Immune-checkpoint inhibitor-associated grade 3 hepatotoxicity managed with enteric-coated budesonide monotherapy: A case report.

RATIONALE: The introduction of immune-checkpoint inhibitors (ICPI) in recent years has changed the natural course of many neoplasms. However, patients receiving these medications may present immune-mediated adverse events; management includes temporary or permanent cessation of treatment and corticosteroids, occasionally combined with other immunomodulators. Such immunosuppression, however, also has numerous adverse events and even if it is effective in controlling toxicity, it delays immunotherapy reinitiation, as current evidence requires dose tapering to ≤10 mg prednisolone equivalent before rechallenge. Enteric-coated budesonide is a corticosteroid formulation acting primarily to the intestine and liver, as a result of its extensive first-pass hepatic metabolism. PATIENT CONCERNS: A 76-year-old woman treated with ipilimumab for metastatic melanoma presented with abdominal pain, vomiting, and diarrhea for at least the previous 4 days. Laboratory tests, among others, revealed elevated aminotransferases and C-reactive protein. During hospitalization, the patient also developed fever. DIAGNOSIS: The patient, after excluding alternative causes of aminotransferase elevation, was diagnosed with grade 3 ipilimumab-associated hepatotoxicity. INTERVENTIONS: Budesonide monotherapy was administered; initial daily dose was 12 mg. OUTCOMES: Fever subsided after the first dose of budesonide. Aminotransferases returned to normal-near normal approximately 1 month after the first dose of budesonide. After this point, daily dose was reduced by 3 mg every 2 weeks, with no clinical or biochemical relapse. CONCLUSIONS: This case of ICPI hepatitis is, to our knowledge, the first in the literature managed with budesonide monotherapy. Therefore, budesonide may be a potentially attractive option for the management of ICPI-associated liver injury in cases where corticosteroid treatment is necessary due to its safety profile and the potential advantage of faster immunotherapy rechallenge in selected patients without requiring dose tapering, in contrast to systemically acting corticosteroids. Clinical trials should be conducted in the future in order to validate or refute these findings.

Concurrence of cat-scratch disease and paradoxical tuberculosis-IRIS lymphadenopathy: a case report.

BACKGROUND: Mycobacterial infections can cause significant morbidity when cellular immunity is compromised. Patients with AIDS can be affected directly from infection or through mycobacterial IRIS, especially if they are previously untreated for HIV. Herein a case of tuberculous lymphadenitis is reported, which primarily responded to antimicrobials but complicated by IRIS and cat-scratch disease at a later course. CASE PRESENTATION: A 23-year-old man, intravenous drug user with untreated HIV and HCV infection presented with fever and painful cervical lymphadenopathy. Mycobacterium tuberculosis was isolated from PCR and culture of ultrasound-guided lymph node aspirate and a four-drug anti-TB regimen was subsequently administered, leading to complete resolution of clinical and laboratory abnormalities. Given the patient's CD4 count (67 cells per mm3), antiretroviral treatment started seven weeks after TB treatment initiation. Within the first month of ART fever recurred along with cervical lymph node inflammation. Paradoxical IRIS was considered as the most probable diagnosis but workup expanded, revealing acute Bartonella infection. A posteriori, the patient remembered being scratched by a stray cat two weeks before his new symptoms started. Doxycycline and corticosteroid monotherapy failed to resolve symptoms, whereas a combination of doxycycline for 3 months and methylprednisolone with long-term tapering led to negative follow-up Bartonella antibodies and complete clinical and biochemical response, without recurrence. CONCLUSIONS: Co-infection with TB and Bartonella presenting with lymphadenitis is unusual. Cat-scratch disease can be a rare clinical presentation of Bartonella infection in patients with AIDS, but coexistence of bartonellosis and paradoxical IRIS has never been reported before. However, physicians treating people living with HIV should be aware of this potential concurrence. Early testing for Bartonella infection could be offered in patients with TB and HIV co-infection in case of acute deterioration or partial response to treatment, especially if they have a history of cat exposure, since clinical picture can be indistinguishable.

PGP 9.5 neuronal marker may differentiate immunohistochemically HIV-related from Mediterranean and immunosuppression-associated Kaposi's sarcoma.

