Acral vascular syndrome during an immune checkpoint inhibitor.

Immune checkpoint inhibitors, including antiprogrammed death cell protein 1 (anti-PD-1) and anti cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), have been associated with a range of autoimmune-related side effects since their introduction in cancer treatment. Small vessel digital necrosis, referred to as the acral vascular syndrome, is a rare but serious complication that can result in loss of digits. Here we present a case report of acral vascular syndrome and review possible aetiologies. A 45- year-old woman with invasive ductal carcinoma of the left breast presented to the emergency department during neoadjuvant treatment with carboplatin, docetaxel and pembrolizumab with complaints of severe pain in her right third digit. She had physical findings consistent with ischaemic necrosis and gangrene of the distal phalanx. Angiography demonstrated Raynaud's phenomenon in the distal portion of the digits. Laboratory testing showed a weakly positive RNA polymerase III antibody level. Her case resulted in surgical amputation of her affected digit after partial resolution of symptoms with prednisone, vasodilators and antibiotics.

Long-term neurotoxicity and Raynaud's phenomenon in patients treated with cisplatin-based chemotherapy for malignant ovarian germ cell tumor.

INTRODUCTION: The aim was to evaluate "overall neuropathy", defined as peripheral paresthesia and Raynaud's phenomenon, in long-term survivors of malignant ovarian germ cell tumors (MOGCTs) treated with cisplatin-based chemotherapy (CBCT). MATERIAL AND METHODS: Ninety-three MOGCT survivors recorded in Norway in 1980-2009 (median follow up: 15 years) were included in this analysis. Forty-nine received CBCT (CBCT group) and 44 received other or no chemotherapy (non-CBCT group). Applying the scale for chemotherapy-induced neurotoxicity, the prevalence of overall neuropathy (ie score >1 on a 0-3 scale) was compared between the two groups. Forty women from the CBCT group also underwent neurophysiological and neurological examinations; results from the neurological examination were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Effects version 4 (NCI-CTCAE scale v4). These women were then categorized into subgroups of low (≤3 cycles of CBCT, n = 23) and high CBCT (≥4 cycles of CBCT, n = 17). RESULTS: Twenty-eight (57%) women from the CBCT group reported overall neuropathy, compared with 20 (45%) in the non-CBCT group (P = .06). Of the 40 MOGCT survivors in the CBCT group who underwent neurophysiological and neurological examinations, 14 (35%) showed NCI-CTCAE grade ≥1 signs or symptoms of peripheral neuropathy. Pathological findings of NCI-CTCAE grade 2 or 3 signs or symptoms were found in four survivors (10%) from the high CBCT subgroup, all of whom also showed objective signs of neuropathy. CONCLUSIONS: Though about half of our MOGCT survivors reported overall neuropathy after CBCT, more severe pathological neurological/neurophysiological findings that impacted daily living were recorded in only 10% of them. Our observations of a similar prevalence of self-reported overall neuropathy in the CBCT and non-CBCT group, combined with limited objective neurological findings, warrant further study to increase the understanding of the specific pathophysiological pathways of long-term CBCT-induced neuropathy.

Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy.

Purpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking ( P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased ( P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs.

An Interesting Case of Basal Cell Carcinoma with Raynaud's Phenomenon Following Chronic Arsenic Exposure.

Arsenic is commonly known to be associated with squamous cell carcinoma. Among the lesser known associations is basal cell carcinoma and even rarer is its effect on blood vessels causing peripheral vascular disease. Here we present a case of a 55 yr old man with ulceroproliferative lesions on scalp and forehead along with several hyperpigmented patches on trunk and extremities. He had symptoms suggestive of Raynaud's phenomenon that eventually led to digital gangrene. FNAC was done which was suggestive of basal cell carcinoma. On further enquiry, he was found to reside in an arsenic endemic zone and was investigated for blood arsenic level which was elevated. Punch biopsy from different lesions from body confirmed nodular basal cell carcinoma. Presently the patient has stopped drinking water from the local tubewell. On follow-up he shows improvement of Raynaud's phenomenon and skin lesions.

Drug-induced Raynaud's phenomenon: beyond ß-adrenoceptor blockers.

