Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma.

PURPOSE: We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. PATIENTS AND METHODS: One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. RESULTS: In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). CONCLUSION: Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

Leptomeningeal Metastasis from Non-Small Cell Lung Cancer and Current Landscape of Treatments.

Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis (LC), is a devastating complication of metastatic cancer that occurs when neoplastic cells invade the meningeal space. Diagnosis of LM remains challenging given the heterogeneous signs and symptoms at presentation and requires thorough neurological examination, cerebrospinal fluid (CSF) analysis, and MRI of the brain and spine with gadolinium. Detecting neoplastic cells in the CSF is the gold standard for diagnosing leptomeningeal metastases; however, it has low sensitivity and may require multiple CSF samples. New emerging technologies, such as liquid biopsy of CSF, have increased sensitivity and specificity for detecting circulating tumor cells in CSF. The management of LM in patients with NSCLC requires an individualized multidisciplinary approach. Treatment options include surgery for ventricular shunt placement, radiation therapy to bulky or symptomatic disease sites, systemic or intrathecal chemotherapy, molecularly targeted agents, and, more recently, immunotherapy. Targeting actionable mutations in LM from NSCLC, such as EGFR tyrosine kinase inhibitors or anaplastic lymphoma kinase gene rearrangement inhibitors, has shown encouraging results in terms of disease control and survival. Although there are limited data regarding the use of immunotherapy in LM, immunotherapy has produced promising results in several case reports. In this review, we focused on the epidemiology, pathophysiology, clinical presentation, diagnosis, and current treatment strategies, with a special emphasis on novel agents, including targeted therapies and immunotherapy of LM in patients with NSCLC.

Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma.

Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.

Discovery, Significance, and Utility of JAK2 Mutation in Squamous Cell Carcinoma of the Lung.

Lung cancer continues to be the leading cause of cancer-related deaths worldwide. Many studies show lung cancer is a histologically and molecularly heterogeneous group, even within the same histological subtype. Liquid biopsies are a new tool that can identify targetable genomic mutations and impact management. JAK2 p.V617F is a mutation commonly found in myeloproliferative neoplasms but rarely identified in non-small cell lung cancer (NSCLCs). The significance of Janus Kinase (JAK2) mutation in lung cancer is not clearly understood. However, it is thought that it may have a role in treating solid tumors, such as lung cancer. We present two cases of patients diagnosed with NSCLC who were discovered to have JAK2 V617F mutation on liquid biopsy.

Primary central nervous system diffuse large B-cell lymphoma masqueraded as Bing-Neel syndrome: Steps in management and review of future directions.

Bing-Neel syndrome (BNS) remains a rare complication of Waldenstrom Macroglobulinemia. Given the paucity of this disease, treatment guidelines are based on small clinical trials with limited participants. Here, we present a case of primary CNS diffuse large B-cell lymphoma masqueraded as BNS that developed while on ibrutinib therapy.

An Unusual Hodgkin's Lymphoma Journey: Cardiac Tamponade, Primary Refractoriness, Immune Thrombocytopenia, and Post-Traumatic Stress Disorder.

Hodgkin's lymphoma (HL) is a lymphoid neoplasm in which malignant Hodgkin or Reed-Sternberg cells are present in tissues mixed with heterogeneous non-malignant inflammatory cells. Pericardial effusion (PEEF) in HL is rare. Furthermore, hemodynamically significant effusions causing cardiac tamponade (CTp) are exceedingly uncommon. CTp as the initial presentation of HL is extremely rare. We describe the case of a 21-year-old man who presented with CTp requiring pericardiocentesis. On further workup, he was found to have a large mediastinal mass with a biopsy consistent with classic HL. His clinical course was complicated by the development of immune thrombocytopenia (ITP) and post-traumatic stress disorder (PTSD).

Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts.

Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m2 on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.

Ado-trastuzumab emtansine: Avoiding side-effects of traditional HER2 positive breast cancer treatment.