Mediterranean Kaposi's sarcoma (MKS), HIV-related KS (HIV-KS) and immunosuppression-associated KS (IS-KS), caused by human herpes virus 8 (HHV-8), share similar histological features. The aim of this study was to investigate differences in epidermal nerve fibers (ENFs) between the three KS types and controls. Skin biopsies from 23 HIV-KS, 16 MKS, 28 IS-KS patients and 18 controls, age-gender matched, were immunostained with PGP 9.5; ENFs in upper epidermal layer (EL) and penetrating the basement membrane were measured. The mean number of nerve fibers penetrating ENFs was significantly lower in HIV-KS (p < 0.001) compared to all other groups. MKS and IS-KS had comparable ENFs but lower than controls (p < 0.00 1). In the upper EL all groups had comparable ENFs and lower than controls. In conclusion, HIV-KS can be distinguished histologically from other types, by counting ENFs. Moreover, KS is associated with decreased ENFs, which may be a histological reflection of nerve damage. This is even more pronounced in HIV-KS patients and could be explained by a neurotoxic action of HHV-8, HIV, and their co-existence.

Chemotherapy ± cetuximab modulates peripheral immune responses in metastatic colorectal cancer.

OBJECTIVE: To identify changes in peripheral immune responses in patients with metastatic colorectal cancer (mCRC) treated with irinotecan/5-fluorouracil/leucovorin (IFL) alone or in combination with cetuximab (C-IFL). METHODS: Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (n = 20) and patients with mCRC receiving treatment with either IFL (n = 30) or C-IFL (n = 30) were tested for cytokine production upon polyclonal stimulation with anti-CD3 monoclonal antibody, T cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR) and T regulatory cell (Treg) frequency. The respective results were evaluated over two treatment cycles and further assessed in relation to response to treatment. RESULTS: PBMCs prior to treatment exhibited significantly lower production of IL-2, IFN-γ, IL-12 and IL-18 cytokines and lower auto-MLR responses, whereas Treg frequency, IL-4, IL-10 cytokines were increased compared to healthy donors. During treatment, IL-2, IFN-γ, IL-12, IL-18 and auto-MLR responses increased, while Treg frequency and IL-10 secretion decreased significantly compared to the baseline. Responders to treatment exhibited a significantly higher increase in IL-2, IFN-γ, IL-12 and IL-18 production and auto-MLR responses, and higher decrease in IL-4, IL-10 secretion and Treg frequency. Among all patient subgroups analysed, responders to C-IFL demonstrated significantly higher increase in auto-MLR responses, IL-12 and IL-18 secretion and higher decrease in Treg frequency. CONCLUSION: The disturbed immune parameters observed in patients with mCRC at presentation can be significantly improved during treatment with IFL and this effect can be potentiated by the addition of cetuximab. Monitoring of the peripheral immune system function could be used as surrogate marker in predicting treatment-related outcome.

Arterial stiffness predicts risk for long-term recurrence in patients with type 2 diabetes admitted for acute coronary event.

OBJECTIVES: to investigate the predictive value of arterial stiffness (AS) estimation for long-term recurrences in patients with type 2 diabetes (DM2) following acute coronary event. PATIENTS AND METHODS: prospective observational study involving 119 DM2 patients without history of coronary heart disease admitted with ST-segment elevation myocardial infarction (STEMI). Medical history, anthropometrics, smoking, HbA1c, lipid profile, troponine-I levels, and left ventricular ejection fraction (LVEF) were recorded. Carotid-femoral pulse wave velocity (cf-PWV) was measured 1 month after discharge. Patients were followed up for 36 months or to reach an end-point: cardiovascular death, acute coronary event, angioplasty or hospitalization for acute heart failure. To facilitate analysis, patients were divided into two groups according to cf-PWV, using the accepted cut-off value of 12m/s. RESULTS: overall, 34 patients had a recurrence. In Kaplan-Meier analysis patients with cf-PWV>12m/s had mean time-to-event 353±43 days compared to 505±115 days for patients with cf-PWV≤12m/s, log rank=0.0252. In multivariate analysis factors independently associated with recurrence were age (66.53±6.87 vs. 61.54±10.77 years, p=0.015), LVEF (41.66±8.21 vs. 47.58±8.11%, p=0.001) and cf-PWV (13.94±2.91 vs. 12.35±2.77m/s, p=0.008). CONCLUSIONS: AS estimation in patients with DM2 after STEMI discriminate patients at higher risk for 3-year recurrence, and maybe valuable for distinguishing patients likely to require a more rigorous therapeutic intervention.

