Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram‐negative infections. After several years of clinical use, its popularity diminished because of ...reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last‐line treatment option for multidrug‐resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram‐negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA‐PmrB and PhoP‐PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last‐line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with ...advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A case of ifosfamide-induced neurotoxicity after the addition of aprepitant to an antiemetic regimen is reported.
A 24-year-old white man diagnosed with a malignant peripheral nerve sheath tumor ...initially in the late 1990s was admitted to the hospital for treatment of a recurrence of the tumor in the supra-clavicular region. In the previous five cycles of ifosfamide, carboplatin, and etoposide, the patient had no problems with the neurotoxic adverse effects associated with ifosfamide use. With the fifth cycle of therapy, the patient suffered severe nausea and vomiting that required his readmission to the hospital. With the initiation of the sixth cycle of chemotherapy, aprepitant was added to the existing antiemetic regimen of ondansetron and dexamethasone. During the sixth cycle, approximately six hours after the infusion of ifosfamide on day 3, the patient exhibited the classic symptoms of ifosfamide-induced neurotoxicity, including visual and auditory hallucinations, obvious sleepiness, confusion, and delirium. Since his symptoms resolved by morning, it was determined that the patient did not require treatment with methylene blue. With the initiation of the seventh cycle of chemotherapy, aprepitant was again added to the standard antiemetic regimen of a corticosteroid and serotonin receptor antagonist. During this hospitalization, around-the-clock methylene blue was added to prevent neurotoxicity. The patient tolerated chemotherapy well without any signs or symptoms of neurotoxicity and was discharged four days later.
A 24-year-old patient treated with ifosfamide, carboplatin, and etoposide for a malignant peripheral nerve sheath tumor developed ifosfamide-induced neurotoxicity after the addition of aprepitant to a standard antiemetic regimen consisting of ondansetron and dexamethasone.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Treatment of locally advanced unresectable or metastatic cutaneous squamous cell carcinoma (mCSCC) is suboptimal with a paucity of robust data on systemic therapy. This retrospective study aimed to ...evaluate the efficacy and outcomes of patients with locally advanced unresectable or mCSCC treated with systemic therapy.
Records of patients with CSCC treated with systemic therapy from January 2001 to January 2011 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon rank-sum test for ordinal responses and Pearson χ test for categorical responses. Survival was calculated by the Kaplan-Meier method.
Of 28 patients identified, 25 patients (M:F=18:7), median age 66 years (range, 39 to 85 y), had the required data for final analysis. Partial response was 44% and stable disease (SD) was 24%. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months (2.3, 13.2) and 10.9 months (5.3, 21.3) respectively; 3-year OS was 22%. Patients with WHO response had improved PFS (20.8 mo; 4.4, NR) and OS (37.5 mo; 10.3, NR) compared with patients with SD/PD (PFS 2.7 mo; OS 5.9 mo). Use of platinum-based therapy significantly improved PFS and OS, whereas taxanes and cetuximab had no impact in this small cohort. There was no difference in PFS or OS with multiagent versus single-agent therapy.
Platinum-based therapy remains as one of the standard options in advanced CSCC management. Agents to improve response rates are needed and future trials should address the use of novel targeted and new chemotherapy combinations in CSCC.
Objective: To examine the current controversies and discuss consensus recommendations regarding treatment sequencing and the role of BRAF inhibitor at disease progression. Data Source: An ...English-language literature search of MEDLINE/PubMed (1966-May 2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, and treatment sequencing was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries. Study Selection and Data Extraction: All relevant published articles and abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. Clinical trial registries and meeting abstracts were used for ongoing studies. Data Synthesis: The availability of new agents has made therapy selection more complex. Immunotherapy supporters reason that immunotherapy offers the best chance for long-term benefit and does not compromise the antitumor activity of subsequent BRAF inhibitors. Targeted therapy advocates rely on the high probability and rapid onset of response to BRAF inhibitors. Currently, there is insufficient evidence regarding the role of BRAF inhibitor at disease progression. Conclusions: Therapy should be individualized based on patient- and disease-specific factors. Immunotherapy represents the best option for durable remission; however, targeted therapy is more appropriate for patients who are symptomatic or have rapidly growing tumors. The novel therapies have also demonstrated meaningful intracranial activity; thus, the presence of brain metastases should be taken into consideration in selecting therapy. Limited data exist about the continuation of BRAF inhibitors after therapeutic failure. Active research is ongoing to define the best option for patients with BRAF inhibitor refractory disease.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than ...without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.
Pneumatosis intestinalis (PI) occurs when inter-luminal air enters the bowel wall of the gastrointestinal tract via a mucosal defect. The condition is caused by numerous disease states, direct ...trauma, and various drugs. When PI is secondary to drug therapy, discontinuation of the offending agent results in the resolution of PI. We report on the case of a 73-year-old male with a history of refractory gastrointestinal stromal tumor experiencing PI while on sunitinib treatment. PI was noted via computed tomography (CT) scans 68 days after starting sunitinib therapy and showed near complete resolution on a follow up CT performed one month after discontinuing sunitinib. Given that a CT scan performed five months prior to the initiation of sunitinib did not show PI, lack of abdominal symptoms in our patient, and resolution of PI after discontinuing sunitinib, the cause of PI in our patient was likely due to sunitinib treatment.
Cancer therapeutics is undergoing a revolution with the advent of new drugs that can selectively target molecules responsible for carcinogenesis and tumor growth. The type and mechanism of these ...targeting drugs vary. Some are small molecules that specifically target a binding site on a receptor or signal transduction molecule. Antibodies have been engineered to bind to the receptors or the corresponding ligands that mediate a critical cancer activity. In almost all cases, the intent is to inhibit or shut down a specific molecular pathway. Unprecedented activity against the cancer is seen without overt traditional toxicities such as alopecia, nausea and/or vomiting, and cytopenias. Unfortunately, an increase in toxicity has now become evident as more experience accumulates with the use of these drugs. In some cases, unexpected cardiotoxicities have arisen when these new drugs have been added to more conventional chemotherapies. Heart failure is the unfortunate manifestation for many of these toxicities. We outline the scope of this problem and examine the mechanisms of drug‐induced heart failure. The distinctive signs and symptoms specific to each drug are described, and the diagnosis and treatment of the condition are discussed. Our aim is to allow the practitioner to recognize the unusual manifestations of heart failure in this setting in order to make a timely diagnosis and begin appropriate treatment measures.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Until recently, options for therapy in metastatic melanoma were limited. The understanding of immune check-point blockade and the discovery of molecular pathways involving driver mutations like BRAF ...has transformed the therapeutic landscape in this disease. Ipilimumab was the first drug shown to improve survival while vemurafenib demonstrated rapid responses never seen before in melanoma. Drugs from these classes and others are now in advanced stages of development and primed to positively impact patient survival in an incremental fashion. In this review, we highlight some of the developments during this renaissance in melanoma therapy and discuss agents of promise. Clinical challenges we face include individualizing therapy for patients, overcoming resistance to molecularly targeted therapy and developing rationale combinations or sequences of drugs. A concerted bench and bedside effort in this direction will undoubtedly keep melanoma in the forefront in an era of personalized medicine.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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