INTRODUCTION: Approach to cancer treatment is dictated by guidelines based on clinical research. New research continuously changes what we consider to be first-line therapy for a given type of cancer. Treatment approach becomes more complex when patient's cultural beliefs have to be considered and incorporated into the therapy. CASE REPORT: We are presenting a case of a patient born and raised in the former Soviet Union, whose understanding of how cancer should be treated was considerably different from what we now deem to be first-line therapy. This patient was diagnosed with metastatic HER2 positive breast cancer.Management and outcome: Having reservations about first-line therapy, she wanted to consider surgery as well as other lines of therapy. Her medical team worked on finding an alternative treatment plan that would be in line with her goals of care. Patient's personal beliefs led her to choose a therapy that is currently a second-line: Ado-trastuzumab emtansine. She was able to achieve full remission. DISCUSSION: Some recent studies discussed in this case showed that first-line therapies don't have significant progression free survival advantage when compared to the second-line therapy that our patient received. Ado-trastuzumab emtansine is a potent cytotoxic drug connected via a stable linker to the anti-HER2 antibody, trastuzumab. More studies need to be done to further investigate positive result presented in this case and whether this could be considered an alternative to current first-line therapy.

New onset diabetes with ketoacidosis following nivolumab immunotherapy: A case report and review of literature.

INTRODUCTION: Immune-checkpoint inhibitors have become an increasingly popular form of systemic therapy for cancer treatment. Their use has proven to be so effective that certain regimens have gained approval as first-line therapy for various solid tumor types. The most common and well-studied forms of immunotherapy include agents that target cytotoxic T-lymphocyte antigen-4, programmed death-1, and programmed death ligand-1. These therapies act by blocking signaling between immune cells and cancer cells which subsequently augment T cell-mediated destruction of tumor cells. CASE REPORT: Here, we report a case of a 77-year-old black male with no history of or risk factors for diabetes mellitus who presented with acute onset of diabetic ketoacidosis after beginning immunotherapy with nivolumab for metastatic high-grade neuroendocrine tumor of the lung. He was admitted and treated for diabetic ketoacidosis but required prolonged use of an insulin infusion with frequent need of intravenous dextrose due to labile blood sugars. The patient was eventually discharged and discontinued further immunotherapy with nivolumab. DISCUSSION: Due to the unique mechanisms by which immune-checkpoint inhibitors cause immune-mediated destruction of tumor cells, clinicians may be challenged with their associated autoimmune complications referred to as immune-related adverse events. In particular, the incidence of endocrine dysfunction following immune-checkpoint inhibitor therapy is approximately 12%, with the development of insulin-dependent diabetes mellitus being a rare complication. Increasing awareness of immune-related adverse events is essential for the early recognition and effective management of patients who present with life-threatening complications related to immune-checkpoint inhibitor therapy.

A Rare Case of Clear Cell Adenocarcinoma of the Cervix with No Intrauterine Diethylstilbestrol Exposure.

Cervical cancer is the fourth most common cancer in females. Clear cell adenocarcinoma of the cervix is an uncommon histological variant and is usually seen with intrauterine exposure to diethylstilbestrol. A 28-year-old female with no intrauterine exposure to diethylstilbestrol presented with postcoital bleeding. A pelvic exam revealed a cervical mass. Imaging confirmed the cervical mass and positron emission tomography scan showed an increased uptake in the cervical mass as well as the para-aortic and pelvic lymph nodes. Biopsy showed a clear cell carcinoma of the cervix. She was treated with cisplatin and paclitaxel for eight cycles and concurrent radiation therapy. She had a complete response to therapy and has been in complete remission nine months from the end of therapy. There are no clear guidelines for the treatment of clear cell carcinoma with current therapy based on the treatment of squamous and non-clear cell adenocarcinoma. Cisplatin and paclitaxel could be an option, given the successful treatment of the patient in our case.

Primary Bone Lymphoma: A Case Series and Review of Literature.

