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Introduction

Oxaliplatin is a cytotoxic platinum compound that is in widespread use in the treatment of gastrointestinal cancers. It has been occasionally associated with acute motor neuropathy, but the precise mechanism is uncertain. To the best of our knowledge, we report the first case of a patient demonstrating post-tetanic facilitation in the setting of transient bilateral abducens neuropathy and hypokalemia, after being infused with oxaliplatin.

Case presentation

A 47-year-old Indian woman with metastatic gastric cancer was receiving an oxaliplatin infusion at the initiation of her third cycle of palliative chemotherapy. She developed acute bilateral abducens neuropathy with post-tetanic facilitation alongside acute laryngopharyngodysesthesia and hypokalemia. Following supportive management, including potassium infusion and warming, her neurological signs and symptoms were spontaneously resolved. This syndrome did not recur in subsequent cycles following prolongation of infusion duration and the addition of supportive calcium and magnesium infusions.

Conclusion

The novel clinical observation of post-tetanic facilitation highlights a possible involvement of voltage-gated channels at the presynaptic terminals in the mechanism of acute oxaliplatin neurotoxicity.

Although spontaneous coronary artery dissection is a rare cause of acute coronary syndrome, it should be considered during the evaluation of patients who have chest pain. Coronary vasospasm can lead to spontaneous dissection. The dopamine agonist cabergoline is known to cause digital vasospasm. Herein, we report a case of spontaneous right coronary artery dissection in a 43-year-old woman who was taking cabergoline as therapy for prolactinoma. To our knowledge, this is the first report of an apparent relationship between cabergoline therapy and spontaneous coronary artery dissection. The possible association of cabergoline with coronary artery spasm and dissection should be considered in patients who present with chest pain while taking this medication.

We report a case of essential thrombocythemia (ET) in a 30-year-old female who exhibited inferior wall ST-elevation acute myocardial infarction (AMI) without significant obstructive coronary artery disease. Right coronary vasospasm was observed after intra-coronary methylergonovine administration and she received verapamil 120 mg/d

thereafter and hydroxyurea 1500 mg/d for thrombocythemia. After discontinuation of the hydroxyurea for 9 mo based on the impression of coronary spasm-related instead of coronary thrombosis-related AMI, her platelet count rose but no chest pain was observed. It is suggested that coronary spasm potentially plays a role in patients with ET, AMI and no significant coronary artery stenosis.

Coronary artery spasm is an uncommon, but well recognized, etiology for acute myocardial infarction. However, cardiogenic shock with myocardial infarction resulting from simultaneous multiple coronary artery spasm has been rarely reported, and not in Korea. Recently, we experienced such a case in a 50-year-old Korean man without previous diagnosis of variant angina. The patient, hospitalized for blood sugar control, developed severe chest pain accompanying ST-segment elevation in multiple leads. The patient immediately received cardiac catheterization because of cardiogenic shock. Coronary angiogram revealed the severe and simultaneous spasm of three major epicardial arteries, which was promptly relieved by an intracoronary administration of isosorbide dinitrate. This case highlights the need to rule out the potential mechanism of coronary spasm even in the most severe episodes of acute coronary syndrome.

A 66-year-old man developed right coronary arterial spasm and hemodynamic decompensation during the early recovery phase of a treadmill exercise test. The unstable condition was corrected immediately after intravenous administration of atropine. A subsequent coronary angiographic study revealed insignificant right coronary artery stenosis. The pathophysiology of this response may be related to rapid alterations in autonomic balance during recovery after exercise. To our knowledge, this is the 1st reported case in which atropine effected immediate reversal of coronary arterial spasm and hemodynamic decompensation that were induced by exercise, rather than by pharmacologic agents. Atropine might be an effective treatment in patients who experience exercise-induced coronary arterial spasm and hemodynamic decompensation, but further investigation is warranted.

Background:

We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer.

Methods:

NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 × 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed.

Results:

The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n=634; 2 × 2 factorial portion, n=1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85–1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83–1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4.

Conclusion:

Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer.

