentration of warfarin. Mistletoe extracts (V. album) are used as complementary medicine in oncology. Warfarin is predominantly metabolized in the liver by 1A2, 2C9, and 3A4 cytochrome P450 (CYP) isoforms. An inhibitor of these cytochromes prevents the degradation of warfarin into inactive metabolites, leading to accumulation or even overdose of this narrow therapeutic index VKA. Nab-paclitaxel and gemcitabine do not act on these cytochromes. V. album is a cytochrome P450 3A4 inhibitor which therefore probably led to an increase in exposure to warfarin. Thus, there are two pharmacokinetic hypotheses that may explain warfarin overdose: the displacement of warfarin from its albumin binding sites or the inhibition of CYP3A4 by mistletoe. This adverse drug event was reported to the Regional Pharmacovigilance Center of Strasbourg on June 30, 2021, and registered under the number ST20212767.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Cytochrome P-450 Enzyme System; Drug Interactions; Gemcitabine; Humans; Male; Paclitaxel; Pancreatic Neoplasms; Plant Extracts; Warfarin

Topics: Adenocarcinoma; Albumins; Anticoagulants; Breast Neoplasms; Deoxycytidine; Female; Gemcitabine; Heart Ventricles; Humans; Magnetic Resonance Imaging; Middle Aged; Paclitaxel; Pancreatic Neoplasms; Thrombosis; Warfarin

A 66-year-old man with acute ischemic stroke in the setting of lung adenocarcinoma developed acute-onset deep vein thrombosis (DVT) of the lower limbs after changing to warfarin from a heparin combination. The diagnosis of warfarin-resistant DVT was established based on the laboratory data and clinical evaluation. Heparin administration resulted in good control of thrombin regulation. Cancer patients are at high risk of venous thromboembolism, and the combination of these 2 conditions is known as Trousseau's syndrome.. Our report suggests that heparin administration may provide good control of thromboembolic events, although there is no established medical treatment to extend the survival of patients with Trousseau's syndrome.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anticoagulants; Diffusion Magnetic Resonance Imaging; Humans; Lung Neoplasms; Male; Stroke; Tomography Scanners, X-Ray Computed; Venous Thrombosis; Warfarin

Experimental evidence suggests that anticoagulants (ACs) may inhibit cancer growth and metastasis, but clinical data have been limited. We investigated whether use of ACs was associated with the risk of death from prostate cancer.. This study comprised 5,955 men in the Cancer of the Prostate Strategic Urologic Research Endeavor database with localized adenocarcinoma of the prostate treated with radical prostatectomy (RP) or radiotherapy (RT). Of them, 2,175 (37%) were receiving ACs (warfarin, clopidogrel, enoxaparin, and/or aspirin). The risk of prostate cancer-specific mortality (PCSM) was compared between the AC and non-AC groups.. After a median follow-up of 70 months, risk of PCSM was significantly lower in the AC group compared with the non-AC group (3% v 8% at 10 years; P < .01). The risks of disease recurrence and bone metastasis were also significantly lower. In a subgroup analysis by clinical risk category, the reduction in PCSM was most prominent in patients with high-risk disease (4% v 19% at 10 years; P < .01). The benefit from AC was present across treatment modalities (RT or RP). Analysis by type of AC medication suggested that the PCSM reduction was primarily associated with aspirin. Multivariable analysis indicated that aspirin use was independently associated with a lower risk of PCSM (adjusted hazard ratio, 0.43; 95% CI, 0.21 to 0.87; P = .02).. AC therapy, particularly aspirin, was associated with a reduced risk of PCSM in men treated with RT or RP for prostate cancer. The association was most prominent in patients with high-risk disease.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Chemoprevention; Clopidogrel; Enoxaparin; Humans; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms; Risk; Ticlopidine; Warfarin