Primary bone lymphoma (PBL) is a subtype of lymphoma that exclusively affects skeletal tissue. Despite the relatively common involvement of skeletal structures as a manifestation of non-Hodgkin's lymphoma (NHL), primary and exclusive involvement of the skeletal system is rare. The prevalence of PBL is estimated to be 3-7% amongst primary bone tumors and less than 2% amongst all lymphomas in adults. However, the definition of primary bone lymphoma has been inconsistent over time. Within our institution, we identified four cases of primary bone lymphoma based on diagnostic criteria formed from the general consensus of multiple organizations, including the World Health Organization (WHO) and International Extranodal Lymphoma Study Group (IELSG). Here, we discuss the distinct characteristics amongst these cases in addition to performing a systematic review of current literature regarding this lymphoproliferative entity.

Idiopathic Granulomatous Mastitis-A Mystery Yet to be Unraveled: A Case Series and Review of Literature.

Idiopathic granulomatous mastitis (IGM) is a chronic inflammatory disease of the breast, the etiology of which, has still not been elucidated. There have been several mechanisms proposed to explain the pathogenesis. Since the first description of the disease, it has proved itself to be a great diagnostic and therapeutic challenge. It is very often misdiagnosed as cancer, resulting in myriad workup by the physician and great distress to the patient. Clear guidelines as to the management have still not been described. Here, we describe two patients who presented with IGM and have been successfully treated. The first patient was treated with a combination of steroids and antibiotics. The second patient achieved remission of the disease with antibiotics alone. We also propose an algorithm for the management of IGM.

Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial.

PURPOSE: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. PATIENTS AND METHODS: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. RESULTS: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001). CONCLUSIONS: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535.

Chordoma: A Case Report and Review of Literature.

BACKGROUND Chordoma is a rare, but aggressive bone tumor, primarily affecting the axial skeleton. Systemic chemotherapies are not effective against the tumor, and treatment primarily consists of surgical resection and radiation. Despite these treatment modalities, recurrence is common. Our case highlights the role of afatinib as an effective treatment option in such cases. CASE REPORT We present case of 68-year-old female with chordoma, who underwent multiple surgical resections, radiotherapy session, and had course complication by disease progression on imatinib and local recurrence. She was eventually placed on afatinib with good effect. CONCLUSIONS This article discusses the effectiveness of afatanib as a treatment modality, along with diagnosis, histopathological features, associated genetic aberrations, currently available and upcoming treatment options. Special emphasis is placed on molecular targeted therapy, emerging immunotherapies and use of vaccination in this field.

A Rare p.T599dup BRAF Mutant NSCLC in a Non-Smoker.

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) mutated non-small-cell lung cancer (NSCLC) is an exceptionally rare form of lung cancer, found only in one to two percent of patients with an NSCLC diagnosis. BRAF NSCLC traditionally affects former or active smokers. BRAF mutations have always been of special interest to the oncological community, as they offer potential for targeted therapies. BRAF mutation spectrum includes mutations that are of both V600 and non-V600 types. BRAF V600 is an activating mutation, which results in high kinase activity and overproduction of active oncoproteins such as rapidly accelerated fibrosarcoma (RAF). This makes them susceptible to targeted therapies with RAF inhibitors. There has been little evidence, however, regarding efficacy of RAF inhibitors towards non-activating mutations that have intermediate to low kinase activity, such as non-V600 BRAF mutations. While several approaches have been investigated to overcome the limitations of RAF inhibitors, such as use of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) inhibitors or combination of MEK and RAF inhibitors, none of them have been proven to have a superior efficacy for low kinase activity non-V600 BRAF tumors. We present a case of an extremely rare variant of NSCLC BRAF p.T599dup mutation in a non-smoker that responded to a targeted combination therapy with RAF and MEK inhibitors. The patient responded well to therapy that usually targets high kinase activity V600 mutations. Our hope is to bring more attention to non-V600 mutations and document their responses to existing and new therapies.

Treatment exceeds expectations in a patient with non-small cell lung adenocarcinoma with an EGFR exon 20 mutation.

