Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia in Adults

Abstract

Patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis with less than 10 % of patients surviving 5 years. Most such patients cannot be rescued with currently available therapies, whatever the initial treatment they receive. Therefore, there is an urgent need for novel treatment options. Fortunately, over the past several years, an improved understanding of the biology of the disease has allowed the identification of rational molecular targets for therapeutic endeavors and the emergence of novel therapies has sparked great interest. This review will discuss the current treatment landscape for adult patients with relapsed and/or refractory ALL.

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Accelerated hyperfractionation plus temozolomide in glioblastoma

Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed as a potential treatment for glioblastoma based on a hypothesized reduction of late radiation injury and preve...

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Downregulation of STAT3/NF-κB potentiates gemcitabine activity in pancreatic cancer cells

Abstract

There is an unmet need to develop new agents or strategies against therapy resistant pancreatic cancer (PanCA). Recent studies from our laboratory showed that STAT3 negatively regulates NF-κB and that inhibition of this crosstalk using Nexrutine® (Nx) reduces transcriptional activity of COX-2. Inhibition of these molecular interactions impedes pancreatic cancer cell growth as well as reduces fibrosis in a preclinical animal model. Nx is an extract derived from the bark of Phellodendron amurense and has been utilized in traditional Chinese medicine as antidiarrheal, astringent, and anti-inflammatory agent for centuries. We hypothesized that "Nx-mediated inhibition of survival molecules like STAT3 and NF-κB in pancreatic cancer cells will improve the efficacy of the conventional chemotherapeutic agent, gemcitabine (GEM)". Therefore, we explored the utility of Nx, one of its active constituents berberine and its derivatives, to enhance the effects of GEM. Using multiple human pancreatic cancer cells we found that combination treatment with Nx and GEM resulted in significant alterations of proteins in the STAT3/NF-κB signaling axis culminating in growth inhibition in a synergistic manner. Furthermore, GEM resistant cells were more sensitive to Nx treatment than their parental GEM-sensitive cells. Interestingly, although berberine, the Nx active component used, and its derivatives were biologically active in GEM sensitive cells they did not potentiate GEM activity when used in combination. Taken together, these results suggest that the natural extract, Nx, but not its active component, berberine, has the potential to improve GEM sensitivity, perhaps by down regulating STAT3/NF-κB signaling. This article is protected by copyright. All rights reserved

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Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations

Abstract

Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant. A key problem is that there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof. Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists. This high cognitive demand has led to an epidemic of shortcut definitions and interpretations that are simply wrong, sometimes disastrously so—and yet these misinterpretations dominate much of the scientific literature. In light of this problem, we provide definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions. Our goal is to provide a resource for instructors, researchers, and consumers of statistics whose knowledge of statistical theory and technique may be limited but who wish to avoid and spot misinterpretations. We emphasize how violation of often unstated analysis protocols (such as selecting analyses for presentation based on the P values they produce) can lead to small P values even if the declared test hypothesis is correct, and can lead to large P values even if that hypothesis is incorrect. We then provide an explanatory list of 25 misinterpretations of P values, confidence intervals, and power. We conclude with guidelines for improving statistical interpretation and reporting.

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Bone metastases in patients with small cell lung carcinoma: rate of development, early versus late onset, modality of treatment, and their impact on survival. A single-institution retrospective cohort study