AIM: Drug-induced Raynaud's phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or ß-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. METHODS: A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles. RESULTS: We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by ß-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. CONCLUSION: Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.

Raynaud's phenomenon in a child with medulloblastoma as a late effect of chemotherapy.

There are a lot of early or late side effects of chemotherapies. One of them is Raynaud's phenomenon (RP). Vascular toxicity associated with antineoplastic agents is notified in bleomycin alone therapy or in combination with cisplatin, vinblastine, and vincristine. The mechanism of RP associated with antineoplastic agents is unknown. All children receiving vinblastine, vincristine, bleomycin and cisplatin therapy, are followed and questioned about their complaint on RP. Long-term follow-up of surviving patients is recommended. Oncologists should be aware of the potential late toxic effects of antineoplastic drugs.

The association of Raynaud's syndrome with cisplatin-based chemotherapy - a meta-analysis.

BACKGROUND: Vasospastic disorders of the digital circulation such as the Raynaud's syndrome (RS) are known side-effects of treatment of cisplatin-based chemotherapy. The prevalence of RS in patients during treatment with cisplatin-based chemotherapy is not well-defined. OBJECTIVE: The objective of this paper was to assess the prevalence of RS in patients receiving cisplatin-based chemotherapy - a meta-analysis of published data was performed. MATERIAL AND METHODS: The PubMed database of the National Library of Medicine and ISI Web of Knowledge was used for studies dealing with RS and patients receiving cisplatin-based chemotherapy. The studies provided sufficient data to estimate the prevalence of RS in patients receiving cisplatin-based chemotherapy. A forest plot was determined by the revealed prevalences. Statistical analysis was based on methods for a random effects meta-analysis and a finite mixture model for proportions. Publication bias was investigated with the linear regression test (Egger's method). A meta-regression was conducted by the year of publication and latitude. RESULTS: 24 eligible studies, contributing data on 2749 subjects, were included in this meta-analysis. For RS in patients receiving cisplatin-based chemotherapy a pooled prevalence of 24% and 95% CI (0.175, 0.313) was obtained. A mixture model analysis found four latent classes. Statistically, publication bias was not present (p-value 0.74). The meta-regression indicated that the odds ratio increased when the latitude increased, too (p-value 0.011). CONCLUSION: Despite some heterogeneity there is a possible indication of an association between RS and patients receiving cisplatin-based chemotherapy.

A case of progressive digital ischemia after early withdrawal of gemcitabine and S-1 in a patient with systemic sclerosis.

The safety of chemotherapy for patients with systemic sclerosis is unclear, and there are few published reports documenting the side effects of chemotherapy in patients with this condition. Here, we report the case of a patient with systemic sclerosis who developed severe digital ischemia during combination gemcitabine/S-1 chemotherapy for pancreatic cancer. In spite of aggressive treatment, the digital ischemia progressively worsened and gangrenous changes developed in multiple fingers and toes. In this patient, the systemic sclerosis had been well controlled, with no digital ischemic symptoms for the previous 6 years, so this progressive clinical course in spite of aggressive treatment strongly suggests that the chemotherapy triggered or aggravated the digital necrosis. To the best of our knowledge, this is only the third reported case of a patient with systemic sclerosis developing digital necrosis after gemcitabine-based chemotherapy. The incidence of digital necrosis during chemotherapy in patients with systemic sclerosis is unknown, and the mechanism by which it occurs is unclear, but the three reports published to date, including the present case, suggest that physicians should be very cautious about administering gemcitabine-based chemotherapy to patients with systemic sclerosis. Any resulting digital ischemia might be refractory to treatment and worsen progressively, even if chemotherapy is withdrawn in the early stages of digital ischemia.

Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer.