To characterize the bleeding toxicity associated with external beam radiotherapy for prostate cancer patients receiving anticoagulation (AC) therapy.. The study cohort consisted of 568 patients with adenocarcinoma of the prostate who were treated with definitive external beam radiotherapy. Of these men, 79 were receiving AC therapy with either warfarin or clopidogrel. All patients were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Bleeding complications were recorded during treatment and subsequent follow-up visits.. With a median follow-up of 48 months, the 4-year actuarial risk of Grade 3 or worse bleeding toxicity was 15.5% for those receiving AC therapy compared with 3.6% among those not receiving AC (p < .0001). On multivariate analysis, AC therapy was the only significant factor associated with Grade 3 or worse bleeding (p < .0001). For patients taking AC therapy, the crude rate of bleeding was 39.2%. Multivariate analysis within the AC group demonstrated that a higher radiotherapy dose (p = .0408), intensity-modulated radiotherapy (p = 0.0136), and previous transurethral resection of the prostate (p = .0001) were associated with Grade 2 or worse bleeding toxicity. Androgen deprivation therapy was protective against bleeding, with borderline significance (p = 0.0599). Dose-volume histogram analysis revealed that Grade 3 or worse bleeding was minimized if the percentage of the rectum receiving >or=70 Gy was <10% or the rectum receiving >or=50 Gy was <50%.. Patients taking AC therapy have a substantial risk of bleeding toxicity from external beam radiotherapy. In this setting, dose escalation or intensity-modulated radiotherapy should be used judiciously. With adherence to strict dose-volume histogram criteria and minimizing hotspots, the risk of severe bleeding might be reduced.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Anticoagulants; Clopidogrel; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Multivariate Analysis; Prostatic Neoplasms; Radiotherapy Dosage; Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Rectum; Severity of Illness Index; Ticlopidine; Transurethral Resection of Prostate; Urologic Diseases; Warfarin

The case of a patient who developed elevated International Normalized Ratio (INR) values after concomitant administration of warfarin and erlotinib is reported.. A 47-year-old Caucasian man with a history of atrial fibrillation, anxiety, and a 40-pack-year smoking history was diagnosed with advanced, moderately differentiated adenocarcinoma of the lung. Soon after being diagnosed with non-small-cell lung cancer, warfarin was initiated for the treatment of a venous thromboembolism. The patient's warfarin dosage was adjusted to reach a target INR of 2-3. His INR was relatively stable (2.1-3.2) for at least eight weeks before erlotinib was added to the chemotherapy regimen. The patient developed a well-disseminated rash and diarrhea soon after starting erlotinib. Seven days after the initiation of erlotinib therapy, the patient's INR value increased from 2.8 to 5.3, with no concurrent changes in warfarin dosage, other medications, or diet. After withholding two doses of warfarin, the patient's INR value increased to 9.1, and the patient developed an elbow hematoma. His anticoagulation was rapidly reversed with the administration of subcutaneous phytonadione. The patient elected to discontinue erlotinib nine days after its initiation. The next day, his INR value was 2.4. The patient returned to the hematology-oncology clinic for follow-up two days later, where his INR was found to be 0.9.. Concomitant administration of erlotinib and warfarin resulted in an increase in INR values in a 47-year-old man with advanced lung cancer.

Topics: Adenocarcinoma; Anticoagulants; Carcinoma, Non-Small-Cell Lung; Drug Interactions; Drug Therapy, Combination; Erlotinib Hydrochloride; Humans; International Normalized Ratio; Lung Neoplasms; Male; Middle Aged; Quinazolines; Thromboembolism; Warfarin

A 56-yr-old man with lung adenocarcinoma presented with subsegmental pulmonary thrombosis. Platelet count on presentation was 531 x 10(9)/L. The patient was anticoagulated with subcutaneous low molecular weight heparin (LMWH). Next day, oral anticoagulation was initiated with 5 mg of warfarin once daily with LMWH and LMWH was discontinued at third hospital day. On the third day of oral anticoagulation therapy, he complained of left leg swelling and prolonged painful penile erection of 24 hr-duration. His platelet count reached a nadir 164 x 10(9)/L at that time, and the patient had a deficiency of protein C and S, with an activity level of 16% and 20% of normal value. Warfarin was stopped and he underwent penile aspiration. The next day, left leg edema and penile erection was disappeared, but penile and glans penis necrosis was started. This case illustrates that processes underlying heparin-induced thrombocytopenia (HIT) may also underlie warfarin-induced skin necrosis.