A 56 year old woman underwent cholecystectomy. Postoperative paralytic ileus was treated with an intravenous infusion of prostaglandin F2 alpha. During infusion she complained of oppressive chest pain. This was accompanied by ST segment depression, and was relieved by sublingual glyceryl trinitrate. Coronary arteriography did not show significant stenosis, but subsequent intravenous infusion of prostaglandin F2 alpha provoked multiple segmental spasm of both the right and left coronary arteries.

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AIM: To investigate endothelium-dependent and -independent coronary microvascular functions in patients with vasospastic angina (VSA).

METHODS: Thirty-six patients with VSA (30 men and 6 women; mean age, 58 years) were enrolled in this study. VSA was defined as ≥ 90% narrowing of the epicardial coronary arteries on angiography performed during a spasm provocation test, presence of chest pain, and/or ST-segment deviation on an electrocardiogram (ECG). Patients (n = 36) with negative spasm provocation test results and those matched for age and sex were enrolled as a control group (nonVSA group). Low-dose acetylcholine (ACh; 3 μg/min) was infused into the left coronary ostium for 2 min during the spasm provocation test. Following the spasm provocation test, nitroglycerin (0.2 mg) was administered intracoronally. Coronary blood flow (was calculated from quantitative angiography and Doppler flow velocity measurements, and the coronary flow reserve was calculated as the ratio of coronary flow velocity after injection of adenosine triphosphate (20 μg) to the baseline value. Changes in the coronary artery diameter in response to ACh and nitroglycerin infusion were expressed as percentage changes from baseline measurements.

RESULTS: Body mass index was significantly lower in the VSA group than in the nonVSA group. The frequency of conventional coronary risk factors and the rate of statin use were similar between the 2 groups. The left ventricular ejection fraction as evaluated by echocardiography was similar between the 2 groups. The duration of angina was 9 ± 2 mo. The results of blood chemistry analysis were similar between the 2 groups. Low-dose ACh did not cause coronary spasms. The change in coronary artery diameter in response to ACh was lower in the VSA group (-1.4% ± 9.3%) than in the nonVSA group (3.1% ± 6.5%, P < 0.05), whereas nitroglycerin-induced coronary artery dilatation and coronary blood flow increase in response to ACh or coronary flow reserve did not differ significantly between the 2 groups.

CONCLUSION: These findings suggest that microvascular coronary function may be preserved despite endothelial dysfunction of the epicardial coronary arteries in patients with VSA.

Background

New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity.

Methods

A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity.

Results

Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients.

Conclusion

Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity.

Introduction

Chest pain with ST-segment elevation is a rare clinical problem during dobutamine stress testing. Although beta-agonists treatment prior to dobutamine stress testing has been shown to reduce the duration and amount of dobutamine infusion and atropine requirement, there is insufficient information about potential complications of this pharmacologic combination.

Case presentation

We present a 67-year-old patient with dobutamine stress testing -induced chest pain and ST elevation who received albuterol for clinical treatment of bronchospastic disease prior to the test. She developed persistent chest pain and ST elevation despite medical management. Urgent cardiac catheterization showed no significant obstructive coronary artery disease. Thus coronary artery spasm was likely responsible for the chest pain and electrocardiogram abnormality in our patient as a result of β-agonist and dobutamine combination.

Conclusions

Beta-agonists pre-treatment with dobutamine stress testing may induce coronary spasm in association with chest pain and ST elevation. Clinicians and nuclear cardiologist should be aware of this potential side effect of β-agonists treatment with dobutamine stress testing, particularly since dobutamine stress testing in nuclear cardiology is done in patient with chronic obstructive lung disease.

Peripartum myocardial infarction is a rare event that is associated with high mortality rates. The differential diagnosis includes coronary artery dissection, coronary artery thrombosis, vascular spasm, and stenosis. Our evaluation of 2 cases over a 5-year time period has led to a hypothesis that peripartum myocardial infarction is an immune-mediated event secondary to coronary endothelial sensitization by fetal antigen. In our patients, we supplemented standard medical therapy with immunotherapy consisting of corticosteroids, plasmapheresis, and intravenous immunoglobulin.