Abstract

The aim of the present study was to further explore the impact of bone metastases (BMs) and their therapeutic management on the overall prognosis of patients with small cell lung carcinoma (SCLC). We performed a retrospective analysis of medical records of 363 patients with histologically or cytologically confirmed SCLC, diagnosed and treated in the Oncology Unit of Sotiria Athens General Hospital, between January 2003 and December 2012. Demographic and clinicopathological features, including BMs, their time point of development (early onset/at diagnosis versus late onset/at a subsequent time point), treatment modality for BMs (radiotherapy, bisphosphonates or both) and the presence of skeletal-related events (SREs), were correlated with overall survival (OS). Survival analysis was performed using the Kaplan–Meier method, log-rank tests and Cox regression analysis. Overall, 130/363 patients (35.8 %) were diagnosed with either early-onset (97/363 cases, 26.7 %) or late-onset BMs (33/363 cases, 9.1 %). Patients with early-onset BMs had a reduced OS as compared to those with late-onset BMs [Hazard ratio (HR) 0.61; 95 % Confidence interval (CI) 0.41–0.91; p = 0.015) or those without BMs (HR 0.76; 95 % CI 0.6–0.96; p = 0.024). SREs and treatment modality of BMs had no impact on OS. Multiple Cox regression analysis showed that increased age, poor performance status (PS), presence of BMs and early onset BMs were independently associated with reduced OS. The results of our single-institution study suggest that the development of early-onset BMs may represent an independent predictor of a worse prognosis among patients with SCLC, in addition to well-established adverse prognostic factors such as poor PS.

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Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells

Abstract

Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Here we evaluate the effects of the aromatase inhibitor letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER−) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX + Letrozole, Intact, and Intact + Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 µg/g body weight. Tumor progression was monitored by bioluminescence imaging (BLI). Following necropsy, inoculated tibiae were scanned via µCT and bone response to tumor was scored from 0 (no ectopic mineralization/osteolysis) to 5 (extensive ectopic mineralization/osteolysis). OVX mice had higher tibial pathology scores indicative of more extensive bone destruction than intact mice, irrespective of letrozole treatment. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Furthermore, mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&E and Ki-67 staining, respectively. In conclusion, BC-inoculated OVX animals had higher tibia pathology scores than BC-inoculated intact animals and letrozole reduced BC metastases to lungs. These findings suggest that, by lowering systemic estrogen level and/or by interacting with the host organ, the aromatase inhibitor letrozole has the potential to reduce ER− BC metastasis to lung.

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Experimental study on blood gases and acid-base parameter changes following oral administration of injectable enrofloxacin 5 % to the horses

Abstract

The objective of this investigation was to evaluate the effects of oral administration of bovine injectable enrofloxacin 5 % on blood gases, acid–base parameters, risk of gastrointestinal ulcers, bleeding, diarrhea, abdominal pain, and clinical joint disturbances in horses. For this purpose, there were nine selected mixed breed horses with ages between 11 month and 15 years old. These horses were divided into three groups of three animals. Bovine injectable enrofloxacin 5 % was administered orally, 5 mg/kg to the first group and 15 mg/kg to the second group, every 12 h, for 21 days. The third or control group did not receive drug but saline in the same way. Heparinized blood samples were collected for evaluation of blood electrolytes and blood gas parameters as well as recording the clinical findings in animals. Occult blood test was performed in all horse stool samples, in five times, before and after the administration of the drug. As a result, the analyzed data did not show significant changes in blood gases and electrolyte parameters, between drug-administered and control groups. There were no observed mucosal ulcer, injury or symptoms of diarrhea, abdominal pain, and gastrointestinal bleeding in the horses. One of the horses showed swollen in the left carpal joint with a dose of 5 mg/kg of drug, at day 12, which improved with suitable treatment until day 20. This study showed that 3 weeks of oral administration of enrofloxacin 5 % had no significant effect on blood gases and electrolyte parameters even at high doses (15 mg/kg). This study showed the lack of drug effect on producing gastrointestinal mucosal ulcers and colic pain in the drug-treated horses. It was recommended that the drug enrofloxacin should not preferably be used in foals and also in mature horses for long duration, because of the possible joint disorder, and its usage should be with caution.

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Scientific Achievements May Not Reach Everyone: Understanding Disparities in Acute Leukemia

Abstract

Over the past decade, scientific advancements have resulted in improved survival from acute leukemia. Continued advancements are expected given the attention to precision medicine and the resulting growth in development and adoption of risk-stratified, personalized therapies. While precision medicine has great potential to improve acute leukemia outcomes, there remain significant barriers to ensuring equitable access to these technologies and receipt of these prescribed targeted, personalized therapies. Over the past 3 years, studies report persistent outcome disparities among patients from specific racial and ethnic backgrounds, insurance and socioeconomic status, and other socio-demographic factors after a diagnosis of acute leukemia. A few recent studies examine etiologies for acute leukemia disparities and highlight the importance of ensuring access and equitable delivery of scientific advancements. In the context of continued scientific progress, future strategies require thoughtfully considered improvements in the delivery of care that can overcome the current challenges our patients face.