Topics: Adenocarcinoma; Anticoagulants; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Necrosis; Penile Erection; Penis; Platelet Count; Protein C; Protein S; Pulmonary Artery; Thrombocytopenia; Thrombosis; Warfarin

Pulmonary embolism (PE) is a common complication in lung cancer patients with a high misdiagnosis rate and high mortality. This study was to investigate the clinical characteristics, diagnosis and treatment approaches for lung cancer accompanied by PE, thus to improve the diagnosis and treatment efficacy of this disease.. Clinical manifestations, comorbid conditions, risk factors, laboratory (indirect) and imaging examinations (direct) and treatment methods of 23 lung cancer patients with PE were retrospectively analyzed.. Among the 23 patients, 14(60.87%) had hypoxemia, all (100%) had elevated serum D-dimer, 11 (47.83%) had characteristic changes in electrocardiogram. Ten out of 12 cases (83.33%) examined by computed tomography angiography were found filling defect in the pulmonary artery; all two case receiving isotope perfusion scanning were detected segmental perfusion defect in the lung; one case undergoing MRI was found segmental filling defect in the pulmonary artery; and one case was discovered the direct sign of PE by pulmonary arteriography. The medium survival time (MST) of five cases who received symptomatic treatment was 13 days, of four cases who received thrombolysis therapy was 22.5 days, of 12 cases who underwent anticoagulation and chemotherapy was 93 days, and of two cases who were only given anticoagulant therapy were 70 days and 189 days respectively.. Diagnosis of lung cancer accompanied by PE mainly depends on direct examinations. Thrombolysis and anticoagulation therapy are recommended for those patients. In addition, chemotherapy may also be considered.

Topics: Adenocarcinoma; Adult; Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Blood Gas Analysis; Echocardiography; Electrocardiography; Female; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Pulmonary Embolism; Retrospective Studies; Survival Rate; Tomography, Spiral Computed; Urokinase-Type Plasminogen Activator; Warfarin

Gemcitabine is the only chemotherapeutic agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced pancreatic cancer. 5-fluorouracil or its oral pro-drug, capecitabine is the second most commonly used agent in this malignancy. Capecitabine or 5-fluorouracil is the second most common agent used either in second-line or as a radiosensitizer. Thromboembolism requiring anticoagulation is a common paraneoplastic complication in these patients. We report a patient with pancreatic cancer, challenged with maintaining the international normalized ratio (INR) with gemcitabine-capecitabine combination, and later with gemcitabine monotherapy with concomitant warfarin, as well as, a brief review of the literature. Patients with pancreatic cancer who receive warfarin and gemcitabine should be monitored for any potential drug interactions. Frequent prothrombin time and INR evaluations are suggested for anticoagulated patients receiving gemcitabine, especially when combined with capecitabine.

Topics: Adenocarcinoma; Aged; Blood Coagulation; Capecitabine; Cholangiopancreatography, Endoscopic Retrograde; Deoxycytidine; Drug Interactions; Female; Fluorouracil; Gemcitabine; Humans; International Normalized Ratio; Pancreatic Neoplasms; Prothrombin Time; Stents; Warfarin

Nutritional deficiencies due to malabsorption occur after major gastric resection, and drugs that are primarily absorbed in the stomach or duodenum also are likely to exhibit decreased absorption. However, we performed a MEDLINE search (1960-2007) and found no evidence in the literature regarding the specific effects of warfarin absorption after total gastrectomy with Roux-en-Y gastric bypass procedure. We describe a 71-year-old woman receiving warfarin therapy for chronic atrial fibrillation who underwent a completion gastrectomy and Roux-en-Y esophagojejunostomy for an invasive adenocarcinoma of her gastric remnant. Before surgery, her international normalized ratio (INR) had been stable in her target range of 2-3 with warfarin 5-6 mg/day. At the time of her admission for the surgery, however, her INR was subtherapeutic at 1.73; warfarin was discontinued, and heparin and, subsequently, enoxaparin were used throughout her admission. After the surgery, the patient was discharged to a skilled nursing facility to continue bridge therapy with enoxaparin while warfarin was restarted and adjusted to a therapeutic INR of 2-3. Three months after discharge, the patient was hospitalized again for shortness of breath and was found to have an INR of 1.30 on admission, despite good compliance with her drugs. During this admission, the patient demonstrated resistance to warfarin therapy, requiring doses up to 20 mg/day to reach a therapeutic INR. To our knowledge, this is the first case report to demonstrate that patients undergoing a complete gastric resection followed by a Roux-en-Y gastric bypass procedure may display warfarin resistance. Close monitoring and dosage adjustment may be necessary to maintain therapeutic anticoagulation in these patients.

