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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.

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., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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 (β-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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

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.

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.

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.

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.

233 SD rats weighing 100 approximately 120 g were divided randomly into 6 groups. The animals in group I and group II received 0.1 mg/kg selenium in the form of sodium selenite only and served as the negative control and positive control, respectively. Animals in groups III, IV and V were fed with selenium as Se-enriched malt supplemented diets (0.3, 1 and 3 mg/kg), and group VI with selenium by using sodium selenite supplemented diets (3 mg/kg). Animals of groups II approximately VI were induced hepatoma by diethylnitrosamine (100 mg/l) for 16 weeks, then drunk with sterilized water for 2 more weeks. Subsequently, the effects of Se-enriched malt and sodium selenite on hepatoma nodules, relative liver weight, the liver function indices including alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin (ALB), total bilirubin (TBIL), and the tumor markers, named as gamma-glutamyltranspeptidase (GGT), alpha-fetoprotein (AFP), insulin-like growth factor-II (IGF-II) were recorded. The calcium concentration, glucose content in plasma and values of the hormones regulating blood glucose, such as insulin, glucagons and thyroid hormones (3,5,3'-tetraiodothyronine, T(3); 3,5,3'5'-tetraiodothyronine, T(4)) were observed as well. At the same time, the correlations between the concentration of plasma glucose and related hormones were also analyzed. The results indicated that Se-enriched malt showed a better chemopreventive efficiency in decreasing the number of hepatoma nodules, relative liver weight and the contents of AFP, GGT, IGF-II, ALT, ALP and TBIL in the plasma, and delaying the descent of hormones in the serum, names as insulin, glucagons, T(3) and T(4) than those feeding with sodium selenite. Effect of Se-enriched malt excelled sodium selenite in the aspects of deadening the descent of glucose concentration in the plasma and the rise of calcium concentration in the serum of the rats with hepatoma induced by diethylnitrosamine. The values of glucose and calcium were significantly related to those items fore-named. In conclusion, the function of Se-enriched malt in deadening the lesion and delaying the development of hepatoma of rats induced by diethylnitrosamine was better than that of sodium selenite. Hypoglycemia and hypercalcemia were significantly correlated with the multifactors mentioned above.

We describe a 65-year-old Caucasian man with Waldenstrom's macroglobulinaemia who developed paraneoplastic pemphigus (PNP) 3 years after his haematological diagnosis. This is a very rare malignancy that is associated with PNP. The evolution of PNP in this patient appears to exhibit the postulated immunological phenomenon of epitope spreading.

Paraneoplastic systemic sclerosis (SSc) occurs in about 3%-7% of individuals with SSc. There are reports of accelerated SSc syndromes associated in particular with breast cancer. Further exacerbations of the rheumatic condition may be induced by treatment of the cancer. We report a 30-year-old African-American woman with a contiguous diagnosis of breast cancer and paraneoplastic SSc. She was treated with neoadjuvant chemotherapy and developed an accelerated SSc syndrome with pericarditis and cardiac tamponade, with lethal results. This case report stresses the need for control of the rheumatic condition prior to the initiation of antineoplastic therapy.

A 48-year-old woman with a follicular, grade III, B-cell non-Hodgkin lymphoma developed clinical, immunopathological and histological features of paraneoplastic pemphigus. The skin symptoms flared after repeated cyclophosphamide infusions, and were preceded and accompanied by a progressive dyspnoea. Although the skin and oral mucosal disease went into remission with high-dose steroid and intravenous immunoglobulin therapy, the severe alveolitis led to death. Immunoblotting of human epidermal extracts showed that the patient's serum IgG reacted with the 210-kDa envoplakin, 190-kDa periplakin, as well as the recombinant protein of BP180 NC16a domain. IgG and IgA enzyme-linked immunosorbent assays for desmoglein 3 were positive, too. Indirect immunofluorescence studies on COS-7 cells transiently transfected with desmocollin 1-3 cDNAs showed that the patient's serum contained IgG and IgA antibodies to desmocollin 3 as well as IgG antibodies to desmocollin 2. Serum IgG and IgA strongly stained rat bronchial epithelium, corresponding to autoantibodies possibly involved in the pathomechanism of the severe lung disease. In this case, which was characterized by a mixed IgA/IgG antibody panel displaying known and unique antigenicity, the serious episodes of paraneoplastic pemphigus flared after cyclophosphamide treatment.

Purpose: Differential diagnosis of maculopathies can be difficult but is important if patients also suffer from other diseases such as breast cancer treated with antiestrogens. The main possible diagnoses, especially in the elderly, are age-related macular degeneration, tamoxifen and cancer-associated retinopathy (CAR)., Methods: We describe an 84-year-old patient with breast and colon cancer, who complained of a decrease in visual acuity after treatment with low-dose antiestrogens. She underwent a general ophthalmological investigation, perimetry and electroretinographic examination with multifocal (m-ERG) and flash-electroretinogram (flash-ERG)., Results: Visual acuity was reduced to 1/50 and 0.3. The ophthalmological examination was normal, except for extensive bilateral maculopathy with shining crystalline deposits, central and peripheral visual field defects, slightly affected scotopic and photopic potentials in the flash-ERG, and an abnormal m-ERG., Conclusions: The findings are expected with age-related macular degeneration with crystalline drusen, but also with CAR. Even if the single and total dosage of antiestrogens given to the patient is sufficient to cause tamoxifen retinopathy, this diagnosis can be excluded because, in tamoxifen retinopathy unlike in the case presented here, the deposits are not distributed in all retinal layers.

