Systemic Effects of Radiation Therapy-Induced Abscopal Responses in Patients with Advanced Lung Cancer.

BACKGROUND: Out-of-field tumor regression effects of radiation therapy (abscopal response) have been sporadically observed in the past, but they have only recently gained significant importance due to the use of innovative high-precision radiation delivery devices for the treatment of various cancers including non-small cell lung cancer (NSCLC). In this study, we provide a detailed overview of the current state of knowledge and clinical experience of radiation therapy-induced abscopal effects in patients with advanced NSCLC. SUMMARY: Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as MEDLINE via PubMed and Google Scholar. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized. Most studies describing the abscopal effects of radiation therapy in patients with advanced NSCLC have been in the form of either case reports or small cohort studies. Although the exact molecular mechanisms for the abscopal effect are yet to be established, current evidence indicates that tumor cell destruction induced by local radiation therapy releases tumor antigens, which stimulate the immune system of the host to activate the body's immune effector cells systemically and trigger the regression of distant nonirradiated cancer cells. These off-target antitumor effects of radiation therapy provide an opportunity to explore the use of the radiation therapy in combination with novel immunotherapy agents to maximize treatment outcomes in patients with advanced NSCLC and other cancers. Key Message: The findings suggest that radiation therapy has the ability to induce abscopal effects with an increased potential to boost these effects when it is used in combination with immunotherapy for the treatment of patients with advanced NSCLC and other cancers. Clinical trials investigating radiation therapy-induced abscopal effects may lead to a dramatic change in its use especially when it is combined with immunotherapy for the treatment of patients with advanced NSCLC.

Systemic Antitumor Effects and Abscopal Responses in Melanoma Patients Receiving Radiation Therapy.

BACKGROUND: Malignant melanoma represents the deadliest form of skin cancer with a high tendency to metastasize during the early course of the disease. Radiation therapy has long played a key role in the management of both local and metastatic melanoma. Although local radiation therapy exerts antitumor effects by damaging the cellular DNA, it also induces an important out-of-field (distant) effect known as the "abscopal effect" in nonirradiated sites. Radiation therapy-induced abscopal effects are believed to be mediated by activation and stimulation of the immune system. OBJECTIVE: To provide a detailed overview of the current state of knowledge and clinical experience of radiation therapy-induced abscopal effects in patients with malignant melanoma. METHODS: Using electronic databases such as MEDLINE via PubMed and Google Scholar, a systematic literature review was performed to find published clinical evidence for radiation therapy-induced abscopal effects in patients with malignant melanoma. The clinical data on radiation therapy-induced abscopal effects were reviewed and the outcomes summarized. RESULTS: Clinical evidence of patients with malignant melanoma was gathered using databases from MEDLINE and those findings were summarized. Although the precise mechanism of the abscopal effect of radiation therapy is still not completely understood, evidence suggests that tumor cell destruction by radiation releases tumor antigens that stimulate the immune system of the host to activate the body's immune effector cells systemically and produce distant non-target antitumor effects. This forms a basis for using the radiation therapy with immunotherapy to augment the abscopal response rates. CONCLUSIONS: Current clinical evidence suggests that there is a large potential to enhance the abscopal effect when radiation therapy is combined with immunotherapeutic agents for the treatment of malignant melanoma. Ongoing and planned clinical trials may provide us with a more in-depth understanding of how this combination therapy can be optimally utilized clinically to achieve improved survival outcomes among patients with malignant melanoma.

Management of metastatic malignant thymoma with advanced radiation and chemotherapy techniques: report of a rare case.