Topics: Adenocarcinoma; Aged; Atrial Fibrillation; Chronic Disease; Drug Resistance; Esophagus; Female; Gastrectomy; Gastric Bypass; Humans; International Normalized Ratio; Jejunum; Stomach Neoplasms; Warfarin

Hemostatic physiology involves a complex interlinking of blood and endothelial factors. Its pharmacological manipulation invariably impacts at multiple molecular sites. Herein is reported an unusual case of coexistent warfarin-induced skin necrosis and heparin-induced thrombocytopenia following mitral valve replacement for thromboembolic phenomena associated with marantic endocarditis and bronchial adenocarcinoma. Thrombophilia in the face of endocarditis should be treated with a suspicion of underlying cancer.

Topics: Adenocarcinoma; Anticoagulants; Bronchial Neoplasms; Endocarditis; Fatal Outcome; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Heparin; Humans; Intracranial Embolism; Male; Middle Aged; Mitral Valve; Necrosis; Postoperative Complications; Skin; Thrombocytopenia; Warfarin

The incidence of venous thromboembolism in cancer patients is reportedly around 15%, and a pulmonary embolism is an important cause of morbidity and mortality. We present a case of duodenal carcinoma with peritoneal carcinomatosis complicated by a pulmonary embolism. Heparin, followed by warfarin, was useful to treat the embolism. The combination chemotherapy with TS-1 and docetaxel was effective for the peritoneal carcinomatosis. The QOL of this patient was maintained for about 5 months.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Combinations; Drug Therapy, Combination; Duodenal Neoplasms; Female; Heparin; Humans; Middle Aged; Oxonic Acid; Peritoneal Neoplasms; Pulmonary Embolism; Quality of Life; Taxoids; Tegafur; Warfarin

Concurrent use of warfarin and 5-fluorouracil has resulted in elevated international normalized ratios (INRs). Although this drug interaction is well established in the literature, we found no documented cases that address its effects on anticoagulation parameters in patients requiring repeated cycles of 5-fluorouracil and continuous warfarin therapy. We describe the effect of multiple cycles of 5-fluorouracil administration in a patient receiving warfarin therapy. The patient's INR increased 11-14 days after each cycle of chemotherapy with 5-fluorouracil and leucovorin. In addition, she required additive reductions of 33-42% in her weekly warfarin dose with each chemotherapy cycle to maintain a therapeutic INR (goal range 2.0-3.0). After three cycles of chemotherapy over a 10-week period, the patient's dosage requirements returned to her baseline level (before treatment with 5-fluorouracil and leucovorin had started). Pertinent literature was reviewed to provide supporting evidence for the mechanism and clinical implications of the drug interaction. Based on this report and previous case reports, caution is advised when concurrent warfarin and 5-fluorouracil are prescribed. In addition, patients should be closely monitored for a possible delayed interaction that may occur with each repeated cycle of 5-fluorouracil chemotherapy.

Topics: Adenocarcinoma; Anticoagulants; Antimetabolites, Antineoplastic; Colonic Neoplasms; Drug Synergism; Female; Fluorouracil; Humans; International Normalized Ratio; Middle Aged; Warfarin

Necrosis of the digits is a rare complication of warfarin therapy of obscure pathogenesis. We report a 61-year-old woman with a 12-month history of Raynaud's phenomenon who developed multiple digital necrosis following aortic valve replacement with mechanical prosthesis for aortic insufficiency caused by nonbacterial thrombotic endocarditis. Exacerbation of Raynaud's phenomenon occurred during the postoperative period, with daily episodes of ischemia of the fingers and toes that improved with local warming. However, coincident with the occurrence of immune heparin-induced thrombocytopenia, and while undergoing routine warfarin anticoagulation because of the mechanical valve prosthesis, the patient abruptly developed progression of digital ischemia to multiple digital necrosis on postoperative day 8, at the time the international normalized ratio reached its peak value of 4.3. All limb pulses were readily palpable, and vascular imaging studies showed thrombosis only in the superficial femoral and popliteal veins of the right leg. Coagulation studies showed greatly elevated levels of thrombin-antithrombin complexes and prothrombin fragment F1.2 levels, consistent with uncontrolled thrombin generation. After vitamin K administration, no abnormalities of the protein C anticoagulant pathway were identified, consistent with previous studies of other patients with warfarin-induced necrosis complicating heparin-induced thrombocytopenia. Subsequently, the patient was shown to have metastatic breast adenocarcinoma, which explained the patient's initial presentation with nonbacterial thrombotic endocarditis. This patient case suggests that multiple digital gangrene can result from the interaction of various localizing and systemic factors, including compromised microvascular blood flow (Raynaud's phenomenon), increased thrombin generation (heparin-induced thrombocytopenia, adenocarcinoma), and warfarin-induced failure of the protein C natural anticoagulant pathway.