Paraneoplastic pemphigus is a relatively recently described immunobullous disease with characteristic features. We report three cases of paraneoplastic pemphigus in adult men with chronic lymphocytic leukaemia arising within a week of completion of treatment with fludarabine. In all cases, withdrawal of fludarabine and treatment of the blistering was associated with marked cutaneous improvement. Fludarabine, a synthetic nucleoside analogue, which has only been available in Britain since 1994, is known to be associated with autoimmune phenomena and may have been involved in the development of paraneoplastic pemphigus in these cases.

Purpose: In a previous study, both recoverin and heat shock cognate protein 70 (hsc 70) were found as autoantigens recognized by sera from four patients with cancer-associated retinopathy (CAR). This observation suggested that autoimmune reactions against recoverin and hsc 70 might be involved together in the pathogenesis of CAR. The purpose of the present study is to investigate the effects of these autoantibodies on retinas in vivo., Methods: Functional and morphologic properties of the retinas were evaluated after anti-recoverin and/or anti-hsc 70 antibodies were intravitreously injected into Lewis rats' eyes., Results: Responses in electroretinogram (ERG) of eyes penetrated with anti-hsc 70 antibody were comparable with the control, but those with anti-recoverin antibody were remarkably reduced during the 3-week period after the injection. Such anti-recoverin antibody-induced reduction was significantly enhanced by copenetration with anti-hsc 70 antibody. Immunofluorescence microscopy demonstrated that after intravitreal injection, anti-recoverin antibody penetrated toward the outer nuclear layer (ONL) and outer segments within 12 to 24 hours, and the presence of the antibody in the retina diminished during the next few days. Histopathology revealed significant thinning of the ONL and inner nuclear layer (INL) in the affected retina in comparison with the control. Throughout the ONL and INL, apoptotic cells were recognized by TdT-dUTP terminal nick-end labeling. The antibody-induced retinal dysfunction was effectively treated by administrations of either corticosteroid or cyclosporin A., Conclusions: These observations suggest that anti-recoverin- and anti-hsc 70 antibody-induced retinal dysfunction in Lewis rat is a good model to study the pathophysiology of CAR.

Patients with malignancy can develop peripheral neuropathies as (1) a direct effect of the cancer by invasion or compression of nerves, (2) a remote or paraneoplastic effect, or (3) an iatrogenic effect of treatment. Focal or multifocal cranial neuropathies, radiculopathies, and plexopathies typically result from tumor infiltration, herpes zoster infection, or radiation-induced injury. Sensorimotor polyneuropathies are the most frequently encountered peripheral nerve syndromes, but motor neuropathies, sensory neuronopathies, polyradiculoneuropathies, and autonomic neuropathies can also occur. Although uncommon, paraneoplastic mechanisms should be considered in a patient with malignancy and an associated peripheral nerve disorder, especially in the setting of small-cell lung cancer or lymphoproliferative cancer. Toxic neuropathies occur with exposure to several chemotherapeutic agents, including the vinca alkaloids, cisplatin, taxanes, and suramin. These neuropathies are usually dose-related, sensory-predominant, and at least partially reversible, with an axonopathic or ganglionopathic mechanism. Suramin is unique in causing subacute, demyelinating polyradiculoneuropathy.

We report the favourable outcome of a patient who suffered from severe arterial and venous thrombosis during chemotherapy for testicular pure choriocarcinoma. An increased paraneoplastic stimulus of HCG secondary to the marker surge phenomenon is suggested as responsible for transient hypercoagulability and subsequent thromboembolism.

The use of interferon (INF) is usually considered safe, the major side-effect being a flu-like syndrome. However, with its ability to alter immune responsiveness, INF has been associated with the induction of autoimmune diseases. We report a patient with Waldenström's macroglobulinaemia who developed a generalized blistering eruption after treatment with systemic INF-alpha 2A (INF) for multiple skin cancers. The patient's skin showed histological features, immunofluorescence findings, and immunoprecipitation diagnostic of paraneoplastic pemphigus. Despite aggressive treatment the patient died. In our patient, the use of INF was temporally related to the development of paraneoplastic pemphigus. Although interferon has been shown to induce other autoimmune diseases, to our knowledge this is only the second report of a patient treated with an interferon who subsequently developed a fatal autoimmune blistering disorder. Paraneoplastic pemphigus is a recently described autoimmune bullous disorder with a poor prognosis. The mechanism by which INF triggered the paraneoplastic pemphigus is not known.

Following lymphography, a 41-year-old woman developed arthritis and papules of multicentric reticulohistiocytosis three years after the beginning of a carcinoma of the cervix, now inoperable and with vulvar metastases. Two further inevitable x-ray investigations with different contrast media led to exacerbation of the disease within 24 hours. 12 month after onset, all symptoms of multicentric reticulohistiocytosis receded spontaneously, and further investigations with contrast media were well tolerated. We assume that iodine compounds may be the cause--directly or indirectly--for provocation and enhancement of histiocytic proliferation.