Hirva Mamdani

Novel therapies in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor of the lung with a tendency to metastasize widely early in the course of the disease. The VA staging system classifies the disease into limited stage (LS) which is confined to one hemithorax and can be included into one radiation field or extensive stage (ES) which extends beyond one hemithorax. Current standard of care is concurrent chemoradiation for LS disease and chemotherapy alone for ES disease. Only a quarter of patients with LS disease will be cured with current standard treatments and majority of the patients ultimately succumb to their disease. A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate, however, at the same time this complexity can form the basis for effective targeted therapy for the disease. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors have been unsuccessful in showing a survival advantage in this disease. Several others including DNA repair inhibitors, cellular developmental pathway inhibitors, antibody drug conjugates (ADCs), as well as immune therapy with vaccines, immunomodulators, and immune checkpoint inhibitors are being tested. So far, none of these agents are approved for use in SCLC and the majority are in phase I/II clinical trials, with immune checkpoint inhibitors being the most promising therapeutic strategy. In this article, we will discuss these novel therapeutic agents and currently available data in SCLC.

Spotlight on the treatment of ALK-rearranged non-small-cell lung cancer

Lung cancer is the leading cause of cancer-related mortality, both worldwide and in the USA. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. At the turn of 21st century, platinum based cytotoxic chemotherapy was shown to offer modest survival benefit in metastatic NSCLC and remained the only viable treatment option for a long time. Over the past decade, the therapeutic landscape of NSCLC has expanded dramatically owing to the discovery of various driver mutations. Several molecularly targeted agents and immune checkpoint inhibitors are now a part of the therapeutic armamentarium against this genetically complex disease. ALK gene encodes for a member of insulin receptor superfamily transmembrane receptor tyrosine kinase [1]. In 2007, chromosomal rearrangement involving ALK gene on chromosome 2 and EML4 gene on chromosome 5 was first found to have potent transforming activity in NSCLC. Subsequently, preclinical studies suggested that this fusion gene might be the driver mutation and potentially be a therapeutic target of NSCLC [2]. Approximately, 3– 7% of patients with NSCLC harbor the EML4–ALK gene rearrangement, which is mutually exclusive with EGFR and KRAS mutations. ALK gene rearrangements are more common in younger patients with adenocarcinoma histology and those with minimal or no smoking history. There are reports of ALK gene rearrangement in patients with squamous cell and small-cell lung cancer; however, its clinical significance and potential as a therapeutic target in these histologic subtypes remain unknown. The testing modalities for ALK rearrangement in NSCLC include immunohistochemistry (IHC), FISH, and PCR; with the former two being the most commonly utilized modalities. However, there is a variable rate of discordance in response to ALK inhibition in IHC-negative but FISH-positive tumors, and therefore both IHC and FISH are currently recommended for ALK testing. Crizotinib, originally developed as a c-MET inhibitor, is the first-in-class ALK inhibitor to show activity in ALKrearranged NSCLC. In addition, it is also active in ROS1-rearranged lung cancer. Crizotinib received accelerated US FDA approval in 2011 based on a Phase I trial showing objective response rate (ORR) of 60% with a median progression free survival (PFS) of 9.7 months and 12-month overall survival of 74.8% in patients with ALK-rearranged NSCLC [3]. Subsequently, two randomized Phase III trials comparing crizotinib with standard chemotherapy in second line and first-line settings confirmed significantly higher response rates and longer PFS with crizotinib. No statistically significant overall survival difference was observed in either of these trials, largely accounted for by significant crossover between the two arms [4,5]. Despite the striking results with this first ALK inhibitor, the success in personalized therapy was fraught with several challenges. First, the majority of patients develop resistance to crizotinib within the first 12 months of treatment. Several resistance mechanisms have been implicated and are broadly divided into two categories: ALKdominant, and ALK-nondominant [6]. ALK-dominant mechanisms predominantly comprise second mutations in the ALK gene which include a gatekeeper mutation L1196M as well as other more recently reported mutations such

Malignant cause of abdominal pain in leukemia: spontaneous splenic rupture.

S pontaneous splenic rupture (SSR) is a devastating etiology of acute abdomen in hematological malignancies. It is rarely associated with leukemia. Overall incidence of splenic rupture in leukemia is extremely low. Most of the cases had been reported in untreated cases of leukemia. Here, we describe the first case of a patient who had allogeneic stem cell transplantation (SCT) for secondary leukemia and about 45 days after the transplantation, he developed subacute presentation of acute abdomen secondary to splenic hematoma from leukemic splenic infiltrates, nonresponsive to therapeutic embolization which progressed into multiorgan failure. Our patient was a 66-year-old man who presented with left-sided abdominal pain of 6 days duration. The patient was diagnosed with myelodysplastic syndrome with high-risk cytogenetic abnormalities (inversion 3, monosomy 7, RPN1) and 6% blasts on bone marrow biopsy. Soon after diagnosis, he was treated with 1 cycle of decitabine, which was complicated by neutropenic fever requiring hospitalization and discontinuation of therapy. Repeat bone marrow biopsy showed 20% blasts concerning for development of acute myeloid leukemia (AML). He had undergone allogeneic hematopoietic SCT (10/ 10 matched unrelated donor peripheral blood SCT) for secondary AML 45 days before presentation. A reduced intensity conditioning preparative regimen of busulfan and fludarabine was used. He had received 17.55 3 106 CD34 cells per kilogram. Filgrastim (480 mcg daily; 4 mcg

Coagulopathy and spontaneous hemorrhage in a patient with nephrotic syndrome.