Malignant thymomas are rare epithelial neoplasms of the anterior superior mediastinum that are typically invasive in nature and have a higher risk of relapse that may ultimately lead to death. Here we report a case of an advanced malignant thymoma that was successfully treated with neoadjuvant chemotherapy followed by surgical resection and subsequently with advanced and novel radiation therapy techniques. A 65-year-old male was diagnosed with a stage IV malignant thymoma with multiple metastatic lesions involving the left peripheral lung and pericardium. Initial neoadjuvant chemotherapy with a cisplatin-based regimen resulted in a partial response allowing the inoperable tumor to become operable. Following surgical resection of the residual disease, the tumor recurred within a year. The patient then underwent a course of targeted three-dimensional intensity modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT). Five years after radiation therapy, the localized soft tissue thickening at the left upper lung anterior pleural space had resolved. Seven years after radiation therapy the tumor mass had completely resolved. No recurrences were seen and the patient is well even 8 years after IMRT/IGRT with a favorable outcome. Chemotherapy with targeted three-dimensional IMRT/IGRT should be considered the primary modality for the management of advanced malignant thymoma patients.

Hematological and hepatic alterations in nonsmoking residents exposed to benzene following a flaring incident at the British petroleum plant in Texas City.

OBJECTIVE: Human exposure to benzene is associated with multiple adverse health effects with an increased risk of developing carcinogenesis. Benzene exposure is known to affect many critical organs including the hematological, hepatic, renal, lung, and cardiac functions. The purpose of this study is to examine the health effects of benzene exposure among nonsmoking subjects from a prolonged flaring incident that occurred at the British petroleum (BP) refinery in the Texas City, Texas. METHODS: The study included nonsmoking subjects who had been exposed and unexposed to benzene. Using medical charts, clinical data including white blood cell (WBC) counts, platelet counts, hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), and alanine amino transferase (ALT) in nonsmoking subjects exposed to benzene were reviewed and analyzed and compared with unexposed adults. RESULTS: A total of 1422 nonsmoking subjects (benzene exposed, n=1093 and unexposed, n=329) were included. Benzene exposed subjects had significantly higher levels of WBC (×10(3) per µL) counts (7.7±2.2 versus 6.8±1.7, P=0.001) and platelet (×10(3) per µL) counts (288.8±59.0 versus 245.3±54.4, P=0.001) compared with the unexposed subjects. The mean serum creatinine (mg/dL) levels were also significantly increased in the benzene exposed group compared with the unexposed group (1.1±0.4 versus 0.8±0.2, P=0.001). Serum levels of ALP (IU/L) was significantly elevated in the benzene exposed subjects compared with the unexposed subjects (87.3±22.6 versus 69.6±16.5, P=0.001). Similarly, benzene exposed subjects had significantly higher levels of AST and ALT compared with those unexposed subjects. CONCLUSION: Benzene exposure from the prolonged BP flaring incident caused significant alterations in hematological and liver markers indicating that these nonsmoking residents exposed to refinery chemicals may be at a higher risk of developing hepatic or blood related disorders.

Health effects of benzene exposure among children following a flaring incident at the British Petroleum Refinery in Texas City.

Human exposure to benzene is associated with multiple adverse health effects leading to hematological malignancies. The objective of this retrospective study was to evaluate the health consequences of benzene exposure in children following a flaring incident at the British petroleum (BP) refinery in Texas City, Texas. The study included children aged <17 years who had been exposed and unexposed to benzene. Using medical charts, clinical data including white blood cell (WBC) counts, platelets counts, hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine amino transferase (ALT), and somatic symptom complaints by the children exposed to benzene were reviewed and analyzed. A total of 312 subjects (benzene exposed, n = 157 and unexposed, n = 155) were included. Hematologic analysis showed that WBC counts were significantly decreased in benzene-exposed children compared with the unexposed children (6.8 ± 2.1 versus 7.3 ± 1.7, P = .022). Conversely, platelet (X 10(3) per µL) counts were increased significantly in the benzene-exposed group compared with the unexposed group (278.4 ± 59.9 versus 261.6 ± 51.7, P = .005). Similarly, benzene-exposed children had significantly higher levels of ALP (183.7± 95.6 versus 165 ± 70.3 IU/L, P = .04), AST (23.6 ± 15.3 versus 20.5 ± 5.5 IU/L, P = .015), and ALT (19.2 ± 7.8 versus 16.9 ± 6.9 IU/L, P = .005) compared with the unexposed children. Together, the results of the study reveal that children exposed to benzene experienced significantly altered blood profiles, liver enzymes, and somatic symptoms indicating that children exposed to benzene are at a higher risk of developing hepatic or blood related disorders.

Immune System Activation in Patients with Metastatic Renal Cell Carcinoma Induced by the Systemic Abscopal Effects of Radiation Therapy.

INTRODUCTION: Renal cell carcinoma (RCC) is characterized by large histopathologic heterogeneity and classified with multiple histological subtypes. Radiation therapy has long played a key role in the management of both local and metastatic RCC. An out-of-field tumor regression (abscopal response) effect of radiation therapy has gained significant importance in the treatment of different tumor types including RCC. In this study, we provide a detailed overview of the current state of knowledge and clinical experience of radiation therapy-induced abscopal effects in patients with advanced RCC. METHODS: The PRISMA guidelines were followed to identify the published articles for the study. Using electronic databases such as MEDLINE via PubMed and Google Scholar, a systematic literature review was performed to find published clinical evidence for radiation therapy-induced abscopal effects in patients with advanced RCC. The clinical data of radiation therapy-induced abscopal effects were reviewed, and the outcomes have been summarized. RESULTS: In this study, we evaluated peer-reviewed published reports to find clinical evidence for the abscopal effect following radiation therapy in patients with advanced RCC. The clinical data on the systemic abscopal effects of radiation therapy were reviewed, and the outcomes were summarized. Our literature search indicated that the evidence for abscopal effects of radiation therapy in advanced RCC yielded over 20 case reports. The evidence indicates that abscopal effects of local radiation therapy may occur in RCC through tumor cell destruction with the subsequent release of tumor antigens that systemically stimulate the immune system of the host to activate the body's immune effector cells and produce distant nontarget antitumor effects. The activation of the immune system by local radiation therapy forms the basis to combine immunotherapy to boost its abscopal effects. CONCLUSIONS: Collectively, these findings suggest that radiation therapy can induce systemic abscopal effects through immune system activation, and thus, the addition of immunotherapeutic agents increases the potential to boost the systemic abscopal responses in patients with advanced cancers including RCC.

Ventriculoperitoneal shunt complications in hydrocephalus patients with intracranial tumors: an analysis of relevant risk factors.

Patients with intracranial tumors are predisposed to persistent hydrocephalus, often requiring a permanent CSF diversion procedure with shunts. This study reviews the long-term experience with ventriculoperitoneal shunts for the management of hydrocephalus in patients with intracranial tumors. Patients with intracranial tumors who underwent ventriculoperitoneal shunt placement for hydrocephalus from October 1990 to October 2009 were included in this study. During the 19-year period, medical charts, operative reports, imaging studies, and clinical follow- up evaluations were reviewed and analyzed retrospectively for all patients. A total of 187 intracranial tumor patients with hydrocephalus were included. The median follow up was 391 days. Malignant tumors were present in 40% of the patients. Overall shunt failure was 27.8%. Single shunt revision occurred in 13% of the patients and 14% had multiple shunt revision. Tumor histology, age and a procedure prior to shunt placement (ventriculostomy/Ommaya reservoirs) were significantly associated with the shunt revisions. Shunt system replacement and proximal shunt complication were significantly attributed to multiple shunt revisions. The overall shunt revision within 3 months, 6 months, 1 year and 5 years was 17.7%, 18.7%, 19.8% and 24.1%, respectively. The results of the study demonstrate that VP shunting is an effective for the management of hydrocephalus in patients with intracranial tumors. The overall incidence of shunt revision was 27.8%. Age, tumor histology, and a procedure prior to shunt placement (ventriculostomy/Ommaya reservoirs) were significantly associated with the shunt revisions. Additional studies using minimally invasive techniques are being explored for the management of hydrocephalus in patients with intracranial tumors.

Systemic Immunostimulatory Effects of Radiation Therapy Improves the Outcomes of Patients With Advanced NSCLC Receiving Immunotherapy.

The understanding of localized radiation therapy's immunostimulatory properties combined with its well-known effects on the cell cycle and insights into the immunomodulation mechanisms that occur at the molecular and cellular levels has changed our traditional view of the anticancer effects of ionizing radiation. The potential interactions between the tumor's immune system and radiation therapy have revealed that local radiation has the ability to induce systemic antitumor responses in patients with advanced cancers. The recognition of systemic antitumor effects of radiation therapy has allowed investigators to begin uncovering the integral players in these pathways. Parallel to this, there has been progress in understanding how tumor immunology leads to the development of novel immunotherapies using immune checkpoint blockade therapies in the treatment of advanced cancers. To date there has been limited success in this benefiting only a small fraction of patients. The concept of priming the body's immune system by radiation to make less responsive tumors more responsive to immunotherapy provides an opportunity to explore the use of the combination of radiation therapy and immunotherapy for the treatment of advanced non-small cell lung cancer and other cancers. This article provides an overview of the current state of knowledge of the clinical experience using radiation therapy in combination with immune therapy and discusses the rationale for integrating these 2 modalities in the treatment of advanced non-small cell lung cancer. Available data supports the use of radiation therapy in combination with immunotherapy to achieve improved local and systemic tumor control. Evidence from the early clinical trials has shown that using radiation therapy and immune checkpoint blockade therapies together produces a greater clinical effect than using either modality alone. To maximize the clinical benefit and successful integration of these two modalities as well as optimizing radiation therapy dosing and its schedule, improvement in its field design and the development of reliable predictors of clinical tumor response needs to be established.

Brain Radiation Induced Extracranial Abscopal Effects in Metastatic Melanoma.

Historically, the brain has been viewed as a specialized neurovascular inert organ with a distinctive immune privilege. Therefore, radiation-induced extracranial abscopal effects would be considered an unusual phenomenon due to the difficulty of the immunogenic signaling molecules to travel across the blood-brain barrier (BBB). However, it is now possible that localized central nervous system radiation has the ability to disrupt the structural integrity of the BBB and increase its endothelial permeability allowing the free passage of immunogenic responses between the intracranial and extracranial compartments. Thus, the nascent tumor-associated antigens produced by localized brain radiation can travel across the BBB into the rest of the body to modulate the immune system and induce extracranial abscopal effects. In clinical practice, localized brain radiation therapy-induced extracranial abscopal effects are a rarely seen phenomenon in metastatic melanoma and other advanced cancers. In this article, we provide a detailed overview of the current state of knowledge and clinical experience of central nervous system radiation-induced extracranial abscopal effects in patients with malignant melanoma. Emerging data from a small number of case reports and cohort studies of various malignancies has significantly altered our earlier understanding of this process by revealing that the brain is neither isolated nor passive in its interactions with the body's immune system. In addition, these studies provide clinical evidence that the brain is capable of interacting actively with the extracranial peripheral immune system. Thus, localized radiation treatment to 1 or more locations of brain metastases can induce extracranial abscopal responses. Collectively, these findings clearly demonstrate that localized brain radiation therapy-induced abscopal effects traverses the BBB and trigger tumor regression in the nonirradiated extracranial locations.

Extracranial Abscopal Effects Induced by Brain Radiation in Advanced Lung Cancer.

An extracranial abscopal effect induced by central nervous system (CNS)-radiation therapy is considered an unusual event because of the belief that brain has a distinctive immune microenvironment. Regular immune responses from radiation therapy or other interventions were thought to be very limited in the CNS. In addition, CNS autoimmunity and neurodegeneration were presumed automatic consequences of immune cell encounters with CNS antigens. Moreover, the traditional assumption is that nascent tumor-associated antigens produced by radiation therapy could not pass through the blood-brain barrier back into the rest of the body to modulate the immune system and induce extracranial abscopal responses. Emerging data from a small number of case series and individual case reports of various malignancies have radically altered our earlier understanding by revealing that the CNS is neither isolated nor passive in its interactions with the body's immune system. Furthermore, current data indicate that the CNS is both immune-competent and interacts actively with the peripheral immune system. Therefore, radiation treatment to ≥1 location of CNS metastases can induce abscopal responses in tumors away from the treated CNS metastatic sites. These observations suggest the abscopal effect traverses the blood-brain barrier. In this article, we reviewed and assessed the clinical evidence of extracranial abscopal responses of CNS-radiation therapy in patients with advanced lung cancer.

Health Risks Associated With Benzene Exposure in Children: A Systematic Review.

Currently, there is a paucity of studies evaluating the adverse health effects of benzene exposure in children or clinical findings of those children who have been exposed. However, emerging studies show that benzene exposure can cause deleterious health effects in children. The objective of this study was to evaluate and summarize published studies on the adverse health effects of benzene exposure in children. More than 77 articles were examined and only the articles that dealt with adverse health effects on pediatric populations were included in the study. The evaluation of those studies provided current understanding of the health effects of benzene exposure in children. Findings from the currently available studies reveal that benzene exposure is associated with abnormalities in hematologic, hepatic, respiratory, and pulmonary functions in children. Published studies clearly support the need for further assessment of the potential adverse effects of benzene exposure in children, and clinical and laboratory findings of these children.

The Development of Long-Term Adverse Health Effects in Oil Spill Cleanup Workers of the Deepwater Horizon Offshore Drilling Rig Disaster.

BACKGROUND: The purpose of this study was to assess the long-term adverse health effects of the 2010 Deepwater Horizon Gulf oil spill exposure in workers who participated in its cleanup work. METHODS: Medical charts of both the oil spill exposed and unexposed subjects were reviewed. The changes in the white blood cells, platelets, hemoglobin, hematocrit, blood urea nitrogen, creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine amino transferase (ALT) levels, as well as their pulmonary and cardiac functions were evaluated. RESULTS: Medical records from 88 subjects (oil spill cleanup workers, n = 44 and unexposed, n = 44) were reviewed during initial and 7 years follow up visits after the disaster occurred. Compared with the unexposed subjects, oil spill exposed subjects had significantly reduced platelet counts (×103/µL) at their initial (254.1 ± 46.7 versus 289.7 ± 63.7, P = 0.000) and follow-up (242.9 ± 55.6 versus 278.4 ± 67.6, P = 0.000) visits compared with the unexposed subjects (254.6 ± 51.9 versus 289.7 ± 63.7, P = 0.008). The hemoglobin and hematocrit levels were increased significantly both at their initial and follow-up visits in the oil spill exposed subjects compared to the unexposed subjects. Similarly, the oil spill exposed subjects had significantly increased ALP, AST, and ALT levels at their initial and follow-up visits compared with those of the unexposed subjects. Illness symptoms that were reported during their initial visit still persisted at their 7-year follow-up visit. Notably, at their 7-year follow-up visit, most of the oil spill exposed subjects had also developed chronic rhinosinusitis and reactive airway dysfunction syndrome as new symptoms that were not reported during their initial visit. Additionally, more abnormalities in pulmonary and cardiac functions were also seen in the oil spill exposed subjects. CONCLUSION: This long-term follow-up study demonstrates that those people involved in the oil spill cleanup operations experiences persistent alterations or worsening of their hematological, hepatic, pulmonary, and cardiac functions. In addition, these subjects experienced prolonged or worsening illness symptoms even 7 years after their exposure to the oil spill.

Adverse Health Complaints of Adults Exposed to Benzene After a Flaring Disaster at the BP Refinery Facility in Texas City, Texas.

OBJECTIVE: The objective of this study was to assess the adverse health symptoms experienced by adult subjects who were exposed to benzene after a flaring disaster at the BP refinery in Texas City, Texas. METHODS: A total of 2162 adults aged 18 years or older and exposed to benzene were included. Using the patients' medical charts, we collected and analyzed data on health complaints as well as the patients' serum levels of beta-2-microglobulin and urinary excretion of phenol. RESULTS: A total of 11,368 health symptom complaints were reported in 2162 adults exposed to benzene. Neurological symptoms occurred most frequently (174%), followed upper respiratory symptoms (115%), cough (31%), painful joints (30%), cardiac symptoms (28%), dermatological symptoms (28%), gastrointestinal symptoms (27%), diarrhea (25%), vision symptoms (21%), and nausea/vomiting (19%). Logistic regression analysis indicated that urinary symptoms (R2=0.65) and painful joints (R2=0.44) were positively associated with increasing age in benzene-exposed subjects. CONCLUSION: Adult subjects exposed to benzene experience a range of adverse health symptoms and an altered profile of urinary phenol, thus indicating they are at high risk of developing serious future health complications. (Disaster Med Public Health Preparedness. 2018;12:232-240).

Benzene exposure from the BP refinery flaring incident alters hematological and hepatic functions among smoking subjects.

OBJECTIVES: To evaluate the health effects of benzene exposure among smoking subjects from a prolonged flaring incident that occurred at the British Petroleum (BP) refinery in Texas City, USA. MATERIAL AND METHODS: The study included smoking subjects who had been exposed and unexposed to the benzene release. Using medical charts, clinical data including white blood cell (WBC) counts, platelet counts, hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in the case of smoking subjects exposed to benzene was reviewed and analyzed. RESULTS: A total of 791 tobacco smoking subjects (benzene-exposed: N = 733, unexposed: N = 58) were included. Benzene-exposed subjects had significantly higher levels of WBC (×103/µl) counts (8±2.1 vs. 7.5±1.6, p = 0.003) and platelet (×103/µl) counts (263.7±69.7 vs. 222.9±44.3, p = 0.000) as compared with the unexposed subjects. The mean hemoglobin, hematocrit, BUN, and creatinine levels did not differ significantly between the benzene-exposed and -unexposed smoking subjects. Serum levels of ALP (IU/l) was significantly elevated in the benzene-exposed subjects compared with the unexposed subjects (84.5±16.9 vs. 73.8±15.9, p = 0.002). Similarly, benzene-exposed subjects had significantly higher levels of AST and ALT as compared with those unexposed subjects. CONCLUSIONS: Despite a smoking history, residents exposed to benzene from the prolonged BP flaring incident experienced significant alterations in hematological and hepatic functions indicating their vulnerability to the risk of developing hepatic or blood related disorders. Int J Occup Med Environ Health 2017;30(6):849-860.

Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma.

Metastatic renal cell carcinoma does not respond favorably to conventional treatment strategies and is not very responsive to cytokine therapy. Therefore, novel targeted treatment approaches have been explored for patients with renal cancer who have chemotherapy-refractory disease. Sorafenib (BAY 43-9006) is a small-molecule inhibitor that has been shown to target members of multiple classes of tyrosine kinases that are known to be involved in tumor cell proliferation and tumor angiogenesis. These kinases include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and Raf kinases. Based on the significant improvement in progression-free survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma. In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma. As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma.

Clinical utility of microarray-derived genetic signatures in predicting outcomes in prostate cancer.

Prostate cancer is a complex heterogeneous disease, and risk stratification remains a significant clinical challenge. Gene microarray has been developed to provide better prediction of clinical outcomes and potentially improve management of patients with various malignancies, including prostate cancer. Currently, several studies are evaluating the clinical significance of gene expression signatures in prostate cancer. These approaches might provide outcome predictions, such as treatment response, progression-free survival, overall survival, and metastatic status and offer new strategies to identify patients at high risk for personalized cancer therapies. This article discusses the latest developments in gene expression-based signatures that predict clinical behavior of prostate cancer. Gene profiling could lead to enhanced early detection and prognosis of prostate cancer, resulting in improved overall survival. The ability to predict clinical outcomes by the microarray-derived genetic signatures is promising; however, further studies are warranted to optimize its clinical utility in patients with prostate cancer.

Current data with mammalian target of rapamycin inhibitors in advanced-stage renal cell carcinoma.

Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. Alterations in the mTOR signaling pathway can lead to neoplastic transformation and progression. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. Thus, mTOR is a promising target for the treatment of human malignancies. Rapamycin and its analogues, including temsirolimus, everolimus, and AP23573, block the mTOR signaling pathway and induce a cellular state akin to starvation, with significant antitumor activity in a variety of malignancies, including renal cell carcinoma (RCC). Current data from ongoing clinical trials suggest that mTOR-targeted therapy with rapamycin derivatives is well tolerated with significant clinical activity in patients with advanced-stage RCC. Specifically, temsirolimus as monotherapy has demonstrated improved progression-free and overall survival in patients with poor-risk advanced-stage RCC. Everolimus has also demonstrated promising antitumor activity in patients with metastatic RCC. However, optimal dose, treatment schedule, selection of patients, and appropriate combination strategies with other novel agents need to be defined for mTOR-targeted therapies in the treatment of advanced-stage RCC.

Illness Symptoms Experienced by Children Exposed to Benzene After a Flaring Incident at the BP Refinery Facility in Texas City.

Objective To evaluate the illness symptoms experienced by children who were exposed to benzene following a flaring incident at the BP refinery in Texas City, Texas. Methods A total of 641 children, aged <17 years, exposed to benzene were included. Using medical charts, data on the children's illness symptoms as well as the serum levels of ß-2-microglobulin and the amount of urinary excretion of phenol were reviewed and analyzed. Results A total of 1790 illness symptoms were reported in 641 children exposed to benzene. Upper respiratory symptoms were the most (67%) frequently reported, followed by neurological symptoms (57%), diarrhea (25%), and cough (24%). Logistic regression analysis indicated that neurological symptoms (R(2) = 0.75), chest pain (R(2) = 0.64), joint pain (R(2) = 0.57), and vision difficulty (R(2) = 0.54) were positively associated with increasing age. ß-2-Microglobulin levels were significantly higher in children <5 years compared with those >5 year (P = .04). Conversely, urinary phenol levels were significantly lower in children <5 years compared with those >5 years (P = .00). Conclusion Together, these findings reveal that children exposed to benzene experience a range of illness symptoms and an altered profile of urinary phenol indicating their vulnerability to potentially increased health complications.

Adverse Health Effects of Benzene Exposure Among Children Following a Flaring Incident at the British Petroleum Refinery in Texas City.

This study examined the health effects of benzene exposure among children from a flaring incident at the British Petroleum (BP) refinery in Texas City, Texas. A total of 899 children (benzene exposed, n = 641 and unexposed, n = 258), aged <17 years, were included. Hematological analysis showed that white blood cell (×10(3)/µL) counts were significantly decreased in the exposed children compared with the unexposed children (7.1 ± 2.2 versus 7.6 ± 2.1, P = .001). Similarly, the hemoglobin (g/dL) levels were decreased significantly in the exposed group compared with the unexposed group (12.7 ± 1.3 vs 13.1 ± 1.5, P = .001). Conversely, platelet (×10(3)/µL) counts were increased significantly in the exposed group compared with the unexposed group (318.6 ± 79.8 versus 266.9 ± 58.8, P = .001). Hepatic enzymes were also significantly elevated among exposed children compared with the unexposed children. These findings suggest that children exposed to benzene are at a higher risk of developing both hepatic and bone marrow-related disorders.