Neurological Immunotoxicity from Cancer Treatment.

The emergence of immune-based treatments for cancer has led to a growing field dedicated to understanding and managing iatrogenic immunotoxicities that arise from these agents. Immune-related adverse events (irAEs) can develop as isolated events or as toxicities affecting multiple body systems. In particular, this review details the neurological irAEs from immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell immunotherapies. The recognition and treatment of neurological irAEs has variable success, depending on the severity and nature of the neurological involvement. Understanding the involved mechanisms, predicting those at higher risk for irAEs, and establishing safety parameters for resuming cancer immunotherapies after irAEs are all important fields of ongoing research.

Cancer and Peripheral Nerve Disease.

Patients with cancer may experience neuropathy at any stage of malignancy, ranging from symptoms that are the earliest signs of cancer to side effects of treatment. Peripheral nerves are affected most commonly in a symmetric, stocking-glove pattern. Sensory neuronopathies, plexopathies, and radiculopathies may also be seen. The most common type of neuropathy in patients with cancer is related to chemotherapy, and recently peripheral nerve complications have been described as an effect of immune checkpoint inhibitors too. Other causes include paraneoplastic syndromes, direct tumor infiltration, and radiation. Treatment focuses on addressing the underlying cancer and management of neuropathic pain.

Paraneoplastic hyperleucocytosis in a melanoma patient after initiation of ipilimumab and nivolumab combination therapy.

BACKGROUND: Paraneoplastic hyperleucocytosis (PH) is sporadically seen in patients with advanced solid tumors. CASE PRESENTATION: We report a female patient with disseminated melanoma metastases. Two days after the first dosage of combined immunotherapy using the cytotoxic T lymphocyte antigen-4 (CTLA-4) blocker ipilimumab and the programmed death receptor-1 (PD-1) blocker nivolumab the patient developed asymptomatic hyperleucocytosis (over 120.000 leucocytes per µl) associated with elevated granulocyte colony-stimulating factor blood levels. Hematological and infectious disorders could be ruled out. Although paraneoplastic hyperleucocytosis spontaneously resolved she died from progressive disease about 60 days after start of treatment. CONCLUSIONS: PH is extremely rare in malignant melanoma, however, most patients who developed this complication had preceding immunotherapies such as interleukin-2. The latter observation and the fact that our patient developed PH rapidly after initiation of ipilimumab and nivolumab immunotherapy indicate an immune-mediated mechanism which may trigger PH under unknown circumstances. The development of paraneoplastic hyperleucocytosis indicates a very poor prognosis.

Paraneoplastic IgA Vasculitis in an Adult with Lung Adenocarcinoma.

A 50-year-old man with lung adenocarcinoma (c-T1aN2M1b) experienced reddish purpura mainly on the lower legs after receiving 12 cycles of second-line chemotherapy with docetaxel. There was tumor enlargement on computed tomography performed to assess the therapeutic response, so paraneoplastic IgA vasculitis was considered. IgA vasculitis was diagnosed based on a biopsy of the skin lesion and histology of an upper gastrointestinal hemorrhagic mucosal erosion. As IgA vasculitis can lead to serious gastrointestinal or systemic complications, IgA vasculitis should be considered as a differential diagnosis for rashes in patients with malignancy.

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature: Part 2: Hematologic, cutaneous and vascular syndromes.

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes associated with lung cancer appears useful. This article is the second of a series of five and deals with hematologic, cutaneous and vascular syndromes.

A case of pseudo-Stauffer's syndrome related to asenapine use.

The authors present a case of suspected pseudo-Stauffer's syndrome in a male with treatment refractory schizoaffective disorder following asenapine use. We discuss our management of this case, and believe knowing about this potential adverse effect and it's management could be useful for clinicians.

Parathyroid Hormone-Related Peptide-Linked Hypercalcemia in a Melanoma Patient Treated With Ipilimumab: Hormone Source and Clinical and Metabolic Correlates.

