Concomitant use of direct-acting antivirals and chemotherapy in hepatitis C virus-infected patients with cancer.

BACKGROUND: Antiviral therapy improves hepatic outcomes in hepatitis C virus (HCV)-infected cancer patients. However, such patients are not treated simultaneously with antivirals and chemotherapy, owing to overlapping toxicities with previous standard of care treatment of pegylated interferon and ribavirin. AIM: To examine the safety and clinically-significant drug-drug interactions observed in patients who received simultaneous treatment with direct-acting antivirals (DAAs) and chemotherapy. METHODS: Safety was determined by the presence of adverse events which were graded according to the division of AIDS Table (version 2.0). Adverse events were monitored throughout antiviral treatment and up to 3 months after its completion. Drug-drug interactions were assessed using current online databases. Sustained virological response (SVR) was defined as absence of serum HCV RNA 12 weeks after end of DAA treatment. Cirrhosis was diagnosed via imaging, biopsy or with the use of non-invasive fibrosis markers. RESULTS: Twenty-one patients received concomitant treatment with DAAs and chemotherapy between January 2013 and September 2016. Concomitant treatment was started either for virological (14; 67%) or oncologic (7; 33%) reasons. DAAs used were sofosbuvir, ledipasvir, simeprevir, daclatasvir ± ribavirin. The adverse events observed were mainly constitutional (12; 57%), hematological and gastrointestinal (7; 33% each). Physicians changed the DAA regimens in two patients (10%) in anticipation of drug-drug interactions with daclatasvir and dexamethasone. The overall SVR rate was 95% (20/21). CONCLUSIONS: Hepatitis C virus-targeted antiviral therapy can be used concomitantly with selected anti-neoplastic agents under close monitoring for drug-drug interactions. This therapeutic intervention may prevent delay in the administration of chemotherapy in HCV-infected cancer patients.

Initial use of combination treatment does not impact survival of 106 patients with haematologic malignancies and mucormycosis: a propensity score analysis.

In view of the poor outcomes associated with mucormycosis in patients with haematologic malignancies (HM) and haematopoietic cell transplant recipients, antifungal combinations are frequently used, yet the value of such strategy remains unclear. We reviewed the records of HM patients treated for mucormycosis from 1994 to 2014. The primary outcome was 6-week mortality after treatment initiation. Of the 106 patients identified, 44% received monotherapy and 56% received combination treatment as initial therapy. Six-week mortality was associated with disseminated mucormycosis (p 0.018), active malignancy (p <0.01), higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (p <0.001), neutropenia (p 0.049), lymphopenia (p 0.0003) and intensive care unit (ICU) admission at diagnosis (p 0.0001). Survivors were more likely to have localized mucormycosis (p <0.01) and to receive hyperbaric oxygen therapy (p 0.02). There were no differences in mortality between monotherapy and combination treatment groups (43% vs. 41%; p 0.85). In multivariate analysis, lymphopenia (odds ratio (OR), 5.5; 95% confidence interval (CI), 1.9-15.9; p 0.002) and ICU admission at diagnosis (OR, 8.2; 95% CI, 2.3-29.2; p 0.001) were associated with increased mortality. Localized mucormycosis was associated with better outcome (OR, 0.06; 95% CI, 0.01-0.6; p 0.019). Initial combination treatment had no impact on mortality, even after propensity score adjustment (OR, 0.8; 95% CI, 0.3-2.4; p 0.69). A weighted mortality risk score was then calculated for each patient based on the factors independently associated with mortality and baseline APACHE II score. In the low-risk group (n = 49), 13% of monotherapy versus 15% of combination therapy patients died within 6 weeks (p >0.99). In the high-risk group (n = 57), 71% of monotherapy versus 61% of combination therapy patients died within 6 weeks (p 0.42). With the current status of mucormycosis diagnosis, there was no difference in mortality in HM patients, whether they received monotherapy or combination treatment as initial therapy. Earlier diagnosis and immune reconstitution are unmet needs to affect outcomes.

Efficacy and safety of antiretrovirals in HIV-infected patients with cancer.

