Hyperpigmentation due to imatinib: A rare case of cutaneous involvement.

CASE REPORT: Imatinib mesylate is a well-known tyrosine kinase inhibitor used to treat chronic myeloid leukemia, gastrointestinal stromal tumor, as well as a variety of other malignancies.Management and outcome: As use of this medication continues to grow, providers must be aware of potential side effects and management thereof. The toxicity profile of imatinib has been well characterized with most patients experiencing a grade 1 or 2 adverse event. These side effects are usually mild, and most patients can continue treatment without interruption. Around 30% of patients on imatinib experience skin toxicity, with 5% being high grade. This rash is typically hypopigmented, which is explained by imatinib's effect on melanocytes. DISCUSSION: Although there have been several case reports describing hyperpigmentation of the oral mucosa or nails, very few have described skin hyperpigmentation. We previously reported the first two cases of imatinib-related squamous cell carcinoma in patients undergoing treatment for gastrointestinal stromal tumors. In this paper, we present a case of a patient on imatinib for management of gastrointestinal stromal tumor who experienced extensive skin hyperpigmentation and review the literature.

Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics.

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU) is extensively used to treat many solid tumors, particularly breast and colorectal cancers. Neurotoxicity of capecitabine has been rarely reported as peripheral neuropathy, cerebellar syndrome, and multifocal leukoencephalopathy. Although very little is known about the pathogenetic mechanisms responsible for this toxicity, dihydropyrimidine dehydrogenase (DPD) deficiency has been found in few of these patients. TYMS gene encodes for the human thymidylate synthase, and is considered a candid factor for toxicity and efficacy of 5-FU and capecitabine. However, TYMS polymorphism has been associated previously with capecitabine-induced neurotoxicity. We report here a 31-year-old patient with metastatic colorectal cancer undergoing chemotherapy consisting of oxaliplatin and capecitabine who developed acute cerebellar syndrome during cycle 5. MRI did not show any abnormalities. We performed pharmacogenetic studies related to capecitabine including DPD deficiency and TYMS polymorphism. DPD gene mutation analysis was negative for the IVS14+1G>A mutation in the DPD gene, which accounts for 50% of the DPD deficiency alleles. However, the patient was found to have 3RG/3RC genotype and Del/Del genotype of TYMS 3'-untranslated region. Withdrawal of capecitabine improved his neurotoxicity in 9 days. No re-challenge was given to this patient but he was able to tolerate irinotecan, oxaliplatin, and bevacizumab without any toxicities. To the best of our knowledge, this is the first patient in the literature who developed acute cerebellar syndrome following capecitabine and was found to have mutations of TYMS. Patients on fluoropyrimidines, including capecitabine with new neurological symptoms must be investigated for a rare but real central neurotoxicity. Though the treatment of 5-FU neurotoxicity is supportive care but use of uridine triacetate may be indicated in few patients, especially with overdose.

Trends in Incidence and Outcomes of Clostridium difficile Colitis in Hospitalized Patients of Febrile Neutropenia: A Nationwide Analysis.

INTRODUCTION: Clostridium difficile infection (CDI) has been attracting attention lately as the most common hospital acquired infection. Patients with neutropenia because of malignancy seem to be at an increased risk for developing CDI. There is currently limited data that assesses the national burden and outcomes of CDI in Febrile Neutropenia (FN). METHODS: We analyzed the National Inpatient Sample (NIS) database for all subjects with discharge diagnosis of FN with or without CDI (ICD-9 codes 288.00, 288.03,780.60, and 008.45) as primary or secondary diagnosis during the period from 2008 to 2014. All analyses were performed with SAS, version 9.4 (SAS Institute). RESULTS: From 2008 to 2014 there were total 19422 discharges of FN patients with CDI. There was a rising incidence of CDI in patients with FN from 4.11% (in 2008) to 5.83% (in 2014). The In-hospital mortality showed a decreasing trend from 7.79% (in 2008) to 5.32% (in 2014), likely because of improvements in diagnostics and treatment. The overall mortality (6.37% vs. 4.61%), length of stay >5 days (76.45% vs. 50.98%), hospital charges >50,000 dollars (64.43% vs. 40.29%), colectomy and colostomy (0.35% vs. 0.15%), and discharge to skilled nursing facility (10.47% vs. 6.43%) was significantly more in FN patients with CDI versus without CDI over 7 years (2008 to 2014). Age above 65 years, Hispanic race, hematological malignancies, urban hospital settings, and sepsis were significant predictors of mortality in febrile neutropenia patients with CDI. DISCUSSION: Despite the significant decrease in mortality, the incidence of CDI is rising in hospitalized FN patients with underlying hematological malignancies. Risk factor modification, with the best possible empiric antibiotic regimen is imperative for reducing mortality and health care costs in this cohort.