Non-small cell lung adenocarcinoma is the most common type of lung cancer but is often difficult to treat. New treatment options have emerged with the class of tyrosine kinase inhibitors, but it has been found that certain genetic mutations in the epidermal growth factor receptor (EGFR) receptor are not as sensitive to this treatment as others. We present a case of a 78-year-old man who was diagnosed with stage IV non-small cell lung adenocarcinoma with an EGFR exon 20 mutations treated with pemetrexed, nivolumab, and then docetaxel. He has lived over four years after his initial diagnosis. This case illustrates the importance of genetic testing of patients to evaluate for specific gene mutations. It highlights the fact that these patients with exon 20 mutations are not sensitive to tyrosine kinase inhibitor treatment and often respond better to chemotherapeutic agents.

Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study.

BACKGROUND: VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM). METHODS: Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS). RESULTS: VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease. CONCLUSIONS: Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.

Hyperprogression in PDL1 Expressive, Recurrent Gastroesophageal-junction Adenocarcinoma After Pembrolizumab.

Hyperprogression is a pattern of accelerated tumor growth noted uncommonly after the use of immune checkpoint inhibitors in some patients. We present a 56-year-old female with gastroesophageal junction (GEJ) adenocarcinoma who was initially treated with neoadjuvant radiation and chemotherapy with carboplatin and paclitaxel, followed by esophagogastrectomy and postoperative FOLFOX chemotherapy. After a stable two-year course, she was noted to have recurrence at the GEJ which was biopsy confirmed. She was started on pembrolizumab, after which she developed several new metastases noted on the PET/CT. Lesions were noted in iliac bones, spine, retroperitoneal lymph nodes, hilar nodes, mediastinum, and lungs. Postdiscontinuation of the pembrolizumab, she received six cycles of paclitaxel with ramucirumab and showed remarkable improvement on the next imaging scan with resolution of osseous lesions, lung nodules and significant improvement in hilar, mediastinal, and retroperitoneal lymph nodes. We hope that this case report sheds further light on this uncommon complication of immune checkpoint inhibitors.

Phase I/II trial of the CXCR4 inhibitor plerixafor in combination with bortezomib as a chemosensitization strategy in relapsed/refractory multiple myeloma.

We tested the hypothesis that using CXCR4 inhibition to target the interaction between the tumor cells and the microenvironment leads to sensitization of the tumor cells to apoptosis. Eligibility criteria included multiple myeloma (MM) patients with 1-5 prior lines of therapy. The purposes of the phase I study were to evaluate the safety and maximal-tolerated dose (MTD) of the combination. The treatment-related adverse events and response rate of the combination were assessed in the phase II study. A total of 58 patients were enrolled in the study. The median age of the patients was 63 years (range, 43-85), and 78% of them received prior bortezomib. In the phase I study, the MTD was plerixafor 0.32 mg/kg, and bortezomib 1.3 mg/m2 . The overall response rate for the phase II study was 48.5%, and the clinical benefit rate 60.6%. The median disease-free survival was 12.6 months. The CyTOF analysis demonstrated significant mobilization of plasma cells, CD34+ stem cells, and immune T cells in response to plerixafor. This is an unprecedented study that examines therapeutic targeting of the bone marrow microenvironment and its interaction with the tumor clone to overcome resistance to therapy. Our results indicate that this novel combination is safe and that the objective response rate is high even in patients with relapsed/refractory MM. ClinicalTrials.gov, NCT00903968.

Everolimus and Bevacizumab in the Management of Recurrent, Progressive Intracranial NF2 Mutated Meningioma.

Meningiomas are primary CNS tumors that arise from the arachnoid layer of the meninges. Genomic sequencing has revealed that NF2 mutations are the most common genetic alteration seen in meningiomas. Meningiomas although usually low grade, can sometimes progress to high grade. A patient who had several recurrences of meningiomas since childhood presented with recurrent headaches. Imaging showed that he had another recurrence of a meningioma. He underwent surgery for resection of the meningioma and histopathology showed NF2 mutation. He was started on everolimus and bevacizumab with good effect. Studies have shown that NF-2 mutated meningiomas have a good response to everolimus and bevacizumab with increased progression-free survival time and progression-free survival time at 6 months.