At 30 years into the HIV infection epidemic, the optimal antiretroviral (ARV) regimen for infected patients with cancer remains unknown. We therefore sought to retrospectively study different ARV regimens used in this population. Data from HIV-infected patients seen at The University of Texas MD Anderson Cancer Center in Houston, Texas, USA, from 2001 to 2012 were reviewed. Patients received nucleoside reverse transcriptase inhibitors (NRTIs) plus protease inhibitors (PIs), non-NRTIs (NNRTIs), integrase strand-transfer inhibitors (INSTIs), or combinations of these. A total of 154 patients were studied. Most patients were male (80%), white (51%) and had haematological malignancies (HMs) (58%). NRTIs were combined with PIs (37%), NNRTIs (32%), INSTIs (19%) or combinations of these (11%). INSTIs were the most commonly used in patients with HM and in those receiving high-dose steroids or topoisomerase inhibitors (p <0.05). Side-effects occurred in 35%, 14%, 3% and 6% of patients receiving PIs, NNRTIs, INSTIs and combinations, respectively (p 0.001). Grade 3-4 adverse events were uncommon. Multivariate logistic regression analysis demonstrated that INSTIs and NNRTIs were nine times (95% confidence interval (CI), 1.4-50.8) and 11 times (95% CI, 1.9-64.7) more likely to be effective at 6 months, respectively, than PIs. This is the largest reported analysis studying different ARV regimens in HIV-infected cancer patients. Combinations that included PIs were the least favourable. NNRTIs and INSTIs had comparable efficacy, but INSTIs appeared to be the better tolerated ARVs in patients with HM or those receiving various chemotherapeutic agents.

Closure of midline contaminated and recurrent incisional hernias with components separation technique reinforced with plication of the rectus muscles.

PURPOSE: Midline incisional hernia reconstruction by defect closure and reinforcement with either prosthetic or biologic materials has shown to significantly decrease recurrence rates even for complex cases. The purpose of this study is to evaluate outcomes regarding large incisional hernia reconstruction with components separation technique using rectus muscle plication as a reinforcement method. METHODS: Thirteen patients having large midline incisional hernias and either history of abdominal wall contamination or recurrence in the presence of mesh were treated between January 2007 and December 2011 with closure using components separation technique reinforced by rectus muscle plication. RESULTS: Average hernia square was 222 cm(2), and mean follow-up was 24 months. Complications occurred in 6 patients with a mean time to resolution of 59 days. One recurrence was present. CONCLUSIONS: When use of mesh or biologic materials is not desired, rectus muscle plication is a feasible tool as a reinforcement method after large hernia closure with components separation.

Fatal cytomegalovirus pneumonia in patients with haematological malignancies: an autopsy-based case-control study.

Cytomegalovirus (CMV) pneumonia is a life-threatening infection in patients with haematological malignancies (HMs) or in haematopoietic stem cell transplant (HSCT) recipients. To assess the incidence and risk factors for developing fatal CMV pneumonia in these patients, a case-control study based on 999 autopsies was performed at The University of Texas M. D. Anderson Cancer Center, Houston, Texas (January 1990 to December 2004). Twenty-five cases (patients who died with CMV pneumonia) were matched with 34 controls (patients who died without CMV pneumonia) by type of HM or HSCT, year of autopsy, age and gender. The incidence of CMV pneumonia declined between January 1990 to June /1997 and July 1997 to December 2004 (CMV pneumonia rates were 22/620 and 3/379 autopsies, respectively; p 0.006). Logistic regression analysis identified complete remission and sustained lymphopenia as independent predictors of CMV pneumonia (all p <0.05). The incidence of fatal CMV pneumonia has decreased over the last 15 years, which might reflect earlier diagnosis or the use of pre-emptive therapy or more effective preventive strategies. Complete remission of an HM does not preclude the development of CMV pneumonia among patients with prolonged lymphopenia.

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin.

In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at > or = 7.5 mg kg(-1) per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (P < or = 0.001) and 11% for combination therapy (P < 0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (P < or = 0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8-32.5; P < 0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (P < or = 0.02) and hepatotoxicity (P < 0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.

Delivery systems for in vivo use of nucleic Acid drugs.

The notorious biotechnological advance of the last few decades has allowed the development of experimental methods for understanding molecular mechanisms of genes and new therapeutic approaches. Gene therapy is maturing into a viable, practical method with the potential to cure a variety of human illnesses. Some nucleic-acid-based drugs are now available for controlling the progression of genetic diseases by inhibiting gene expression or the activity of their gene products. New therapeutic strategies employ a wide range of molecular tools such as bacterial plasmids containing transgenic inserts, RNA interference and aptamers. A nucleic-acid based constitution confers a lower immunogenic potential and as result of the high stringency selection of large molecular variety, these drugs have high affinity and selectivity for their targets. However, nucleic acids have poor biostability thus requiring chemical modifications and delivery systems to maintain their activity and ease their cellular internalization. This review discusses some of the mechanisms of action and the application of therapies based on nucleic acids such as aptamers and RNA interference as well as platforms for cellular uptake and intracellular delivery of therapeutic oligonucleotides and their trade-offs.