Herein, we present our most recent case—that of a 29-year-old black woman (gravida V, para IV), 2 weeks postpartum with no relevant medical history. She presented with a 1-week history of chest pain. Initial electrocardiographic and cardiac biomarkers were consistent with acute coronary syndrome. Echocardiography revealed reduced systolic function with inferior-wall hypokinesis. Angiography revealed diffuse disease with occlusion of the left anterior descending coronary artery not amenable to revascularization. We were successful in treating the myocardial infarction without the use of catheter-based interventions, by modifying the immunologic abnormalities.

Two cases do not make a protocol. Yet we believe that this case and our earlier case lend credence to the hypothesis that peripartum myocardial infarction arises from sensitization by fetal antigens. This concept and the immune-modifying treatment protocol that we propose might also assist in understanding and treating other inflammatory-disease states such as peripartum cardiomyopathy and standard acute myocardial infarction. All of this warrants further investigation.

Coronary revascularization in patients with dextrocardia is not a common clinical condition. There are very few cases of off-pump coronary artery bypass. A 64-year-old woman was admitted to a university hospital due to exertional chest pain. Her primary diagnosis was coronary artery disease superimposed on dextrocardia, which was first suspected on physical examination, with the patient having right-sided heart sounds on auscultation. It was corroborated by chest X-ray. After diagnostic evaluations, including coronary angiography, she underwent off-pump coronary artery bypass grafting due to a significant left main coronary artery stenosis associated with dextrocardia. Two years later, multi-slice CT angiography revealed patent grafts, demonstrating good clinical results.

The start of chemotherapy treatment usually requires a delay of about 4 weeks after surgical resection in patients with primary colorectal cancer and synchronous distant metastasis. However, there is no evidence to indicate the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. Here, we present a case in which combination chemotherapy with capecitabine and oxaliplatin (XELOX) was started within 1 week after a right hemicolectomy for synchronous multiple liver metastases. To our knowledge, this is the first report of the start of chemotherapy, involving treatments such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX); folinic acid, fluorouracil, and irinotecan (FOLFIRI); and XELOX, within 1 week after a colorectal cancer operation with anastomosis. The findings suggest possible changes in the start time of chemotherapy after surgery in the future.

Cardiotoxicity associated with 5-fluorouracil (FU) is an uncommon, but potentially lethal, condition. The case of an 83-year-old man with colon cancer who developed chest pain during 5-FU infusion is presented. The electrocardiogram (ECG) showed pronounced ST elevation in the lateral leads, and the chest pain was resolved after infusion of nitroglycerin. A coronary angiogram (CAG) revealed that the patient had significant atherosclerosis in the proximal left circumflex artery. Coronary artery spasm with fixed stenosis was considered, and a drug-eluting stent was implanted. After 8 hours, the patient complained of recurring chest pain, paralleled by ST elevation on the ECG. The chest pain subsided after administration of intravenous nitroglycerin followed by sublingual nifedipine. Repeated CAG showed patency of the previous stent. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective in the prevention or treatment of 5-FU cardiotoxicity.

For many years, ergotamine has been used for the acute treatment of migraine. Ergotamine may produce coronary vasospasm, which is often associated with ischemic electrocardiography changes and angina pectoris. A 62-year-old woman who was admitted to the emergency department because of chest pain is described. She had a history of severe migraine attacks and started to use ergotamine tartrate 0.75 mg daily the day before. Electrocardiography revealed sinus tachycardia with left anterior hemiblock and T wave inversion in the precordial leads. Cardiac biomarker levels were elevated. After discontinuation of the drug and initiation of vasodilator treatment, her chest pain resolved. Patients with migraine may have an underlying vasospastic disorder predisposing them to coronary artery spasm. Physicians should be alerted to potential cardiac vasospastic effects of low-dose ergotamine in the treatment of migraine.