BACKGROUND: Testicular cancer is curable in the majority of men, and persisting treatment toxicity is a concern. The authors report a cross-sectional study of the long-term effects of chemotherapy (C) on neurologic function and development of Raynaud phenomenon. METHODS: Seven hundred thirty-nine patients who were treated between 1982 and 1992 gave consent to enter the study. Patients were classified according to the receipt of C (n = 384) or no C (n = 355). Patients completed a general health questionnaire and a quality-of-life form (the European Organization for Research and Treatment of Cancer Quality-of-Life C30 questionnaire with testicular module). Symptom scores of 3 or 4 were considered clinically significant. Patients were assessed in the clinic, and clinical history was used to diagnose Raynaud phenomenon (RP) and tinnitus. Examinations included peripheral nerve function testing for light touch and vibration sense. Five hundred seventy-seven patients underwent audiometry. RESULTS: On physician assessment, peripheral neuropathy and RP were more common after C (21.7% vs 9.1% [P<.001] and 20.3% vs 1.7% [P<.001], respectively). Similar results were obtained for symptom scores (12.5% vs 5.5% [P = .002] and 9.7% vs 3.7% [P<.001], respectively). On multivariate analysis, for peripheral neuropathy, the significant predictors were cisplatin dose, carboplatin dose, and age. For RP, the significant predictor was bleomycin. Significant differences in hearing thresholds were noted at 8000 hertz only and, on multivariate analysis, were related to age, cisplatin dose, and vincristine dose. Auditory symptom scores did not differ between groups. CONCLUSIONS: With long-term follow-up, peripheral neuropathy and RP remained detectable in approximately 20% of patients and caused significant symptoms in 10% of patients. Detectable effects on high frequency remained but caused little symptomatic problem. These effects persisted and were related to the cumulative chemotherapy dose.

Fenómeno de Raynaud por exposición a cloruro de vinilo / Raynaud's phenomenon secondary to vinyl chloride exposure

El policloruro de vinilo (PVC) es el polímero que ocupa el tercer puesto en el mercado de producción de plásticos a nivel mundial. Como consecuencia de la exposición crónica, los operarios pueden desarrollar cambios óseos degenerativos, Raynaud, trastornos circulatorios en extremidades, trombocitopenia y lesiones cutáneas semejantes a esclerodermia; esto se conoce como “enfermedad por cloruro de vinilo”. Presentamos un paciente masculino de 24 años de edad que presenta fenómeno de Raynaud, cefaleas, malestar en manos y pies, sensación de frío, fatiga y pérdida de apetito asociado a exposición a policloruro de vinilo. El estudio de la microcirculación cutánea periungueal por videocapilaroscopía muestra alteraciones estructurales y funcionales características. Se recomienda un seguimiento multidisciplinario estricto de los trabajadores expuestos a PVC.

Observational study of prevalence of long-term Raynaud-like phenomena and neurological side effects in testicular cancer survivors.

BACKGROUND: Sensory neuropathy (paresthesias), tinnitus, hearing impairment, and Raynaud phenomena are side effects of cisplatin-based chemotherapy used to treat testicular cancer patients. We assessed the long-term occurrence of these side effects among testicular cancer survivors according to the treatment they received. METHODS: A total of 1814 men who were treated for unilateral testicular cancer in Norway during 1980-1994 were invited to participate in a national multicenter follow-up survey conducted during 1998-2002. The men were allocated to six groups according to the treatment they had received. Self-reported symptoms were assessed by a mailed questionnaire that included the Scale for Chemotherapy-Induced Neurotoxicity. A total of 1409 participants who responded to the questionnaire and/or underwent audiometry were assessable in this study. Respondents to the questionnaire (n = 1402) scored the relevant symptoms according to how troubled they were by each (not at all, a little, quite a bit, or very much). Hearing impairment was objectively assessed by audiometry at 4000 Hz in 755 men (seven of whom did not respond to the questionnaire). Group comparisons of symptom assessments were performed with chi2 or Kruskal-Wallis tests. Associations between relevant factors and self-reported symptoms or hearing impairment measured by audiometry were assessed using proportional odds ordinal logistic regression models and linear regression models, respectively. All statistical tests were two-sided. RESULTS: The median follow-up for the 1409 assessable men was 10.7 years (range = 4-21 years). All chemotherapy groups had statistically significantly higher odds for increasing severity of all assessed symptoms and inferior audiometric results compared with men who did not receive chemotherapy. Among chemotherapy-treated men, 39% (95% confidence interval [CI] = 35% to 43%) reported Raynaud-like phenomena (defined as white or cold hands or fingers [or feet or toes] on cold exposure), 29% (95% CI = 25% to 33%) reported paresthesias in the hands or feet, 21% (95% CI = 18% to 25%) reported hearing impairment, and 22% (95% CI = 19% to 26%) reported tinnitus as major symptoms troubling them quite a bit or very much. Hearing impairment (odds ratio [OR] = 5.3, 95% CI = 3.0 to 9.2) and tinnitus (OR = 7.1, 95% CI = 4.1 to 12.4) were particularly common in the dose-intensive chemotherapy group compared with the no chemotherapy group. Men who were treated with radiotherapy had higher odds of self-reported paresthesias in feet compared with those not treated with radiotherapy (OR = 1.5, 95% CI = 1.01 to 2.1, P = .04). CONCLUSION: Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy were more often troubled by dose-dependent neurological side effects and Raynaud-like phenomena compared with those who were not treated with chemotherapy.