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Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations

Abstract

Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant. A key problem is that there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof. Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists. This high cognitive demand has led to an epidemic of shortcut definitions and interpretations that are simply wrong, sometimes disastrously so—and yet these misinterpretations dominate much of the scientific literature. In light of this problem, we provide definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions. Our goal is to provide a resource for instructors, researchers, and consumers of statistics whose knowledge of statistical theory and technique may be limited but who wish to avoid and spot misinterpretations. We emphasize how violation of often unstated analysis protocols (such as selecting analyses for presentation based on the P values they produce) can lead to small P values even if the declared test hypothesis is correct, and can lead to large P values even if that hypothesis is incorrect. We then provide an explanatory list of 25 misinterpretations of P values, confidence intervals, and power. We conclude with guidelines for improving statistical interpretation and reporting.

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Continuous intraoperative monitoring of pelvic autonomic nerves during TME to prevent urogenital and anorectal dysfunction in rectal cancer patients (NEUROS): a randomized controlled trial

Abstract

Background

Urinary, sexual and anorectal sequelae are frequent after rectal cancer surgery and were found to be related to intraoperative neurogenic impairment. Neuromonitoring methods have been developed to identify and preserve the complex pelvic autonomic nervous system in order to maintain patients' quality of life. So far no randomized study has been published dealing with the role of neuromonitoring in rectal cancer surgery.

Methods/design

NEUROS is a prospective two-arm randomized controlled multicenter clinical trial comparing the functional outcome in rectal cancer patients undergoing total mesorectal excision (TME) with and without pelvic intraoperative neuromonitoring (pIONM). A total of 188 patients will be included. Primary endpoint is the urinary function measured by the International Prostate Symptom Score. Secondary endpoints consist of sexual, anorectal functional outcome and safety, especially oncologic safety and quality of TME. Sexual function is assessed in females with the Female Sexual Function Index and in males with the International Index of Erectile Function. For evaluation of anorectal function the Wexner-Vaizey score is used. Functional evaluation is scheduled before radiochemotherapy (if applicable), preoperatively (baseline), before hospital discharge, 3 and 6 months after stoma closure and 12 months after surgery. For assessment of safety adverse events, the rates of positive resection margins and quality of mesorectum are documented.

Discussion

This study will provide high quality evidence on the efficacy of pIONM aiming for improvement of functional outcome in rectal cancer patients undergoing TME.

Trial registration

Clinicaltrials.gov: NCT01585727. Registration date is 04/25/2012

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An uncommon manifestation of paraneoplastic cerebellar degeneration in a patient with high grade urothelial, carcinoma with squamous differentiation: A case report and literature review

Abstract

Background

Paraneoplastic neurological syndromes (PNS) are rare disorders associated with malignant tumours, which are triggered by autoimmune reactions. Paraneoplastic cerebellar degeneration (PCD) is the PNS type most commonly associated with ovarian and breast cancer. Two bladder cancers manifesting in PCD were previously reported. However, the cancers in these cases had poor outcomes.

Case presentation

Here, we present a 68-year old man with history of high-grade papillary urothelial carcinoma of the bladder. The patient suffered from persistent cerebellar ataxia accompanied by bladder cancer recurrence five months after transurethral resection of the bladder tumour (TURBt). Laboratory screening for the specific antibodies of paraneoplastic neurological syndromes revealed no positive results. Symptoms were not remitted after a 7-day-course of high-dose glucocorticoid therapy. To our surprise, the patient recovered fully after laparoscopic radical cystectomy. Postoperative pathology revealed that surgical specimens were urothelial carcinoma in situ (CIS) and squamous cell carcinoma of the bladder. The patient remained asymptomatic and there was no evidence of recurrence after the followup period of 11 months.