Influence of type of cancer and hematopoietic stem cell transplantation on clinical presentation of Pneumocystis jiroveci pneumonia in cancer patients.

Pneumocystis jiroveci pneumonia is a common infection in patients with AIDS but an infrequent cause of pneumonia in cancer patients. Little is known about the impact of cancer type and hematopoietic stem cell transplantation on the presentation and outcome of P. jiroveci pneumonia in cancer patients. A retrospective cohort study of all patients with cancer and P. jiroveci pneumonia cared for at The M.D. Anderson Cancer Center during 1990-2003 was conducted. Eighty episodes of P. jiroveci pneumonia in 79 patients were identified. In most (67%) episodes, patients had a hematologic malignancy. In 23 (29%) episodes, patients had undergone hematopoietic stem cell transplantation. Twenty-seven percent of patients with histopathologically confirmed P. jiroveci pneumonia had nodular infiltrates on the radiographic study. Pleural effusion and pneumothorax were more common in patients with hematopoietic stem cell transplantation than in those with solid tumors. Clinical suspicion of P. jiroveci pneumonia was less common in patients with nodular infiltrates than in those without such a radiographic finding (7 vs. 39%; p=0.002). Twenty-six of 76 (34%) patients with data available died of P. jiroveci pneumonia. Predictors of death by univariate analysis included older age, tachypnea, high APACHE II score, use of mechanical ventilation or vasopressors, lower arterial pH level, absence of interstitial component, pneumothorax, and comorbid conditions (all p<0.05). Multivariate analysis identified the use of mechanical ventilation as an independent predictor of death. Death attributable to P. jiroveci pneumonia appeared to be higher in patients with hematopoietic stem cell transplantation. The clinical presentation of P. jiroveci pneumonia in cancer patients may be affected by the category of cancer and the history of hematopoietic stem cell transplantation. P. jiroveci pneumonia remains a rare yet severe infection in cancer patients.

Proven pulmonary cryptococcosis due to capsule-deficient Cryptococcus neoformans does not differ clinically from proven pulmonary cryptococcosis due to capsule-intact Cr. neoformans.

We compared the clinical manifestations, laboratory and radiologic findings, and outcomes of eight patients with proven pulmonary cryptococcosis (PC) caused by capsule-deficient Cryptococcus neoformans with those of six patients with PC caused by capsule-intact Cr. neoformans. The presentations and outcomes did not differ significantly between the groups.

High-dose fluconazole therapy for cancer patients with solid tumors and candidemia: an observational, noncomparative retrospective study.

BACKGROUND: Response rates for candidemia treated with standard-dose fluconazole (400 mg/day) are approximately 70%. Higher doses of fluconazole have been recommended for susceptible dose-dependent Candida isolates. Herein, we describe the outcome of 20 patients with solid tumors and candidemia treated with high-dose fluconazole (HDF) at The University of Texas M.D. Anderson Cancer Center (1998-2002). PATIENTS AND METHODS: Patients were identified either by searching the microbiology laboratory database or through direct referral from primary oncology services to the Infectious Diseases Consultative Services. A retrospective review of cases was performed. HDF was defined as > or =600 mg/day. RESULTS: Five patients were treated with 600 mg/day, whereas 15 patients received 800 mg/day. Only one patient was neutropenic. The median APACHE II score at the onset of candidemia was 12 (range 6-24). The most common species identified were Candida albicans (eight patients, 40%) and Candida parapsilosis (seven patients, 35%). Of 19 patients whose quantitative data were available, eight (42%) had high-grade candidemia [> or =200 colony forming units (CFU)/ml]. Fifteen (83%) of 18 isolates were fluconazole susceptible, and two (both Candida glabrata) were fluconazole resistant (MIC 64 each) in vitro. Nineteen patients (95%) responded to HDF therapy. The only HDF failure occurred in a patient with C. glabrata (MIC 64.0) infection. The other patient with C. glabrata (MIC 64.0) infection responded to HDF. Central venous catheters were removed from all patients with > or =10 CFU/ml candidemias. All patients with high-grade candidemias responded to HDF. The median duration of HDF therapy was 16 (range 6-42) days. No significant toxicity occurred. CONCLUSIONS: Although our data are limited, HDF appears to be well tolerated and may be associated with higher response rates than standard-dose fluconazole in a selected group of patients with solid tumors and candidemia caused by species that are susceptible to this triazole.