Polyneuropathy induced by HIV disease and antiretroviral therapy.

OBJECTIVE: To investigate the underlying mechanisms of polyneuropathy induced by HIV infection or antiretroviral drugs. METHODS: We tested 100 HIV patients (59 with AIDS). Ninety-three patients received antiretroviral drugs. Forty-four were treated with neurotoxic compounds (ddI, ddC, d4T). Nerve conduction velocities and the sympathetic skin response (SSR) in palms and soles were measured in all patients. In skin biopsies (ankle and thigh), the intraepidermal nerve fiber density (IENFD) and the number of epidermal fibers without contact to the basal membrane (fragments) were quantified using PGP9.5 staining. RESULTS: Severity of the disease (CD4 +count) correlated to conduction velocities of peroneal (p < 0.01, Spearmans rank correlation), sural (p < 0.01) and median nerves (p < 0.05/p < 0.001, sensory/motor). In contrast, the duration of neurotoxic treatment did not impair conduction velocities (p > 0.3) but correlated to reduced IENFD in the ankle (r = -0.24, p < 0.05). Despite their reduced IENFD, patients with long neurotoxic treatment had a high number of fragments irrespective of their CD4 +count. CONCLUSIONS: Neurotoxic treatment appears to primarily impair thin fiber conduction, whereas HIV neuropathy is linked to large fiber impairment and reduction of fragments of nerve fibers. SIGNIFICANCE: These findings emphasize the differential pattern of polyneuropathy in HIV patients caused by the infection or induced by antiretroviral treatment.

Prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.

BACKGROUND: Most patients with pancreatic adenocarcinoma are diagnosed with locally advanced (unresectable) or metastatic disease. The aim of this study was to investigate possible prognostic factors of survival in such patients. PATIENTS AND METHODS: Two hundred and fifteen patients were studied retrospectively. Twenty-four potential prognostic variables (demographics, clinical parameters, biochemical markers, treatment modality) were examined. RESULTS: Mean survival was 29.0 weeks. 21.9% survived more than 36 weeks. On multivariate analysis, 10 factors had an independent effect on survival: tumour localisation, metastasis, performance status, jaundice, weight loss, C reactive protein, CEA, CA 19-9, palliative surgery and chemotherapy. Patients managed only with palliative care had a hazard ratio of 8.94 versus those offered a combination of palliative surgery and chemotherapy. CONCLUSION: Many factors could be used as predictors of survival in patients with advanced or metastatic pancreatic cancer. Chemotherapy and palliative surgery are associated with increased survival, and should be offered to all eligible patients.

Aspects of the association between leishmaniasis and malignant disorders.

Given the prevalence of leishmaniasis and cancer, the co-existence of these two diseases may be merely coincidental. However, a number of epidemiological, experimental and laboratory studies suggest that an association between these two entities does exist. The aim of this review is to summarise the occurrence of leishmaniasis as an opportunistic infection associated with malignant disorders and to present the available literature potentially linking this infection with the development of cancerous lesions. We searched electronic databases and evaluated 37 studies involving 44 patients. Four different types of association between leishmaniasis and cancer were established: leishmaniasis mimicking a malignant disorder, such as lymphoma; leishmaniasis arising as a difficult to diagnose and treat infection among patients receiving chemotherapy for various malignant disorders; simultaneous diagnosis of leishmaniasis and a neoplastic disorder in the same tissue samples of immunocompromised patients; and direct involvement of Leishmania spp. in the pathogenesis/occurrence of malignant lesions, especially of the skin and mucous membranes. The main conclusion of this review is that leishmaniasis can directly or indirectly affect the presentation, diagnosis and course of various malignant disorders and it should be considered in the differential diagnosis of malignancies in geographic areas where it is endemic and/or in patients with travel history to these areas.

Comparison of two oral regimens for the outpatient treatment of low-risk cancer patients with chemotherapy-induced neutropenia and fever: ciprofloxacin plus cefuroxime axetil versus ciprofloxacin plus amoxicillin/clavulanate.