A 39 year old woman sustained life threatening arrhythmias associated with coronary artery spasm. On both occasions she was attending hospital outpatient clinics and was successfully resuscitated. Electrocardiography performed during further episodes of pain suggested that spasm could occur in either the right or left coronary artery.

 Keywords: coronary artery spasm;  life threatening arrhythmias

Hyperthyroidism is associated with many heart diseases. Thyrotoxic state has a relationship with coronary spasm. We present a case of a non-menopausal woman with hyperthyroidism who complained of chest pain. The diagnosis of coronary spasm was confirmed by coronary angiography (CAG). She is treated well with anti-thyrotoxicosis and anti-anginal medication. We recommend not use CAG as the first diagnostic choice among the patients with medication-uncontrolled hyperthyroidism and chest pain.

We present the case of a 51-year-old male patient who received adjuvant chemotherapy consisting of oxaliplatin, bolus and continuous 5-fluorouracil (5-FU) and leucovorin after anterior resection because of locally advanced rectal cancer. Preoperative chemotherapy with capecitabine (an oral 5-FU prodrug) had been well tolerated. Two days after initiation of the first course of chemotherapy, the patient reported typical chest pain. The ECG showed ST elevations and prominent T waves in almost all leads. Due to suspicion of a high-risk acute coronary syndrome, an urgent cardiac catheterization was performed. It showed a generally reduced coronary flow with multiple significant stenoses (including the ostia of the left and right coronary artery), as well as a highly reduced left ventricular function with diffuse hypokinesia. Due to the meanwhile completely stable situation of the patient after medical acute coronary syndrome treatment, no ad hoc intervention was performed to allow further discussion of the optimal management. Thereafter, the patient remained clinically asymptomatic, without any rise in cardiac necrosis parameters; only NT-pro-BNP was significantly elevated. A control cardiac catheterization 2 days later revealed a restored normal coronary artery flow with only coronary calcifications without significant stenoses, as well as a normal left ventricular ejection fraction. Cardiovascular symptoms occurred on the second day of continuous 5-FU treatment. As cardiotoxic effects seem to appear more frequently under continuous application of 5-FU, compared to the earlier established 5-FU bolus regimens, treating medical oncologists should pay special attention to occurring cardiac symptoms and immediately interrupt 5-FU chemotherapy and start a cardiologic work-up.

Background

Oxaliplatin is a platinum compound used in the treatment of gastrointestinal malignancies, including colorectal cancer. The incidence of hypersensitivity reaction in patients receiving oxaliplatin is approximately 15%, with severe reaction (grade 3 and 4) occurring in 2% of patients.

Case presentation

We report two patients with metastatic colorectal cancer who developed de novo hypersensitivity reaction and acute thrombocytopenia after oxaliplatin infusion. Both patients had oxaliplatin treatment several years before and exhibited hypersensitivity on the third dose of oxaliplatin in recent treatment. Oxaliplatin was discontinued when clinical reaction was identified. Both patients were confirmed to have strong oxaliplatin-induced IgG platelet-reactive antibodies. Both patients' thrombocytopenia resolved within two weeks after discontinuation of oxaliplatin. One patient had disease stabilization lasting for three months without chemotherapy. Both patients subsequently received other chemotherapeutic agents without evidence of hypersensitivity reaction or immune-mediated thrombocytopenia.

Conclusion

We recommend vigilant monitoring of complete blood count and signs and symptoms of bleeding after the occurrence of oxaliplatin-induced hypersensitivity to avoid serious complications of immune-mediated thrombocytopenia.