A patient diagnosed with metastatic melanoma developed the paraneoplastic syndrome of humoral hypercalcemia of malignancy and cachexia after receiving ipilumumab. The cause of the hypercalcemia was thought to be secondary to parathyroid hormone-related peptide (PTHrP) as plasma levels were found to be elevated. The patient underwent two tumor biopsies: at diagnosis (when calcium levels were normal) and upon development of hypercalcemia and cachexia. PTHrP expression was higher in melanoma cells when hypercalcemia had occurred than prior to its onset. Metabolic characterization of melanoma cells revealed that, with development of hypercalcemia, there was high expression of monocarboxylate transporter 1 (MCT1), which is the main importer of lactate and ketone bodies into cells. MCT1 is associated with high mitochondrial metabolism. Beta-galactosidase (ß-GAL), a marker of senescence, had reduced expression in melanoma cells upon development of hypercalcemia compared to pre-hypercalcemia. In conclusion, PTHrP expression in melanoma is associated with cachexia, increased cancer cell lactate and ketone body import, high mitochondrial metabolism, and reduced senescence. Further studies are required to determine if PTHrP regulates cachexia, lactate and ketone body import, mitochondrial metabolism, and senescence in cancer cells.

Rheumatology and oncology: an updated review of rheumatic manifestations of malignancy and anti-neoplastictherapy.

OBJECTIVE: Review of the literature addressing the rheumatic manifestations of various malignancies as well as of common chemotherapeutic agents. METHODS: A literature search was performed to identify key articles regarding the association of rheumatic disease with malignancy. RESULTS: Our review focused on the association of rheumatic disease with malignancy, paraneoplastic syndromes with rheumatic manifestations, and chemotherapeutic agents related to rheumatic syndromes. We have discussed the importance of a newly described autoantibody that may identify patients at risk for malignancy associated myositis. CONCLUSION: Based on our literature review, recommendations are suggested regarding who and how patients should be screened for malignancy when presenting with various rheumatic symptoms.

[Subacute cutaneous lupus erythematosus and cancer: two cases and literature review]. / Lupus cutané subaigu et cancer: deux cas et revue de la littérature.

BACKGROUND: Subacute cutaneous lupus erythematosus is an uncommon dermatosis characterised by a non-scarring, annular photo-distributed dermatosis associated with anti-Ro/SSA antibodies. It is remarkable as a paraneoplastic syndrome (12 cases in the literature). We report two cases of subacute cutaneous lupus erythematosus occurring in patients treated for metastatic breast adenocarcinoma. CASE REPORTS: Case 1: a 72-year-old woman with breast carcinoma relapsing after surgery, chemotherapy, hormone therapy, and without treatment for 6 months, was admitted for an acute erythematous slightly squamous and photo-distributed eruption. On clinical examination, she was found to be presenting polyadenopathy and pleural effusion. Case 2: a 46-year-old woman with a history of breast carcinoma was admitted for an erythematopapular, annular and photo-distributed eruption occurring after a second breast cancer relapse and five months after initiation of docetaxel. A new line of chemotherapy initially resulted in regression of the lesions, and progression of the breast cancer was associated with cutaneous relapse. DISCUSSION: The diagnosis of subacute cutaneous lupus erythematosus was supported in our two patients by the presence of an annular photo-distributed eruption associated with positive testing for anti-Ro/SSA antibodies. Occurrence of the eruption in both cases with relapse of the neoplasia and its improvement after oncological treatment reinforced the diagnosis of paraneoplastic syndrome in one case, and the use of chemotherapy known to trigger lupus could have suggested a diagnosis of drug-induced subacute cutaneous lupus erythematosus. Thus, the association between lupus and cancer is relevant.

Treatment of acute promyelocytic leukemia with PETHEMA LPA 99 protocol: a Tunisian single center experience.