Topics: Adenocarcinoma; Anticoagulants; Aortic Valve; Endocarditis; Female; Fingers; Heart Valve Prosthesis Implantation; Heparin; Humans; Ischemia; Middle Aged; Necrosis; Postoperative Period; Raynaud Disease; Thrombocytopenia; Thrombosis; Toes; Warfarin

A 53-year-old man with lung adenocarcinoma developed pulmonary embolism and bilateral popliteal venous thrombosis. Treated with intravenous unfractionated heparin and discharged home on warfarin, he returned a week later with extending thrombosis. Treatment with heparin followed by warfarin was reinitiated. Twenty-four hours following the re-administration of warfarin, the patient's INR increased to 14.5. The platelet count dropped by more than 50%, and he developed venous limb gangrene of the left leg and skin necrosis of the right leg. Heparin-induced thrombocytopenia was ruled out, and coagulation studies showed a severe depletion of protein C as well as increased thrombin generation. The patient was transfused with fresh frozen plasma, and vitamin K was given. Heparin was continued, and after 4 weeks, the patient improved markedly showing only minimal necrosis of the toes. Venous limb gangrene is a major complication associated with warfarin therapy. Its pathogenesis is explained by a transient hypercoagulable state produced by protein C depletion that leads to microvascular thrombi progressing to venous limb gangrene. The present case emphasizes the importance of careful anticoagulation with heparin followed by slow initiation of low-dose warfarin, in order to minimize thrombotic complications.

Topics: Adenocarcinoma; Anticoagulants; Fatal Outcome; Gangrene; Heparin; Humans; Male; Middle Aged; Popliteal Vein; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism; Thrombosis; Warfarin

Topics: Adenocarcinoma; Adult; Anticoagulants; Arterial Occlusive Diseases; Autoimmune Diseases; Drug Resistance; Female; Heparin; Heparin, Low-Molecular-Weight; Hepatitis C, Chronic; Hirudins; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Neoplasms, Unknown Primary; Platelet Aggregation Inhibitors; Portal Vein; Pulmonary Embolism; Recombinant Proteins; Recurrence; Thrombocytopenia; Vena Cava, Inferior; Venous Thrombosis; Warfarin

Acute pulmonary thromboembolism is fatal if the diagnosis and treatments are delayed. Here we present a case of acute thromboembolism to the right and left pulmonary arteries after right lung lobar resection. A 52-year-old woman who admitted to our hospital with lung cancer was performed right upper lobectomy with mediastinal lymph node dissection (pT1N0M0, well differentiated adenocarcinoma). Two days after surgery, she complained sudden chest discomfort and dyspnea. The blood pressure and oxygen saturation were rapidly decreased. Because there was no lung edema or atelectasis in the chest portable roentgenogram and no ischemic change in the electrocardiogram, pulmonary thromboembolism was suspected and emergency chest computed tomography (CT) was performed. The CT showed left and right pulmonary arterial thromboembolism and immediate anti-coagulator therapy was started. Her condition was improved and chest CT, which was performed three days after the onset of the thromboembolism, showed decreased but still remained thrombus. The anti-coagulator therapy was continued and one month after the onset of the thromboembolism, thrombus was disappeared on chest CT. She is doing well 17 months after surgery. Early diagnosis and treatments are critical for the pulmonary thromboembolism.