An update on the management of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) are a rare and heterogeneous group of neoplasia and differ in their clinical presentation, behavior, and prognosis based on both histological features and cancer stage at the time of diagnosis. Although small-sized tumors can be surgically resected, locally advanced and metastatic tumors confer a poor prognosis. In addition, only limited treatment options are available to the latter group of patients with PNETs, such as hormonal analogs, cytotoxic agents, and targeted therapy. In selected patients, liver-directed therapies are also used. As expected, clinicians taking care of these patients are challenged to develop an effective and comprehensive treatment strategy for their patients amid a wide variety of treatment modalities. Targeted therapy for PNETs is limited to sunitinib and everolimus. Presently, a number of clinical studies are ongoing to assess the efficacy of newer targeted agents alone and in combination with previous agents for the treatment of advanced PNETs. The authors reviewed the current treatment and also discussed the emerging agents and emphasized the need to identify biomarkers.

Pancrelipase-Induced Hypersensitivity Reaction: Case Report and Review of Literature.

INTRODUCTION: Drug-induced exanthems are commonly associated with NSAIDs, antibiotics, and anti-epileptics. Pancrelipase is frequently used for conditions resulting in pancreatic exocrine insufficiency. Published case reports of pancrelipase hypersensitivity focus on the respiratory manifestations. CASE REPORT: Here we report a case of skin hypersensitivity resulting from pancrelipase use. To further assess this association, we used a Naranjo nomogram, which determines the likelihood that an adverse drug reaction is the result of the drug itself. Our patient had a score of seven, suggesting our patient had a probably adverse drug reaction. DISCUSSION: As pancrelipase is a commonly prescribed drug, clinicians should be aware of the potential hypersensitivity skin reactions associated with pancrelipase.

Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors.

PURPOSE: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS: A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS: Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS: The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.

Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation.

Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of double-stranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCA-related PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future.

Immunohistochemical expression of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins in urothelial bladder carcinoma: correlation with clinicopathological parameters.

PURPOSE: To reevaluate the expression levels of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins and their potential association with standard clinicopathological parameters, including tumor stage and grade, in urothelial bladder carcinoma (UBC). METHODS: Immunohistochemistry was performed in 100 transurethral resection specimens obtained from prospectively identified patients with primary UBC. RESULTS: Overall, 26, 41 and 75% of the cases showed positive staining for p53, p63 and c-myc, respectively, while p21(WAF1/cip1) and p27(kip1) expression levels were altered in 75 and 88% of the cases, respectively. Positive staining for p53 was associated with increased tumor stage (pT2) (p=0.037), while altered expression of p27(kip1) was strongly associated with male gender (p=0.009). CONCLUSION: The results of our study imply that p53 overexpression may be a useful marker of tumor invasion in UBC. In contrast, we failed to demonstrate any statistically significant correlation between the remaining markers evaluated and tumor stage or grade.

Ten-Fold Elevation of Chromogranin A Level Unrelated to a Neuroendocrine Tumor: A Case Report of the Diagnostic Interference of Proton Pump Inhibitors.

Chromogranin A (CgA) is a well-known biomarker for neuroendocrine tumors (NETs). However, due to its non-specificity, a proper assessment of CgA test results requires a detailed knowledge of the factors, conditions, and medications influencing its serum concentration. We describe a case of a 61-year-old patient presenting with a mass suspicious of a gastrointestinal NET and an exceedingly high level of serum CgA persistent after mass resection. Following a thorough review of patient's medical history and clinical presentation, along with radiographic and pathological findings, no evidence of a NET was detected. A trial of proton-pump inhibitor (PPI) withdrawal led to a dramatic normalization of CgA level, marking it as the culprit causing this tumor marker elevation. This case highlights the significant impact of PPI use on CgA level, and should incentivize clinicians to provide proper education to patients prior to testing.

Pulmonary blastoma with submandibular, scrotum and adrenal metastases: case report.

A 62-year-old patient diagnosed with pulmonary blastoma with submandibular, scrotum and adrenal metastases was admitted to Sotiria General Hospital in Athens. No other such case has been published to date. The patient started receiving chemotherapy, but the scrotum metastasis grew rapidly and erupted. This led to sepsis despite surgical excision of infected and necrotic tissues and intravenous antibiotics. Treatment strategy in pulmonary blastoma should be defined by a multidisciplinary team, and surgical treatment should be considered as quickly as possible when such a tumor is suspected.

Novel agents and new combination treatments on phase I studies on solid tumors and pancreatic cancer.