Acute promyelocytic leukemia (APL) has now become the most curable of all subtypes of acute myeloid leukemia. A cure rate of 75-80% can be anticipated with a combination of all-trans retinoic acid (ATRA) and anthracyclines. In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens of a combination of ATRA with anthracycline and cytarabine (APL93), and without cytarabine (LPA99). From 2004, 39 patients with confirmed APL either by t(15;17) or PML/RARA were treated by the PETHEMA LPA 99 trial. The rationale of this protocol by avoiding cytarabine is to reduce death in complete remission (CR) without increasing the incidence of relapse. Thirty-three patients achieved CR (84.6%). The remaining six patients were considered as failure due to early death: three caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Baseline blood cell count (WBC) >10 x 10(9)/l (P=0.26) and creatinine >1.4 mg/dl (P=0.42) were not predictive of mortality. DS was observed in 11 patients (30.5%) with a median onset time of 12 days (range: 3-23 days) and median WBC of 29 x 10(9)/L (range: 1.2 x 10(9)-82.7 x 10(9)/l). DS was severe in seven cases, moderate in four, and fatal in three cases. Body mass index > or =30 (P=0.044) and baseline WBC > or =20 x 10(9)/l (P=0.025) are independent predictors of DS. The median follow-up of this study is 36 months. Thirty patients are alive in continuous complete remission; two patients died in CR from septic shock and secondary myelodysplastic syndrome respectively; one patient died 47 months after achieving two relapses. Event free survival from diagnosis was 80% and overall survival was 82%. Our results are quite acceptable and can be improved by reducing mortality rate.

Treatment of nausea and vomiting in terminally ill cancer patients.

Nausea and vomiting is a common and distressing symptom complex in patients with far-advanced cancer, affecting up to 60% of individuals at some stage of their illness. The current approach to the palliative care of patients with nausea and vomiting is based on identifying the cause, understanding its pathophysiology and knowing the pharmacology of the drugs available for its amelioration. The following six main syndromes are identified: gastric stasis, biochemical, raised intracranial pressure, vestibular, mechanical bowel obstruction and ileus. A careful history, focused physical examination and appropriate investigations are needed to elucidate the syndrome and its cause, so that therapy is rational. Drugs are the mainstay of treatment in terminal cancer, and the main classes of antiemetic agents are prokinetics, dopamine antagonists, antihistamines, anticholinergics and serotonin antagonists. Dexamethasone and octreotide are also used, especially in bowel obstruction. Non-drug measures are important in relieving the associated distress. Patients should be able to die comfortably, without tubes. Despite decades of practice affirming this approach, the evidence base is weak and well designed studies are urgently needed.

[Acquired ichthyosis revealing an Hodgkin's disease]. / Ichtyose acquise révélant une maladie de Hodgkin. Une nouvelle observation.

INTRODUCTION: Acquired ichthyosis is a rare condition that usually reveals malignant diseases. CASE REPORT: A 70-year-old man was admitted with weight loss, diffuse ichthyosis, lymphadenopathy of the inguinal lymph nodes and elevated inflammatory markers in peripheral blood. Histology of the lymph node revealed mixed-cellularity Hodgkin disease. The evolution was fatal in spite of the chemotherapy. DISCUSSION: Acquired ichthyosis is a cutaneous paraneoplastic syndrome, generally related to hematologic malignancies. A possible pathomecanism is the stimulation of epidermal growth secondary to the production of epidermal growth factor (EGF) by tumour cells. Acquired ichtyosis can rarely reveal systemic or infectious diseases. It can also be drug-induced or idiopathic.

Paraneoplastic pemphigus associated with fludarabine use.

Paraneoplastic pemphigus is a severe mucocutaneous disease associated with B-cell lymphoproliferative disorders. A 51-yr-old man presented to the oncology clinic with mucocutaneous skin lesions after six cycles of fludarabine for non-Hodgkin's lymphoma. A punch biopsy from the skin showed suprabasal acantholysis and blister formation in the epidermis and upper dermis. Direct immunofluorescence demonstrated intercellular IgG deposition in all epidermal layers and complement (C3) at the basement membrane. The indirect immunofluorescence on rat bladder showed intercellular binding of IgG. These findings were consistent with paraneoplastic pemphigus associated with fludarabine use. The temporal association between fludarabine use and paraneoplastic pemphigus suggests there is an etiopathological link between these two entities.