Topics: Adenocarcinoma; Anticoagulants; Female; Heparin; Humans; Lung Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Middle Aged; Pneumonectomy; Postoperative Complications; Pulmonary Embolism; Warfarin

Topics: Adenocarcinoma; Adult; Anticoagulants; Antimetabolites, Antineoplastic; Drug Interactions; Drug Therapy, Combination; Female; Fluorouracil; Humans; International Normalized Ratio; Prothrombin Time; Stomach Neoplasms; Thrombophlebitis; Warfarin

The increased mortality of emergency vs. elective colonic surgery applies equally to the right and left colon. Recent interest has surrounded the application of expandable metal stenting in acute obstruction but has been confined to the left colon. We describe successful application of stenting in the right colon, allowing postponement of a particularly high-risk laparotomy.. A patient with acute bilateral iliofemoral thromboses simultaneously developed complete obstruction of the proximal transverse colon. After heparinization and under fluoroscopic control, a 10-cm-long, self-expanding Wall-stent (Schneider, Bulach, Switzerland), 22 mm in diameter, was manipulated across the obstruction.. Immediate decompression with symptomatic relief ensued. The stent prevented obstruction during a 10-week period of anticoagulation, and repeat duplex scanning showed resolution of iliac thrombus. An elective right hemicolectomy was then performed. Postoperative course was uncomplicated, and histopathology confirmed a Dukes B carcinoma.. This case, in which a potentially hazardous laparotomy was delayed until the operative risk improved, defines a new role for stenting in colonic obstruction and demonstrates an extension of its applicability to the right colon. Literature review found no other report of stent application in the right colon.

Topics: Acute Disease; Adenocarcinoma; Aged; Anticoagulants; Colonic Neoplasms; Contraindications; Elective Surgical Procedures; Humans; Intestinal Obstruction; Laparotomy; Male; Stents; Thrombophlebitis; Warfarin

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cyclophosphamide; Drug Interactions; Female; Fluorouracil; Humans; Methotrexate; Middle Aged; Mitral Valve Stenosis; Prothrombin Time; Time Factors; Warfarin

CYP2C9 is involved in the metabolism of warfarin and a wide array of other therapeutic agents. It also appears to play a role, along with other cytochrome P450 enzymes, in the metabolism of benzo[a]pyrene, a carcinogen in tobacco smoke. A relatively common allelic variant (termed R144C, Cys144 or more recently CYP2C9*2) has been described that results in the substitution of cysteine for arginine at residue 144 and appears to reduce enzyme activity. We therefore examined the possible association between the presence of the CYP2C9*2 variant allele and risk of lung cancer using peripheral blood DNA from 329 incident cases of lung cancer (152 African-American and 177 Caucasian) and 700 (239 African-American and 461 Caucasian) population controls in Los Angeles County, California. Among the population controls the frequency of the CYP2C9*2 variant allele was lower (p = 0.00002) among African-Americans (0.036) than among Caucasians (0.100). The presence of the CYP2C9*2 variant allele was not associated with a decreased risk of lung cancer; slight but nonstatistically significant elevations in risk were observed for both African-Americans [odds ratio (OR) 1.22, 95% confidence interval (CI) 0.48-3.11] and Caucasians (OR = 1.55, 95% CI 0.96-2.48). The ORs were slightly and nonsignificantly elevated for all histologic types without substantive variation. The association also did not vary materially according to smoking history or whether subjects had the homozygous deletion of the GSTM1 gene. We found no support for the hypothesis that the CYP2C9*2 variant allele decreases the risk of lung cancer. The role of P450s, including CYP2C9, in benzo[a]pyrene metabolism is not fully defined, and CYP2C9 catalyses detoxication as well as activation steps. Thus it is not inconceivable that diminished CYP2C9 activity could increase metabolic activation of benzo[a]pyrene to carcinogenic intermediates. Nonetheless, the small increased risk associated the CYP2C9*2 variant allele in our data is consistent with chance and should not be overinterpreted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Alleles; Aryl Hydrocarbon Hydroxylases; Benzo(a)pyrene; Black People; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cohort Studies; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Genetic Variation; Genotype; Humans; Los Angeles; Lung Neoplasms; Middle Aged; Polymorphism, Genetic; Reference Values; Risk Factors; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Warfarin; White People

Topics: Adenocarcinoma; Aged; Colonic Neoplasms; Drug Interactions; Fluorouracil; Humans; Male; Warfarin

Among patients with various malignancies, three to 15 per cent may have associated idiopathic thrombosis. In a two-year period, we saw three patients with signs and symptoms demonstrating the association of neoplasia and coagulopathy. Their clinical courses and eventual outcomes are summarized. All had thrombophlebitis of multiple sites. There were difficulties in demonstrating their underlying occult malignancies, and all three patients showed resistance to oral anticoagulation drugs. Current hypotheses concerning the pathophysiology of coagulopathy associated with cancer are discussed, and recommendations for management of such patients were presented.

