Edgardo S. Santos

Primary hepatic non-Hodgkin's lymphomas: case report and review of the literature

A 31-yr-old man presented with a 1-wk history of fever, chills, weakness, headaches, and a significant 20-lb weight loss over the preceding 2 months. His past medical history was relevant for liver amebiasis during childhood. Two days before admission, the patient noticed jaundice. He denied abdominal pain or other GI symptoms, and there was no history of alcohol intake, medications, or illicit drugs. His physical examination revealed generalized jaundice, hepatosplenomegaly, and bilateral leg edema. Neurologically, the patient was agitated, with periods of disorientation, and he had bilateral flapping. His blood tests revealed pancytopenia, renal failure, liver failure, and coagulopathy. Because the patient had a fever, hepatosplenomegaly, and pancytopenia, a further workup also included a bone marrow and liver biopsy. No conclusive diagnosis could be made from the above tests, and the patient died 5 days after admission. Postmortem evaluation, including flow cytometry and gene rearrangement in the tissue obtained from the liver, revealed large B cell lymphoma. This case illustrates an unusual presentation of hepatic non-Hogdkins lymphoma. Current information regarding this entity is scant, mainly owing to its rarity. We present a review of the literature, including the incidence, presentation, treatment, and prognosis of primary hepatic lymphoma.

Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors

INTRODUCTION Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. AREAS COVERED This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. CONCLUSION Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC.

Overcoming the resistance to Crizotinib in patients with Non-Small Cell Lung Cancer harboring EML4/ALK translocation

The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.

Targeting the Met pathway in lung cancer.

Dysregulation of Met signaling has been implicated in the initiation, progression and metastasis of human cancers, and therefore represents an attractive target for anticancer drug development. Met is overexpressed in non-small-cell lung cancer and its lack of staining in normal lung tissue makes it an attractive target. To date, erlotinib and gefitinib have established themselves as first-line therapy for non-small-cell lung cancer patients whose tumors harbor an EGF receptor gene mutation, and hence, it is crucial that we identify mechanisms of resistance that could be targeted by novel agents, while keeping an acceptable toxicity profile at the same time; something very important when we develop these new drugs. Inhibitors of the Met pathway represent a therapeutic alternative in this setting. In this review, we discuss the early clinical studies reported using two Met inhibitors, a monoclonal antibody (MetMAb) and a small molecule tyrosine kinase inhibitor (MGCD265).

Novel molecular targeted therapies for refractory thyroid cancer

The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine‐refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B‐Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR‐2) angiogenesis pathways are some of the known genetic alterations playing a crucial role in the development of thyroid cancer. Several novel agents have demonstrated promising responses. Of the treatments studied, multi‐kinase inhibitors such as axitinib, sorafenib, motesanib, and XL‐184 have shown to be the most effective by inducing clinical responses and stabilizing the disease process. Randomized clinical trials are currently evaluating these agents, results that may soon change the management of thyroid cancer.

The role of proteasome inhibition in nonsmall cell lung cancer.

Lung cancer therapy with current available chemotherapeutic agents is mainly palliative. For these and other reasons there is now a great interest to find targeted therapies that can be effective not only palliating lung cancer or decreasing treatment-related toxicity, but also giving hope to cure these patients. It is already well known that the ubiquitin-proteasome system like other cellular pathways is critical for the proliferation and survival of cancer cells; thus, proteosome inhibition has become a very attractive anticancer therapy. There are several phase I and phase II clinical trials now in non-small cell lung cancer and small cell lung cancer using this potential target. Most of the trials use bortezomib in combination with chemotherapeutic agents. This paper tends to make a state-of-the-art review based on the available literature regarding the use of bortezomib as a single agent or in combination with chemotherapy in patients with lung cancer.

Oxaliplatin in first-line therapy for advanced non-small-cell lung cancer.

Platinum doublets are the recommended standard first-line chemotherapy for stage IIIB/IV non-small-cell lung cancer (NSCLC). As efficacy outcomes associated with currently approved agents (cisplatin and carboplatin) are broadly similar, the decision about which platinum-based doublet to use is based on other factors such as toxicity. The goals for new platinum agents are to maintain and perhaps improve current efficacy and to improve toxicity. The aim of this article is to review the available clinical data from studies investigating the third-generation platinum analogue oxaliplatin in patients with advanced NSCLC. Information was obtained from the PubMed database and from recent presentations at national and international meetings. Oxaliplatin has been studied as monotherapy and in combination with a wide range of other chemotherapies (vinca alkaloids, taxanes, gemcitabine, and pemetrexed), mainly in phase II trials. Preliminary results from studies in which oxaliplatin-based doublets have been combined with targeted agents (eg, bevacizumab) are now available. In general, the clinical activity observed with oxaliplatin-based therapy is similar to that seen with other currently used platinum regimens, although outcomes vary between individual trials (response rates, 23%-48%; median progression-free survival, 2.7-7.3 months; median overall survival, 7.3-13.7 months). The toxicity profile of oxaliplatin, particularly when compared with cisplatin, makes it an alternative treatment, especially in patients unable to tolerate cisplatin. However, well-conducted randomized phase III trials will be needed to clarify which particular groups of patients with NSCLC may benefit from oxaliplatin-based therapy.

The utility of a bone marrow biopsy in diagnosing the source of fever of unknown origin in patients with AIDS.

A bone marrow (BM) aspiration and biopsy is often believed to be a needed diagnostic procedure in the work-up of patients with fever of unknown origin (FUO), especially in the setting of AIDS. Is it worthwhile to proceed with this invasive diagnostic method? Clinical information obtained on 104 patients in whom AIDS had been previously diagnosed and who had been admitted with a presumptive diagnosis of FUO was retrospectively analyzed. Seventy-two cases met the inclusion criteria. A BM aspiration and biopsy had a low sensitivity as a diagnostic tool even in patients who had abnormal hematologic parameters. BM biopsy was also not helpful in diagnosing non-Hodgkin lymphoma (NHL) cases in this study. Although the incidence of NHL has risen since the emergence of HIV, the predominant types of lymphoma seen in AIDS patients are intermediate/high-grade lymphomas rather than low grade, and consequently, the incidence of BM involvement is low, decreasing the sensitivity of a BM biopsy as a diagnostic tool. These observations were validated in this study. The majority of BM biopsies in this series revealed diagnostic features of infections. This observation can likely be related to the high prevalence of HIV/AIDS patients in this community and opportunistic infections associated with this disease.

Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor

SummaryAngiogenesis is considered one of the major components of tumor progression and metastasis. Interfering with the formation and stabilization of tumor blood vessels could increase tumor response rates and may translate into improved clinical outcomes in cancer patients. The clinical efficacy demonstrated in phase III trials with bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor ligand, suggests that targeting angiogenesis is a rational approach to cancer management. Agents that target additional proangiogenic intracellular signaling pathways also have the potential to contribute to our anticancer armamentarium. Novel targeted agents that have antiangiogenic properties have been developed in recent years such as sorafenib, sunitinib, vandetanib, and others. Many of them inhibit additional pathways beyond vascular endothelial growth factor signaling. One of these investigational targeted agents is a triple angiokinase inhibitor known as BIBF 1120. This compound targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, and platelet-derived growth factor receptors. The preliminary clinical efficacy of BIBF 1120 is discussed in the context of the most relevant clinical data in several malignancies including non-small cell lung cancer.

Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer?

Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent ‘cancer immunoediting’ has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment.