Biweekly cetuximab and irinotecan as second-line therapy in patients with gastro-esophageal cancer previously treated with platinum

Background  

Until recently there has been no proven second-line therapy for patients with advanced gastro-esophageal cancer (GEC). Since 2004, Denmark has had a national health program where non-proven therapy can be offered to patients with advanced cancer, after approval by an expert panel appointed by the National Board of Health. This program has accelerated the introduction and implementation of new therapies in Denmark. Inspired by therapy in metastatic colorectal cancer, a combination of cetuximab and irinotecan (Cetiri) was chosen for second-line therapy in GEC patients. We report our experience with Cetiri as second-line therapy in patients with GEC.     

Clinical efficacy of primary combined androgen blockade for Japanese men with clinically localized prostate cancer unsuitable for local definitive treatment: a single institution experience

Background  

Primary hormonal therapy has been mostly used for patients with advanced prostate cancer, as international guidelines do not recommend its use for patients at earlier disease stages. However, there seems to be a discrepancy between the guideline recommendations and clinical practice on the use of primary androgen deprivation therapy for localized prostate cancer in Japan. Therefore, we retrospectively analyzed a single-institution experience in primary combined androgen blockade (CAB) for localized prostate cancer.     

Apoptosis of human pancreatic carcinoma cells induced by all-trans retinoic acid and interferon

Objective  To investigate the apoptosis of human pancreatic carcinoma PC3 cells induced by the combination of all-trans retinoic acid (ATRA) with interferon alpha (IFN-α). Methods  PC3 cells were treated with ATRA and IFN-α. The inhibitory rate of PC3 cell proliferation was detected using MTT method. Cellular apoptosis was determined with flow cytometry. The percentage of PC3 cell apoptosis was assayed using TUNEL methods. Results  ATRA and IFN-α could inhibit cellular proliferation and induces cellular apoptosis of PC3 cells. The inhibitory effect was stronger when the ATRA and IFN-α were combined as a therapy. Conclusion  ATRA inhibits the proliferation of PC3 cells and induce the apoptosis of PC3 cells. The combination of IFN-α with ATRA may enhance these effects on PC3 cells.      

血液系统恶性肿瘤细胞免疫治疗的研究进展

近年来,血液系统恶性肿瘤的治疗虽然取得了很大进展,但多数患者最终仍会复发并遭受化疗或放疗引起的严重副作用. 因此,过继性细胞免疫治疗作为一种耐受良好、安全有效的创新性疗法应运而生. 它是将体外扩增或处理后的免疫效应细胞回输到患者体内杀灭肿瘤或控制复发的一种疗法,被积极应用于各类血液系统恶性肿瘤的治疗,并取得了显著的疗效,为更多的复发难治性血液病患者带来了希望.     

Decreased rate of infection in glioblastoma patients with allelic loss of chromosome 10q

Introduction Chromosome 10q allelic loss commonly occurs in glioblastoma. Disruption of PTEN, one of three known 10q tumor suppressor genes, affects the immune system by increasing tumor expression of immunosuppressive protein B7-H1 and by increasing tumor release of Th2-inducing cytokines. While the former might impair antitumor cellular immunity, a consideration for immunotherapy, the latter could cause 10q-maintaining tumor patients to experience comparatively higher rates of bacterial infections, a source of morbidity and mortality in glioblastoma patients. Methods We retrospectively reviewed 58 glioblastoma patients whose tumors were designated “normal-10q” (n = 16) or “LOH-10q” (n = 42) using loss of heterozygosity (LOH) assays of microsatellite markers in constitutional/tumor DNA pairs. Records were reviewed for symptomatic, microbiologically or radiographically confirmed infections in the first 2 years after diagnosis. Results Infection occurred more frequently in “normal-10q” than “LOH-10q” patients (56% vs. 14% of patients experiencing infection; P = 0.001). “Normal-10q” patients more commonly developed all four infection types studied (urinary tract = 38% vs. 13%, craniotomy wound = 19% vs. 0%, pneumonia = 19% vs. 5%, sepsis = 6% vs. 3%). “Normal-10q” and “LOH-10q” patients had similar survival, ages, chemotherapy treatment rates, and frequency of patients on dexamethasone 1 month after radiation therapy (P = 0.4–0.98), making these factors unlikely to explain the observed difference in infection rates. Conclusion While tumor mutations may inhibit antitumor immunity, the effects of these mutations on systemic immunity remain undetermined. We found higher infection rates after glioblastoma diagnosis in patients whose tumors maintained chromosome 10q than in patients whose tumors had allelic 10q loss. Differing effects of this genetic alteration on antitumor and systemic immunity may warrant further investigation, potentially providing insight into mechanisms of antitumor immunity and host defenses against local and systemic infections.     

Patient attendance at molecular tumor board: A new means of shared decision making?

Patient engagement in medical decision-making improves patient related outcomes through compliance and patient satisfaction. The Inova Schar Cancer Institute has a weekly molecular tumor board (MTB) to match comprehensive genomic sequencing results with targeted therapies for patients. Primary oncologists extended MTB invitations to their patients. Ultimately, 20 of the 139 patients attended and completed pre- and post MTB surveys. There was a statistically significant change from the pre- to post- survey for the question “I am satisfied with how well informed I am about targeted therapy” with P = 0.016. Patients who attended MTB reported higher levels of satisfaction with their knowledge of targeted therapy after MTB as compared to before. A more holistic method of studying this practice would include sampling a larger patient population and a formal evaluation of the physicians’ experience with patients attending.     

Effect of Photodynamic Therapy with BPD-MA on the Proliferation and Apoptosis of Human Bladder Cancer Cells

OBJECTIVE To explore the effect of photodynamic therapy with benzoporphyrin derivative monoacid ring A (BPD-MA) on the proliferation and apoptosis of human bladder cancer cells.METHODS Rhotosensitization of BPD-MA was activated with a red light laser (632.8 nm) delivered at 10 mw/cm2 to give a total dose of 2.4 J/cm2.Cellular proliferative activity was measured using the 3-(4,5-dimethylethiazil-2-yl)-2,5-Diph3-eyl tetrazolium bromide (MTT) assay and 3H-thymidine incorporation. Cell apoptosis was determined with flow cytometry analysis and the terminal deoxyuridine nicked-labeling (TUNEL) assay.RESULTS At 24 h post photodynamic treatment, photodynamic therapy significantly decreased cellular proliferative activity. The rate of apoptosis in BIU-87 cells 8 h after photodynamic treatment significantly increased up to 26.11± 2.59% as analyzed with flow cytometry. In situ labeling of DNA cleavage products with the terminal deoxyuridine nicked-labeling (TUNEL) assay reinforced these observations, BPD-MA-mediated photosensitization increased the number of TUNEL-positive cells compared to the controls. However, laser irradiation alone, BPD-MA alone and sham radiation did not affect cellular proliferative activity or apoptosis of the human bladder cancer BIU-87 cells.CONCLUSION Photodynamic therapy with BPD-MA significantly decreases cellular proliferative activity and enhances apoptosis. Therapy using this method might be a promising approach to treat patients with bladder cancer.     

Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma

Even after gross tumor resection and combined radiochemotherapy, glioblastomas recur within a few months. Salvage therapy often consists of rechallenging with temozolomide in a dose-intensified schedule. Previously, low-dose metronomic temozolomide in combination with cyclo-oxigenase 2 inhibitors has had a beneficial effect as first-line treatment for glioblastoma. We report our experience with this procedure in recurrent glioblastomas after standard treatment. From June 2007 to April 2009, 28 patients with recurrent glioblastoma received continuous low-dose temozolomide of 10 mg/m² twice daily and 200 mg celecoxib. Before therapy the recurrent tumor was resected in 19 of 28 patients. Microvessel density (MVD) was determined by immunohistochemistry in 19 patients, and MGMT promoter methylation status, using the pyrosequencing method, was determined in 17 patients. In 14/28 patients, positron emission tomography with [F-18]-fluoroethyl)-l-tyrosine (FET-PET) was performed. Tumor progression was defined by the Macdonald criteria on MRI every 8–12 weeks or by clinical deterioration. The median time to progression was 4.2 months. Progression-free survival (PFS) after 6 months was 43%. Except for a lymphopenia in one patient, there was no grade 3 or 4 toxicity. PFS did not correlate with MVD or MGMT status. A high FET uptake correlated with tumor control after 6 months under therapy (P = 0.041, t-test). Low-dose continuous temozolomide in combination with celecoxib seems to have activity in recurrent glioblastoma without relevant toxicity. High FET uptake correlated with a better outcome under metronomic therapy.     

Anticoagulation for radiation-induced neurotoxicity revisited

No effective treatment for delayed radiation-induced neurotoxicity has been established. Its natural course is highly variable, but spontaneous recovery has been well documented. Here we report our experience with therapeutic anticoagulation in patients with cerebral lesions (n = 3), cranial nerve lesions (n = 1) or myelopathy (n = 4) attributed to irradiation. Two of three patients with cerebral lesions and the patient with cranial nerve lesions showed a minor improvement of clinical symptoms. In contrast, none of the patients with radiation myelopathy improved. No patient suffered hemorrhage or other adverse effects of anticoagulation. Overall, anticoagulation therapy demonstrates only modest activity for delayed radiation-induced neurotoxicity in this small case series.     

Lipid replacement/antioxidant therapy as an adjunct supplement to reduce the adverse effects of cancer therapy and restore mitochondrial function

The most common complaints of cancer patients undergoing chemoor radiotherapy are fatigue, nausea, vomiting, malaise, diarrhea and headaches. These adverse effects are thought to be due to damage of normal tissues during the course of therapy. In addition, recent evidence indicates that fatigue is related to reduced mitochondrial function through loss of efficiency in the electron transport chain caused by membrane oxidation, and this occurs during aging, in fatiguing illnesses and in cancer patients during cytotoxic therapy. Lipid Replacement Therapy administered as a nutritional supplement with antioxidants can prevent oxidative membrane damage to normal tissues, restore mitochondrial and other cellular membrane functions and reduce the adverse effects of cancer therapy. Recent clinical trials using patients with chronic fatigue have shown the benefit of Lipid Replacement Therapy plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue by protecting mitochondrial and other cellular membranes from oxidative and other damage. In cancer patients a placebo-controlled, cross-over clinical trial using Lipid Replacement Therapy plus antioxidants demonstrated that the adverse effects of chemotherapy can be reduced in 57–70% of patients. Dietary use of unoxidized membrane lipids plus antioxidants is recommended for patients undergoing cancer therapy to improve quality of life but should not be taken at the same time of day as the therapy. The author has no financial interest in the products discussed in this contribution.     

ACNU-based chemotherapy for recurrent glioma in the temozolomide era

No standard of care for patients with recurrent glioblastoma has been defined since temozolomide has become the treatment of choice for patients with newly diagnosed glioblastoma. This has renewed interest in the use of nitrosourea-based regimens for patients with progressive or recurrent disease. The most commonly used regimens are carmustine (BCNU) monotherapy or lomustine (CCNU) combined with procarbazine and vincristine (PCV). Here we report our institutional experience with nimustine (ACNU) alone (n = 14) or in combination with other agents (n = 18) in 32 patients with glioblastoma treated previously with temozolomide. There were no complete and two partial responses. The progression-free survival (PFS) rate at 6 months was 20% and the survival rate at 12 months 26%. Grade III or IV hematological toxicity was observed in 50% of all patients and led to interruption of treatment in 13% of patients. Non-hematological toxicity was moderate to severe and led to interruption of treatment in 9% of patients. Thus, in this cohort of patients pretreated with temozolomide, ACNU failed to induce a substantial stabilization of disease in recurrent glioblastoma, but caused a notable hematotoxicity. This study does not commend ACNU as a therapy of first choice for patients with recurrent glioblastomas pretreated with temozolomide.     

A pilot study of allogeneic cellular therapy for patients with advanced hematologic malignancies

Allogeneic hematopoietic stem cell transplantation provides curative therapy for some patients with advanced hematologic malignancies. Disease response after allogeneic transplant is, at least in part, mediated by donor immune cells. In this report we describe a cellular therapy using haploidentical peripheral blood stem cells administered after very low dose total body irradiation (TBI) (100 cGy). The donor cells were anticipated to be rejected, so no graft-versus-host (GVHD) prophylaxis was used. Patients with persistent disease beyond 8 weeks could be further treated with infusions of irradiated haploidentical donor cells. Of the 10 patients enrolled in the study, durable engraftment of allogeneic cells was seen in one patient. Two patients with resistant relapsed acute myelogenous leukemia (AML) had a disease response. Analysis of T cell reactivity from one patient who achieved a complete response but did not have durable engraftment of donor cells indicated that disease response was associated with the generation of host-derived anti-leukemic cytotoxic CD8+ T cells that reacted with an AML-associated proteinase 3 epitope. Results from this patient suggest that allogeneic therapy induced a host anti-tumor response associated with cytotoxic T cells reactive with a low affinity self-antigen.     

Critical care management of chimeric antigen receptor T-cell therapy recipients

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T-cell therapy represents a prime example for the successful bench-to-bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T-cell products have shown high response rates and long-term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T-cell therapy can induce severe life-threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state-of-the-art in the clinical management of severe life-threatening events in CAR T-cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.     

Contemporary issues and the potential uses of capecitabine in metastatic breast cancer

Since its first regulatory approval more than 10 years ago, oncologists have gained wide experience in using the oral fluoropyrimidine, capecitabine, as monotherapy or in combination with other agents and the body of evidence supporting these approaches continues to grow. Alongside this increasing experience has been the appearance of new challenges in patient management. We now recognise several different biological subtypes of breast cancer, such as HER2-positive disease. The standard of care in these tumours comprises anti-HER2 therapy, and phase III data show that capecitabine can be effectively combined with such agents. Another increasingly prominent and currently unresolved issue resulting from more effective treatment of metastatic disease is the management of patients with brain metastases. The introduction of new, well-tolerated, oral chemotherapies also provides the opportunity for longer duration of therapy. These new clinical scenarios are discussed in the current review.     

Characterization of bortezomib-adapted I-45 mesothelioma cells

Background  

Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy.     

SOHO State of the Art Updates and Next Questions: The Past,Present and Future of Venetoclax-Based Therapies in AML

The use of venetoclax in combination with hypomethylating agents (HMA) has changed the paradigm for the treatment of acute myeloid leukemia (AML) in elderly patients and those unfit for intensive chemotherapy. A phase 3 study has shown superior response rates and improved overall survival for patients treated with venetoclax + azacitidine compared with the previous standard of care, azacitidine alone. This success has led to multiple exciting follow-up studies, including investigations related to the discovery of predictors of response, relapse, and the mechanism of action of this therapy. While venetoclax + HMA has shown significant benefit in elderly patients unfit for chemotherapy, further questions remain as to how this therapy can be expanded into other populations including relapsed or refractory patients and younger newly diagnosed patients with adverse risk features. In this article, we discuss the clinical outcomes of AML with venetoclax + HMA, established and potential predictors of response to this regimen, its mechanisms of action, and speculate on the future of venetoclax + HMA therapy in AML.     

Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL–Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia

BackgroundAcute myeloid leukemia (AML) accounts for approximately 20% of pediatric leukemia cases; 30% of these patients experience relapse. The antileukemia properties of natural killer (NK) cells and their safety profile have been reported in AML therapy. We proposed a phase 2, open, prospective, multicenter, nonrandomized clinical trial for the adoptive infusion of haploidentical K562-mb15-41BBL–activated and expanded NK (NKAE) cells as a consolidation strategy for children with favorable and intermediate risk AML in first complete remission after chemotherapy (NCT02763475).Patients and MethodsBefore the NKAE cell infusion, patients underwent a lymphodepleting regimen. After the NKAE cell infusion, patients were administered low doses (1 × 10⁶/IU/m²) of subcutaneous interleukin-2. The primary study endpoint was AML relapse-free survival. We needed to include 35 patients to demonstrate a 50% reduction in relapses.ResultsSeven patients (median age, 7.4 years; range, 0.78-15.98 years) were administered 13 infusions of NKAE cells, with a median of 36.44 × 10⁶ cells/kg (range, 6.92 × 10⁶ to 193.2 × 10⁶ cells/kg). We observed chimerism in 4 patients (median chimerism, 0.065%; range, 0.05-0.27%). After a median follow-up of 33 months, the disease of 6 patients (85.7%) remained in complete remission. The 3-year overall survival was 83.3% (95% confidence interval, 68.1-98.5), and the cumulative 3-year relapse rate was 28.6% (95% confidence interval, 11.5-45.7). The study was terminated early because of low patient recruitment.ConclusionThis study emphasizes the difficulties in recruiting patients for cell therapy trials, though NKAE cell infusion is safe and feasible. However, we cannot draw any conclusions regarding efficacy because of the small number of included patients and insufficient biological markers.     

Strategy of radiation therapy for bone metastases and MSCC in breast cancer patients

Bone metastasis is a common event in advanced cancers such as prostate, breast, lung, and renal cancers. Radiation therapy has been widely used for bone metastasis. However, it remains a challenging therapy because no radiation therapeutic guidelines, including radiation dose, radiation field, and fractionation, for patients with bone metastasis have been established. Many randomized controlled trials for bone metastasis have been carried out. They showed no significant difference in pain relief with a short course of radiation therapy such as 8 Gy/1 Fr and 20 Gy/5 Fr or with a long course of radiation therapy such as 30 Gy/10 Fr, 37.5 Gy/15 Fr, and 40 Gy/20 Fr. Toxicity rates with short and long courses were also the same. Recurrence rate at 2 years, however, was significantly higher in patients irradiated with a short course than in patients irradiated with a long course. Those trials also showed that response rate is affected by patient’s age, performance state, tumor type, pathological state, number of metastatic tumors, and span from diagnosis of cancer to development of metastatic tumor. Breast cancer has a better prognosis than most other cancers. Recently, there have been significant advances in cancer therapy techniques and improvement in clinical results. Bone metastasis can cause extreme pain and motor deficits. Quality of life for patients with bone metastasis is drastically worsened. Patients with bad prognosis should be treated with radiation therapy when analgesia is the main aim of treatment. Survival of patients with oligometastasis or predominantly bone metastasis is expected to be better than that of patients with visceral metastasis. For patients with vertebral or weight-bearing long bone metastasis, long-course therapy is recommended. Many patients who are expected to have a good prognosis should be treated with a long course of radiation.     

SOHO State of the Art Updates and Next Questions: Novel Transplant and Post-Transplant Options in Acute Lymphoblastic Leukemia

Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment approach for patients with high-risk acute lymphoblastic leukemia (ALL). Despite development of several novel therapies targeting B-cell ALL, alloHCT continues to play an essential role in management, but the identification of patients who are most likely to benefit from alloHCT in first or subsequent remissions continues to evolve. Broader donor options, including haploidentical donors and umbilical cord blood, have enabled alloHCT for more patients, but improvements in front-line therapy and increasing use of high-sensitivity measurable residual disease (MRD) quantification continue to modify the calculus for selecting which patients require transplantation. MRD quantification has become increasingly important as a prognostic indicator, as well as a trigger for therapeutic intervention, since the achievement of MRD negative complete remission is well-established to be associated with improved transplant outcomes. ALL remains the only malignancy with approved therapy for MRD positivity after achievement of remission, and use of Blinatumomab in this setting currently appears to be most effective when used as a bridge-to-transplant, rather than a destination or purely consolidative therapy. Expanding options for those with relapsed/refractory disease, including chimeric antigen receptor (CAR)-T cells, also render more patient in suitably deep remissions to enable alloHCT with a high likelihood of success. It remains unclear whether CAR-T cell therapies may obviate the need for alloHCT in some patients, and currently available data suggest there remains a role for alloHCT after CAR-T. Together, these therapeutic advances appear to be improving post-transplant outcomes. Nevertheless, more remains to be studied regarding how to optimize use of available and emerging cellular and immune modulating therapies to maximize the likelihood of long-term post-alloHCT remission in high-risk ALL.     

Role of cellular,molecular and tumor microenvironment in hepatocellular carcinoma: Possible targets and future directions in the regorafenib era

Hepatocellular carcinoma (HCC) remains as one of the major causes of cancer-related mortality, despite the recent development of new therapeutic options. Regorafenib, an oral multikinase inhibitor, is the first systemic therapy that has a survival benefit for patients with advanced HCC that have a poor response to sorafenib. Even though regorafenib has been approved by the FDA, the clinical trial for regorafenib treatment does not show significant improvement in overall survival. The impaired efficacy of regorafenib caused by various resistance mechanisms, including epithelial–mesenchymal transitions, inflammation, angiogenesis, hypoxia, oxidative stress, fibrosis and autophagy, still needs to be resolved. In this review, we provide insight on regorafenib microenvironmental, molecular and cellular mechanisms and interactions in HCC treatment. The aim of this review is to help physicians select patients that would obtain the maximal benefits from regorafenib in HCC therapy.