Topics: Adenocarcinoma; Adult; Blood Coagulation; Female; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Thrombophlebitis; Warfarin

Coumarin anticoagulants inhibit metastasis in several animal models, but the mechanism of this effect is uncertain. In order to determine the role of cytotoxic and/or cytostatic actions of coumarins on the tumour cells, we have studied the effects of warfarin on tumour cell growth in a model in which tumour metastasis is inhibited by this drug. Clonogenic assay, growth curve analysis and thymidine labelling index revealed that warfarin had no effects on Mtln3 mammary carcinoma cell growth in vitro at concentrations below 1 mM. The growth rate of subcutaneously implanted Mtln3 tumour deposits in female F344 rats, assessed by weight and by stathmokinetic analysis of the tumour tissue, was identical in warfarin-treated and control animals. Spontaneous metastasis from such tumours to the lungs was, however, significantly reduced in warfarin-treated animals (median 0 pulmonary tumours per animal in warfarin treated, eight tumours per animal in control animals; P less than 0.05, Mann-Whitney). The mean plasma warfarin concentration in warfarin treated rats was 1.63 microM. These results suggest that warfarin treatment of the host animal can inhibit tumour metastasis without having any direct or indirect effect on the growth rate of the tumour cells.

Topics: Adenocarcinoma; Animals; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Neoplastic Stem Cells; Rats; Rats, Inbred F344; Tumor Cells, Cultured; Warfarin

Topics: Adenocarcinoma; Female; Follow-Up Studies; Heparin; Humans; Middle Aged; Ovarian Neoplasms; Retrospective Studies; Thrombophlebitis; Warfarin

Patchy necrosis of the skin is a rare and unpredictable complication of oral anticoagulant therapy. Of the four patients that we have seen with this disorder, three had metastatic adenocarcinoma; in two, this was an unexpected finding. The association of a malignant neoplasm with warfarin-induced skin necrosis has not been emphasized previously. Whether such necrosis represents a clue to the presence of cancer or occurs only coincidentally in patients requiring anticoagulant therapy because of adenocarcinoma-associated thrombophlebitis must await further experience. A congenital or acquired deficiency of protein C may be the primary initiating factor.

Topics: Adenocarcinoma; Aged; Drug Eruptions; Female; Foot; Glycoproteins; Humans; Leg; Male; Necrosis; Neoplasm Metastasis; Pancreatic Neoplasms; Protein C; Sigmoid Neoplasms; Skin Diseases, Vesiculobullous; Warfarin

The PAIII rodent metastatic prostatic adenocarcinoma model was employed to evaluate the effects of dietary warfarin, a prototypic antagonist of thrombin generation on the lymphatic and pulmonary metastases of the tumor from the tail site of subcutaneous transplantation in male Lobund Wistar (LW) rats. In addition, the anticoagulant effects of warfarin were determined in the same animals. Warfarin, administered in the diet at concentrations equivalent to 0.063, 0.125 or 0.250 mg./kg. b.w. for 30 days had no effect on final body weight, gluteal or iliac lymph node weights. Significant (p less than 0.05) dose-dependent extensions of whole blood prothrombin (WBPT), activated partial thromboplastin (WBAPTT) and clotting times (WBCT) over control values were observed with warfarin treatment. Preliminary studies demonstrated that the 0.500 mg./kg. dose produced 50 per cent mortality at +14 days. Warfarin produced significant (p less than 0.05) dose-dependent decreases in the number of PAIII pulmonary metastases as indicated by reductions in dry lung weights and lung colony numbers when compared to untreated tumor-bearing controls. While the therapeutic index of warfarin is a limiting factor in clinical use as an antimetastatic agent, these results suggest that compounds capable of altering hemostatic mechanisms may be potential inhibitors of tumor metastasis. The PAIII prostatic adenocarcinoma model may be a useful system to quantitatively evaluate potential antimetastatic and cytotoxic agents.