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Locally Advanced Non-Small Cell Lung Cancer: Optimal Chemotherapeutic Agents and Duration

d21) was given for 16 days after SCT to help with posttransplantation engraftment. Mycophenolate and tacrolimus along with 1 dose of thymoglobulin were started for graft versus host disease prophylaxis. A bone marrow biopsy 40 days after transplantation had shown 2% myeloblasts. The patient also had significant coronary artery disease with 3 previous myocardial infarctions with the last being 3 months before the current presentation. The abdominal pain had started insidiously and was radiating to the left shoulder. He did not report lightheadedness, recent infections or trauma. On presentation, vitals were normal. Physical examination was remarkable for distended tender abdomen without any guarding or rigidity and marked hepatosplenomegaly (liver span of 17 cm and tip of the spleen palpable up to umbilicus). Laboratory findings revealed hemoglobin of 7.9 g/dL and platelets 34,000/mm3, which were unchanged from his previous blood counts. Computed tomography (CT) scan of abdomen revealed markedly enlarged spleen measuring 25 cm. The patient was treated conservatively with analgesics and hydration. On day 6, his hemoglobin acutely dropped to 6 g/dL accompanied by hypoxia and hypotension. Serum troponin I was undetectable. Transthoracic echocardiogram showed normal left ventricular ejection fraction and normal collapsibility of inferior vena cava. Repeat CT abdomen revealed free peritoneal fluid and markedly enlarged spleen measuring 27 cm with ill-defined anterior margin studded with clots, consistent with splenic rupture with intraperitoneal hemorrhage (Figure 1A). He was deemed very high risk for surgical mortality with splenectomy because of significant coronary artery disease and fairly recent myocardial infarction as well as current hemodynamic instability. Hence, splenic artery embolization was performed as a temporizing measure to allow resuscitation and possible stabilization of hemodynamic status. Despite embolization, his clinical status rapidly deteriorated with development of multiorgan failure and acute respiratory distress syndrome requiring mechanical ventilation. At that point, surgical intervention was deemed extremely high risk with minimal, if any, potential benefit. Eventually, he died to multiorgan failure. Autopsy showed hemoperitoneum, enlarged spleen (4190 g) and liver (2850 g) and splenic congestion with widespread infarction due to embolization. Immunohistochemical stain of the spleen sections confirmed infiltration with myeloblasts positive for CD34 expression (Figure 1B). SSR is a rare complication of AML. Although splenomegaly is reported in context of granulocyte colony stimulating factor (G-CSF) use (for stem cell mobilization in patients and healthy donors as well as for engraftment), splenic rupture with G-CSF use is extremely rarely associated. Mechanisms responsible are infiltration of the spleen by leukemic cells leading to distortion of the splenic architecture, splenic infarction with subcapsular hemorrhage and capsule rupture. Risk factors for SSR in patients with hematologic malignancies include adult age, male sex, severe splenomegaly and previous or present use of G-CSF. Abdominal pain is the most common presenting symptom, which is usually acute and may be accompanied by lightheadedness. However, an absence of abdominal pain does not exclude the diagnosis since approximately one-third of the patients do not have abdominal pain or it is insidious in onset. Physical examination clues to the diagnosis are frank or orthostatic hypotension, abdominal tenderness and distension. Although splenomegaly is present in most of the patients, its absence does not exclude the diagnosis as about one-third of the patients do not have a palpable spleen. Abdominal ultrasound is usually the first radiologic modality used but is nondiagnostic in up to 30% of the cases. CT abdomen is overall the best diagnostic test. Splenectomy is the treatment of choice; however, many patients are not the candidates for it because of hemodynamic instability, and underlying coagulopathy. Irradiation of the rupture site or embolization of the splenic artery is an alternative therapeutic intervention in such cases. Our patient had splenic rupture from refractory AML. This complication is rare but should be considered as a cause of new onset abdominal pain in patients with refractory disease. Furthermore, subacute presentation of splenic rupture is frequently misdiagnosed as more benign etiologies such as gastritis, peptic ulcer disease or nephrolithiasis. The diagnosis is often challenging because of the absence of any history of trauma, initially stable vital signs and absence of frank splenomegaly on examination. The physicians should be aware of the importance of maintaining a high index of suspicion for this condition, especially in patients at high risk and not to exclude the diagnosis on the basis of seemingly benign physical examination findings as mortality approaches 100% in untreated cases.

Excellent response to anti-PD-1 therapy in a patient with hepatocellular carcinoma: Case report and review of literature

Patients with nephrotic syndrome, particularly those with membranous nephropathy tend to be in a hypercoagulable state and often present with thromboembolic phenomena. The association of nephrotic syndrome with a bleeding diathesis however is much less common and the etiologies less well recognized. We report a patient who presented with coagulopathy and recurrent spontaneous hemorrhage in association with nephrotic syndrome. The case highlights key diagnostic and therapeutic challenges and strategies: 1) work up to establish a unifying etiology for both nephrotic syndrome and the bleeding disorder; 2) decision making to obtain a tissue biopsy, select the site of biopsy and understand the relative yields for each site; 3) recognizing the risk and managing peri-procedural bleeding; and 5) developing a treatment strategy with the lowest risk of possible complications. Our patient underwent a kidney biopsy without any complications and a definitive diagnosis of AL amyloidosis was reached. He was treated with anti-plasma cell chemotherapy followed by autologous stem cell transplant with resultant complete hematologic response, improved coagulation parameters, and no further bleeding.