Pancreatic cancer is a relatively rare malignancy with a very aggressive natural course, not restrained by the existing current treatments. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of few phase I clinical studies on solid tumors and pancreatic cancer were presented. In particular, in the field of immunotherapy, a pilot phase I study tested for first time a carcinoembryonic antigen (CEA)-based vaccine (Abstract #2561) on patients with pancreatic adenocarcinoma and another one the optimal dose and efficacy of trabedersen, an inhibitor of tissue growth factor-beta 2 (TGF-ß2) aiming to enhance antitumor immune responses (Abstract #4034). Other phase I studies explored the pharmacokinetic and pharmacodynamic properties of an oral gemcitabine pro-drug (LY2334737; Abstract #2554), or of the combination of gemcitabine with sirolimus (Abstract #3096) or the combination of gemcitabine with an inhibitor of mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase (ERK) (MEK 1/2; Abstract #4034).

Clinical studies in the second line setting of advanced pancreatic cancer: are we making any progress?

Despite the enormous advances in clinical research in oncology, the prognosis of pancreatic carcinoma remains poor. The therapeutic options in this type of cancer are very limited, with modest results at present. In the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, four interesting trials on the second line treatment of pancreatic cancer were presented. The first study (Abstract #4017) with a phase II design suggested that maintenance therapy with sunitinib, after a complete course of standard first line treatment, was feasible and effective while the second phase I/II study (Abstract #4034) evaluated the role of trabedersen, an agent that inhibits TGF-ß2 expression. Finally, the efficacy and toxicity of lapatinib combined with either FOLFOX (Abstract #e14533) or capecitabine (Abstract #e14569) were examined in the second line setting of pancreatic cancer.

Updates on treatment of gemcitabine-refractory pancreatic adenocarcinoma. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011.

Gemcitabine monotherapy and gemcitabine-based regimens are the current standard of care for locally advanced or metastatic pancreatic adenocarcinoma. However, there is still great controversy over the role of salvage chemotherapy after failure of gemcitabine. This review is an update on the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting regarding the most important developments in the treatment of refractory pancreatic cancer, as they were reported in Abstracts #e14542 and #e14588.

Locally advanced pancreatic adenocarcinoma: are we making progress?. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011.

Pancreatic cancer, as the 4th leading cause of cancer death in the U.S., remains a challenging disease for all oncologists. Less than 20% of all cases could be potentially cured by surgical resection, while the majority of cases are deemed either unresectable or metastatic upon diagnosis. In this year's American Society of Clinical Oncology (ASCO) Annual Meeting, several studies were presented with novel approaches towards treating locally advanced pancreatic cancer. The LAP-07 study, a large phase III study with two separate randomizations, updated their accrual status, but with no interim data yet reported (Abstract #e14619). A single institutional review study reported its promising results on the incorporation of interferon to chemoradiation, but the toxicities could be concerning (Abstract #e14648). Abstract #e14607 demonstrated promising survival data from a tri-modality approach incorporating local and systemic chemotherapy concurrent with external beam radiation as well as radiofrequency ablation. The tolerability of sorafenib in locally advanced pancreatic cancer was shown in a small phase I study (Abstract #e14525). CyberKnife® stereotactic body radiation therapy was investigated as a modality for local palliation (Abstract #e14506). More effective therapeutic agents and approaches are still needed in this difficult disease. This highlight article will focus on the management of locally advanced pancreatic cancer.

New Potential Options for SBRT in Pancreatic Cancer.

Stereotactic body radiotherapy (SBRT) is an emerging treatment option for patients with pancreatic cancer, as it can provide a therapeutic benefit with significant advantages for patients' quality of life over standard conventional chemoradiation (CRT). The objective of this review is to present alternative clinical settings in which SBRT may benefit patients with pancreatic cancer. These include palliation of pain, elderly patients who are not surgical candidates, local therapy in oligometastatic cases and salvaging local failures after surgery or external beam radiation. We will review these individually and provide supporting literature for each.

Phase II clinical trial of paclitaxel loaded polymeric micelle in patients with advanced pancreatic cancer.