Topics: Adenocarcinoma; Animals; Blood Coagulation; Blood Coagulation Tests; Diet; Dose-Response Relationship, Drug; Male; Neoplasm Metastasis; Prostatic Neoplasms; Rats; Warfarin

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Interactions; Etoposide; Humans; Lung Neoplasms; Male; Prothrombin Time; Vinblastine; Vindesine; Warfarin

Twenty-five patients with advanced measurable adenocarcinoma of the colon were treated with 5-fluorouracil (FUra), 15 to 20 mg/kg/week i.v., plus warfarin p.o. at a dosage which maintains therapeutic levels of anticoagulation. Sixty-four % of patients achieved either objective response (20%) or stable disease (44%). Overall median survival was 19.2 months. Three patients (all with intraluminal lesions) developed gastrointestinal blood loss requiring transfusion and discontinuation of anticoagulation. The interaction between warfarin and FUra as measured by plasma levels was investigated in seven rabbits and three patients. Plasma samples were obtained for 2 hr after FUra administration, both before and after anticoagulation with warfarin. FUra was measured by gas chromatography, and warfarin was assayed using a thin-layer chromatographic fluorescence method. In rabbits, prolongation of FUra plasma t1/2 was seen with high (0.6 mg/kg/hr) but not low (0.025 mg/kg/hr) rates of warfarin infusion. In patients, FUra t1/2 was not changed by therapeutic warfarin anticoagulation. Thus, (a) plasma clearance interaction between FUra and warfarin does not occur in patients receiving therapeutic levels of anticoagulation; (b) FUra and warfarin anticoagulation can be safely given and frequently result in stable disease status for patients with advanced colon cancer. Further trials of this combination are warranted in adenocarcinoma of the colon.

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Kinetics; Rabbits; Warfarin

Size-frequency distribution curves of erythrocytes were generated with the Coulter Counter in 73 normal subjects and patients. Mean corpuscular volume (MCV) determined by routine calculation and MCV determined by size-frequency distribution were similar in all normal subjects and in patients with a single population of erythrocytes. Some patients with iron-deficiency anemia, folate deficiency, and vitamin B12 deficiency had two discrete erythrocyte populations. Some patients with microcytic anemia were shown to have a population of normocytes in addition to the predominant microcytic population. Reticulocytes and normocytes were identified in two patients recovering from macrocytic anemia. Transfused blood was identified as a separate population in a patient with microcytic anemia. In cases with two erythrocyte populations, the MCV of the principal population, as determined from size-distribution curves, differed from the MCV of the entire erythrocyte pool, as was determined by routine methods. Analysis of sequential erythrocyte size distributions in patients under treatment demonstrated the dynamics of erythrocyte subpopulations. Anisocytosis was quantified and shown to be associated frequently with hospitalized patients.

Topics: Adenocarcinoma; Anemia, Hypochromic; Anemia, Macrocytic; Anemia, Pernicious; Brain Diseases; Electronics, Medical; Erythrocyte Count; Erythrocytes; Female; Folic Acid Deficiency; Heart Failure; Hematocrit; Hemorrhage; Humans; Male; Methotrexate; Middle Aged; Reticulocytes; Thrombophlebitis; Vitamin B 12 Deficiency; Warfarin

Topics: Adenocarcinoma; Animals; Aspirin; Heparin; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Neoplastic Cells, Circulating; Sodium Chloride; Warfarin

Topics: Adenocarcinoma; Animals; Female; Fluorouracil; Leukemia L1210; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Warfarin

Topics: Adenocarcinoma; Animals; Mammary Neoplasms, Experimental; Mice; Postoperative Complications; Sarcoma, Experimental; Warfarin

Topics: Adenocarcinoma; Animals; Blood Coagulation; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Monitoring, Physiologic; Neoplasm Metastasis; Neoplasm Transplantation; Prothrombin Time; Sarcoma, Experimental; Time Factors; Transplantation, Homologous; Warfarin

Topics: Adenocarcinoma; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Thrombophlebitis; Warfarin