Protothecosis in patients with cancer: case series and literature review.

OBJECTIVE: To review our recent experience with protothecosis in patients with cancer at The University of Texas MD Anderson Cancer Center, and compare these cases with others reported in the literature. METHODS: We report on three patients with protothecosis and cancer who were seen at The University of Texas MD Anderson Cancer Center from January 1979 to May 2002, and reviewed all cases of protothecosis in patients with cancer reported in the literature since 1966. RESULTS: Overall, 13 cases of protothecosis complicating cancer were evaluated. The median age of the patients was 41 years (range, 7-73 years). Seven patients (54%) had an underlying hematologic malignancy, and one infection occurred after bone marrow transplantation. Neutropenia was uncommon in these patients (14%). Prototheca wickerhamii was the most common Prototheca species identified as the causative agent of infection. Skin infection was the most common presentation of protothecosis, occurring in five patients (38%), followed by disseminated disease in three patients (23%), algaemia in three patients (23%), pulmonary infection in one patient (8%), and olecranon bursitis in one patient (8%). Information on the use of antifungal therapy was available for ten patients. Seven of the ten patients received amphotericin B, while three received triazoles (fluconazole in two, itraconazole in one). Breakthrough protothecosis occurred during the administration of systemic antifungal therapy with itraconazole in one patient. All seven patients who received amphotericin B showed a response, as did one of the three patients given triazoles. Seven (58%) of the patients died during the study period, only one (17%) of protothecosis. CONCLUSIONS: Protothecosis is an uncommon infection in cancer patients, implying that Prototheca spp. have a low pathogenic potential in this population. Pulmonary involvement in particular is uncommon in these patients. Amphotericin B appears to be the most effective antifungal agent; the role of triazoles in treating protothecosis is uncertain, but they may be less effective.

Listeria monocytogenes infection in patients with cancer.

Listeriosis (LT) is an important infection in immunocompromised patients, but no large series of LT in cancer patients have been recently described. We reviewed the records of 34 cancer patients with LT at our institution (1990-2001). Twenty patients (59%) had an underlying hematologic malignancy. In 11 patients, LT complicated bone marrow transplantation. Lymphocytopenia was observed in 62% of the patients. Twenty-six patients (76%) received prior corticosteroids. Bacteremia was the most common presentation of LT (74%) followed by meningoencephalitis (21%). The most common treatment of LT was ampicillin with or without gentamicin (68%). The median duration of treatment was 26 days (range, 8-74 days). The rate of response to antimicrobial therapy was 79%. No relapses were identified. LT contributed to death in 9 (75%) of the 12 patients who died. Meningoencephalitis had the worst prognosis (3 of 6 cases were fatal). Treatment of central nervous system LT continues to have a high failure rate.

Infections caused by Fusarium species.

Fusariosis, an emerging opportunistic mycosis caused by Fusarium species, carries a high mortality rate in immunocompromised patients. The dismal prognosis of patients with fusariosis is aggravated by the limited therapeutic options. Here we give an overview of the epidemiology, pathogenesis, clinical manifestations, antifungal susceptibility and management of fusariosis.

Open lung biopsy in bone marrow transplant recipients has a poor diagnostic yield for a specific diagnosis.

The diagnostic yield of open lung biopsy (OLB) in bone marrow transplantation (BMT) recipients having pulmonary infiltrates has not been evaluated recently. Therefore, we reviewed our 2-year experience (1998-99) with such patients at The University of Texas M. D. Anderson Cancer Center. We found 12 BMT recipients who underwent OLB analysis for the evaluation of pulmonary infiltrates. A treatable infectious etiology leading to the initiation or modification of antimicrobial agent administration was found in only two patients having bilateral nodular disease and one having bilateral parenchymal infiltrates. We conclude that OLB in BMT patients having diffuse pulmonary infiltrates has a low diagnostic yield for treatable infectious etiologies.

Pulmonary candidiasis in patients with cancer: an autopsy study.

For patients who had cancer and autopsy-proven pneumonia, we evaluated whether cultures of respiratory secretions (sputum and/or bronchoalveolar lavage) performed < or =4 weeks before autopsy were a reliable basis for the diagnosis of pulmonary candidiasis. Pulmonary candidiasis was identified at autopsy in 36 patients, but common clinical predictors were insensitive for this diagnosis. For sputum culture, the sensitivity, specificity, and the positive and negative predictive values were 85%, 60%, 42%, and 93%, respectively; for bronchoalveolar lavage culture, these values were 71%, 57%, 29%, and 89%, respectively.