PURPOSE: To determine in patients, with locally advanced or metastatic pancreatic cancer (APC), efficacy and safety of treatment with intravenous paclitaxel loaded polymeric micelle (GPM). PATIENTS AND METHODS: This was a multicenter, open-label Phase II study. Patients with APC, ECOG performance status < or = 2, no prior chemotherapy and adequate organ function were treated with 3-hour GPM infusions every 3 weeks. Initial patients were treated with 435 mg/m(2) (n = 11). The dose was reduced for subsequent patients to 350 or 300 mg/m(2) (n = 45). Primary endpoint was time to tumor progression (TTP). RESULTS: 56 patients were enrolled. Median TTP for patients treated with 300 or 350 mg/m(2) doses was 3.2 months (95% CI, 2.6-4.2). Median progression free survival (PFS) was 2.8 months (95% CI, 1.4-4.0). Median overall survival (OS) was 6.5 months (95% CI, 5.1-7.9). Among patients treated with above doses of GPM, there was 1 complete remission (CR) and 2 partial remissions (PR) with an overall response rate (ORR) of 6.7%. Disease control rate (CR + PR + stable disease) was 60.0%. Most common grade 3 toxicities were: neutropenia (40.0%), fatigue (17.8%), infection, dehydration, neuropathy (each 13.3%), and abdominal pain (11.1%). CONCLUSIONS: Treatment of APC with GPM at a dose of 300 mg/m(2) q 3 weeks was well tolerated and common toxicities were qualitatively similar to Cremophor-based paclitaxel. GPM monotherapy resulted in OS and other efficacy parameters preferable to that seen historically with gemcitabine. Future studies of GPM in combination with other agents for treatment of APC are warranted.

Hypersensitivity reactions to oxaliplatin: a retrospective study and the development of a desensitization protocol.

BACKGROUND: We recorded the epidemiologic and clinical features of hypersensitivity reactions (HSRs) to oxaliplatin in colorectal cancer (CRC) patients in order to provide information on the management of these patients. We also developed a desensitization protocol and evaluated its clinical application. For these reasons, we analyzed retrospectively the records of 215 CRC patients treated with oxaliplatin-containing regimens either as an adjuvant, first-line, second-line, or more. PATIENTS AND METHODS: Data from 52 patients with HSRs were analyzed according to the Common Toxicity Criteria for Adverse Events (CTCAE), v3.0. Three patients were chosen for the desensitization protocol. After determining the starting point for desensitization, we applied the standard protocol for parenteral desensitization to b-lactam antibiotics. Oxaliplatin treatment was then carried out with serial 10-fold dilutions in sufficient volume to administer the total dose. A total of 52 patients (24.2%) were recorded as having an allergic reaction to oxaliplatin. RESULTS: Hypersensitivity reactions were recorded after a mean of 6.5 (SD +/- 4.5) cycles. Only 4 patients (4 of 215; 1.8%) developed CTCAE grade 3/4 HSRs. Hypersensitivity reactions were seen more likely in patients receiving second-line or more of chemotherapy compared with chemotherapy-naive patients. No other correlations were seen (the presence of atopic disease, positive skin prick test). The 3 patients, having completed the parenteral desensitization protocol, completed their treatment uneventfully as well. CONCLUSION: Hypersensitivity reactions from oxaliplatin respond quickly to the discontinuation of the drug and appropriate support. Premedication and an increased infusion time could allow for readministration. The desensitization protocol we developed can provide a reliable alternative to permanent discontinuation of oxaliplatin.

Hypersensitivity reactions to antineoplastic agents: an overview.

Hypersensitivity reactions to antineoplastic agents are defined as unexpected reactions with signs and symptoms inconsistent with known toxicity of antineoplastic drugs. These reactions are uncommon and usually associated with certain antineoplastic categories, such as taxanes, platinum-containing compounds, epipodofyllotoxins, asparaginase, procarbazine and, more rarely, with doxorubicin and 6-mercaptopurine. The mechanisms that are responsible for hypersensitivity reactions are unclear and vary between agents. Symptoms of these reactions range from mild skin rashes to more severe reactions, such as arthralgia, respiratory arrest or even death in some cases. Once hypersensitivity reactions are observed, basic principles that allow their management and possible continuance and completion of the regimen should be followed.

Combining epidermal growth factor receptor inhibitors and radiation therapy in pancreatic cancer: small step or giant leap?

Targeting the epidermal growth factor receptor (EGFR) with small molecule inhibitors or monoclonal antibodies in combination with chemotherapy and radiation is a theoretically appealing strategy in pancreatic cancer. EGFR inhibitors have shown efficacy as radiosensitizers and activity against metastatic pancreatic cancer when combined with gemcitabine. This paper examines the available clinical data, with a focus on locally advanced, unresectable disease. Further studies with a focus on understanding the basic biology of EGFR inhibition are needed to identify an optimal multi-modality regimen.

Pneumonitis related to docetaxel: case report and review of the literature.

Taxotere has recently been making a noticeable impact on breast, gastric, ovarian, prostate and non-small cell lung cancers. Its side effects include dyspnea, pruritus, skin rashes, fever and hypotension. The patient presented the less common, however potentially fatal, toxicity of pneumonitis. He initially presented with a flu-like illness and hypoxia that was unresponsive to antibiotic treatment and actually progressed. He presented 14 days after his second dose of taxotere, although in retrospect noted symptoms several days prior. Although some patients described in the literature have progressed to respiratory failure requiring mechanical ventilation, this patient responded to steroid treatment and withdrawal of taxotere.