The cause of chest pain in patients with anomalous origin of the right coronary artery from the left sinus of Valsalva has not yet been elucidated. In the following case, this anomaly was demonstrated, upon angiography, in a patient with recurrent chest pain and a negative stress test; in addition, spasm of the left anterior descending coronary artery was documented during ergonovine provocation. To our knowledge, this is the first time coronary artery spasm has been documented in a patient with this anomaly. On the basis of this case, we recommend ergonovine testing for all angina patients with aberrant coronary arteries in whom no other cause of chest pain is found at cardiac catheterization. (Texas Heart Institute Journal 1988; 15:124-127)

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A 60 year old man with a history of frequent episodes of chest pain and dizziness was referred for evaluation of coronary artery disease. He had no significant coronary artery stenosis at baseline coronary angiography. A carotid sinus massage was performed for evaluation of carotid sinus hypersensitivity in the patient. Both heart rate and blood pressure decreased a little, and returned to baseline level immediately after carotid sinus massage. However, 2.5 minutes after carotid sinus massage, ECG showed ST segment elevation in leads II, III, and aVF. Four minutes after carotid sinus massage, he had chest pain with a progressive elevation in the ST segment in the same leads, when he had 99% focal spasm in the right coronary artery. The vasospasm induced by carotid sinus massage was reproducible over several minutes and resolved spontaneously. Coronary artery spasm may be provoked by the enhanced vagal activation due to carotid sinus massage.


Keywords: coronary vasospasm; vasospastic angina; coronary artery spasm; carotid sinus massage

This phase III trial compared the efficacy and safety of bevacizumab alone with that of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer. Noninferiority could not be confirmed, but the median progression-free survival detriment was >3 weeks.

Purpose.

The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC).

Patients and Methods.

Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety.

Results.

The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0–53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand–foot syndrome, and neuropathy.

Conclusion.

Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.

Oxaliplatin is a third-generation platinum compound that is used as a single agent and in combination with fluorouracil (5-FU) to treat colorectal and gastric carcinoma. The patients treated with oxaliplatin may develop hypersensitivity and idiosyncratic reactions, although these complications are known to be rare. We report here on two patients who suffered with metastatic colorectal cancer and who underwent palliative combination chemotherapy with oxaliplatin; they then developed hypersensitivity reactions to oxaliplatin. The first case had an anaphylatic reaction immediately after the beginning of the 7th to 8th cycle infusion of oxaliplatin. The second case developed repeated febrile episodes from the 4th to 8th cycles of oxaliplatin infusion. With the increasing use of oxaliplatin in clinical practice, we are now encountering an increasing incidence of suspected hypersensitivity reactions. Physicians should keep their eyes wide open and carefully observe for the clinical manifestations of these hypersensitivity reactions.

We report the case of a 52-year-old woman with advanced colorectal cancer who was treated with oxaliplatin on a FOLFOX schedule. After 3 cycles of chemotherapy, she started to complain of visual loss, altered color vision and neurological symptoms. Due to the suspicion of ocular and neurological toxicity, antineoplastic treatment was stopped. Her visual field showed a concentric bilateral scotoma and the electrooculogram test revealed severe impairment of the retinal pigment epithelium. Visual acuity, color vision and visual field recovered completely 8 months later, although electrooculogram remained abnormal. Ocular toxicity has been reported as an infrequent adverse event of oxaliplatin. Findings in this case indicate toxicity of this chemotherapeutic agent on the retinal pigment epithelium, which has not been reported before. This damage could be permanent, and it thus differs from previously described oxaliplatin-induced ocular toxicities, which are usually transient and reversible. With increasing use of oxaliplatin as first-line treatment in advanced colorectal cancer, we have to be aware of this possible toxicity.

Although both coronary artery dissection and heparin-induced thrombocytopenia may provoke myocardial infarction, it is extremely rare for both conditions to develop simultaneously in a single patient. We report a case of a 69-year-old woman who sustained a head-on motor vehicle accident with associated chest trauma. During a subsequent hospitalization, she was exposed to subcutaneous heparin and developed significant thrombocytopenia. Shortly thereafter, she re-presented with an acute myocardial infarction. Coronary angiography revealed a spiral dissection with superimposed thrombosis within the right coronary artery, while laboratory testing confirmed the diagnosis of heparin induced thrombocytopenia. She was treated with catheter-based thrombectomy and adjunctive direct thrombin inhibitor therapy, followed by three months of systemic anticoagulation with warfarin. To our knowledge, this represents the first published case of a native vessel myocardial infarction due to the combination of coronary artery dissection and heparin-induced thrombocytopenia.