Methylphenidate and dextroamphetamine-induced peripheral vasculopathy.

Methylphenidate and dextroamphetamine are central nervous system stimulants used in the treatment of attention deficit hyperactivity disorders in children. These medications have been associated with cerebral arteritis, renal necrotizing vasculitis, and systemic and pulmonary hypertension. We report 4 patients, 2 on methylphenidate and 2 on dextroamphetamine who presented with acral cyanosis, livedo reticularis, or Raynaud phenomenon. Two patients were found to have a positive ANA at low titers, 1 of whom had histopathologic evidence of stratum malgiphian necrosis with perivascular lymphocytic infiltration on skin biopsy. Two had positive antihistone antibodies. One patient improved after withdrawal of dextroamphetamine; others had worsening of their symptoms on higher doses of medications. These cases indicate the potential for development of acral cyanosis, livedo reticularis, or Raynaud symptoms with these medications and their potential contribution to a vasculopathy.

Treatment of refractory ischemic pain from chemotherapy-induced Raynaud's syndrome with spinal cord stimulation.

UNLABELLED: We report the successful treatment of refractory ischemic pain from cisplatin-induced Raynaud's syndrome with spinal cord stimulation after failed pharmacologic management and surgical sympathectomy. CASE REPORT: A 48-year-old man developed ischemic pain of the hands while undergoing cisplatin and gemcitabine chemotherapy for metastatic pancreatic carcinoma. After extensive pharmacologic management and surgical sympathectomy failed to provide adequate analgesia, the patient underwent a percutaneous spinal cord stimulation trial followed by permanent implantation and received significant pain relief prior to succumbing to his illness. Spinal cord stimulation provided effective therapy for refractory ischemic pain, even after failed sympathectomy.

Glutathione S-transferase M1 and GST T1 genetic polymorphisms and Raynaud's phenomenon in French vinyl chloride monomer-exposed workers.

Occupational vinyl chloride monomer (VCM) exposure can induce Raynaud's phenomenon (RP). However, not all VCM workers developed RP, which suggests an underlying genetic susceptibility. Genetic polymorphisms of glutathione S-transferases (GSTs), involved in VCM metabolism, have been shown to influence certain VCM-related health effects. We have conducted a case-control study of 58 subjects with RP along with 247 subjects without RP, from a population of 305 French workers exposed or formerly exposed to VCM, to assess any association between GST M1 and GST T1 gene polymorphisms, either separately or in combination, and the presence of RP. None of the GST M1 or GST T1 genotypes were significantly associated with the presence of RP among studied VCM workers. A combination of positive genotypes for both GST M1 and GST T1 was significantly associated with RP presence, compared to the other combinations of genotypes (OR=2.1, 95% CI=1.1-3.8). OR adjusted for age, smoking status, alcohol consumption and history of treated hypertension did not reach significance (OR=2.0, 95% CI=0.9-5.2). None of the GST M1 and GST T1 genotypes seem to contribute separately to the presence of RP, suggesting that they are not, when taken alone, a major determinant of interindividual variability for VCM-induced PR. However, the combination of both positive GST M1 and GST T1 genotypes appears to contribute slightly to susceptibility to RP in VCM-exposed subjects. Nevertheless, our study-the first to examine the role of a genetic component in the occurrence of RP secondary to occupational exposure to a chemical-corroborates the previous considerations that interaction between the genetic constitution and environmental factors is of importance in determining the health-adverse effects of VCM exposure.