The objective of this investigation was to assess retrospectively the safety and the efficacy of oral ciprofloxacin plus cefuroxime axetil compared to the combination of oral ciprofloxacin plus amoxicillin/clavulanate, as initial outpatient treatment, in low-risk cancer patients with fever and neutropenia. We analysed retrospectively 120 episodes of febrile neutropenia, treated on an outpatient basis at 2 different oncology units; 63 episodes were treated with the oral regimen of ciprofloxacin plus amoxicillin/clavulanate and 57 were treated with the combination of oral ciprofloxacin plus cefuroxime. 20 treatment failures were recorded-2 of them among patients receiving ciprofloxacin plus amoxicillin/clavulanate and 18 in the ciprofloxacin plus cefuroxime group. Univariate analysis showed that the administration of ciprofloxacin plus cefuroxime was associated with a worse outcome compared to the regimen ciprofloxacin plus amoxicillin/clavulanate (OR 11, CI 2.42-49.9, p =0.002). In the multivariate model, after adjusting for the absolute number of neutrophils and the duration of neutropenia, the effect of the antibiotic regimen on the outcome disappeared, and no significant differences between the 2 regimens were noted, although the regimen of ciprofloxacin plus cefuroxime was associated with a trend to a worse outcome (OR 4.74, CI 0.72-31.1, p =0.10). In conclusion, the 2 regimens appeared equally safe and effective but prospective studies are needed to confirm these results.

Differential sensitivity of thick and thin fibers to HIV and therapy-induced neuropathy.

The study assessed HIV-related and anti-retroviral therapy-induced neuropathy in myelinated and unmyelinated nerve fibers. One hundred consecutive HIV patients were examined clinically and standard nerve conduction velocities were measured. In addition, electrically induced sympathetic skin response (SSR) was assessed in the palms and soles. The difference in delay of SSR in palms and soles (DeltaSSR) was calculated as an indirect measure of C-fiber conduction velocity. Thick fiber conduction velocities significantly decreased with age and increasing stage of the disease, whereas no effect of stage was found for DeltaSSR (p=0.6). In contrast, medication of at least one of the most known neurotoxic drugs zalcitabine, stavudine, or didanosine did not result in significantly lower conduction velocities in thick fibers (51.29+/-3.4 m/s vs. 50.86+/-3.5 m/s), but was related to an increased DeltaSSR. DeltaSSR allows an indirect measurement of C-fiber conduction velocity. In HIV this measure of unmyelinated sympathetic fibers was most sensitive to anti-viral treatment whereas conduction velocity of myelinated somatic fibers was more sensitive to disease-related neuropathy. The results suggest that HIV neuropathy preferably affects myelinated and anti-retroviral therapy unmyelinated fibers.

A phase II study of the docetaxel-carboplatin chemotherapy regimen in advanced non-small-cell lung cancer.

The efficacy of the docetaxel-carboplatin combination chemotherapy was studied in various phase II studies. Based on these data we aimed to test the regimen in previously untreated patients with advanced advanced non-smoking lung cancer (NSCLC) with docetaxel 80 mg/m2 a standard dose of carboplatin at AUC = 5, in an attempt to define the efficacy and tolerability of the combination in an open-label phase II study. Patients with histologically confirmed advanced NSCLC stage IIIB and IV were candidates for the present study. Docetaxel was administered at 80 mg/m2 over 1 h by intravenous (IV) infusion followed by carboplatin AUC = 5 in 30 min IV infusion, both on day 1, and recycled every 21 days. Sixty patients received 263 courses of therapy in total; 231/263 (88%) were administered according to the planned doses, and 48/60 (80%) patients received chemotherapy without decrement of the dose; 32/263 (12%) of the courses were administered with a 10%-30% dose reduction. Complete responses (CR) were seen in 5 patients (8.3%) and partial responses (PR) in 16 patients (26.7%) for an overall response rate of 35%. Median duration of response was 7.5 months [95% confidence interval (CI)-7.1-7.9], time to progression (TIP) 11.5 months (95% CI-8.2-14.8), median overall survival (OS) 15.0 months (95% CI-10.8-19.2). One-year survival was 61.7%. Toxicity was acceptable; it was calculated according to the administered cycles and was mainly neutropenia: grade 3, 9% and grade 4, 2%; anemia: grade 3, 8%; nausea and vomiting: grade 3, 8%. The outpatient regimen of docetaxel-carboplatin is effective with acceptable toxicity in patients with advanced NSCLC.