Conclusion

To our knowledge, this is the third report of PCD in a patient with bladder cancer. This case showed that tumour resection cured the PCD. To assist clinical evaluation and management, literature regarding basic PNS characteristics and bladder cancers was reviewed.

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Looking for answers: the current status of neoadjuvant treatment in localized soft tissue sarcomas

Abstract

Purpose

Sarcomas are a rare and heterogeneous variant of cancer. The standard of care treatment involves surgical resection with radiation in high-risk patients. Despite appropriate treatment approximately 50 % of patients will suffer and die from recurrent disease. The purpose of this article is to review the current evidence concerning the use of neoadjuvant chemotherapy with or without radiation in soft tissue sarcomas.

Methods

An in-depth literature search was conducted using Ovid Medline and PubMed.

Results

The most active chemotherapeutic agents in sarcoma are anthracyclines and ifosfamide. Adjuvant chemotherapy trials show only minimal benefit. Neoadjuvant chemotherapy offers the potential advantage of reducing the extent of surgery, increasing the limb salvage rate, early exposure of micrometastatic disease to chemotherapy, and assessment of tumor response to chemotherapy. Some retrospective and phase II trials suggest a benefit to neoadjuvant chemotherapy. Unfortunately, no clearly positive phase III prospectively randomized trials exist for neoadjuvant therapy in soft tissue sarcomas.

Conclusions

The current neoadjuvant chemotherapy trials that do exist are heterogeneous resulting in conflicting results. However, neoadjuvant chemotherapy with or without radiation can be considered in patients with high-risk disease in an attempt to improve long-term outcomes.

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Risk and survival outcomes of radiation-induced CNS tumors

Abstract

Patients treated with cranial radiation are at risk of developing secondary CNS tumors. Understanding the incidence, treatment, and long-term outcomes of radiation-induced CNS tumors plays a role in clinical decision-making and patient education. Additionally, as meningiomas and pituitary tumors have been detected at increasing rates across all ages and may potentially be treated with radiation, it is important to know and communicate the risk of secondary tumors in children and adults. After conducting an extensive literature search, we identified publications that report incidence and long-term outcomes of radiation-induced CNS tumors. We reviewed 14 studies in children, which reported that radiation confers a 7- to 10-fold increase in subsequent CNS tumors, with a 20-year cumulative incidence ranging from 1.03 to 28.9 %. The latency period for secondary tumors ranged from 5.5 to 30 years, with gliomas developing in 5–10 years and meningiomas developing around 15 years after radiation. We also reviewed seven studies in adults, where the two strongest studies showed no increased risk while the remaining studies found a higher risk compared to the general population. The latency period for secondary CNS tumors in adults ranged from 5 to 34 years. Treatment and long-term outcomes of radiation-induced CNS tumors have been documented in four case series, which did not conclusively demonstrate that secondary CNS tumors fared worse than primary CNS tumors. Radiation-induced CNS tumors remain a rare occurrence that should not by itself impede radiation treatment. Additional investigation is needed on the risk of radiation-induced tumors in adults and the long-term outcomes of these tumors.

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Risk and survival outcomes of radiation-induced CNS tumors

Abstract

Patients treated with cranial radiation are at risk of developing secondary CNS tumors. Understanding the incidence, treatment, and long-term outcomes of radiation-induced CNS tumors plays a role in clinical decision-making and patient education. Additionally, as meningiomas and pituitary tumors have been detected at increasing rates across all ages and may potentially be treated with radiation, it is important to know and communicate the risk of secondary tumors in children and adults. After conducting an extensive literature search, we identified publications that report incidence and long-term outcomes of radiation-induced CNS tumors. We reviewed 14 studies in children, which reported that radiation confers a 7- to 10-fold increase in subsequent CNS tumors, with a 20-year cumulative incidence ranging from 1.03 to 28.9 %. The latency period for secondary tumors ranged from 5.5 to 30 years, with gliomas developing in 5–10 years and meningiomas developing around 15 years after radiation. We also reviewed seven studies in adults, where the two strongest studies showed no increased risk while the remaining studies found a higher risk compared to the general population. The latency period for secondary CNS tumors in adults ranged from 5 to 34 years. Treatment and long-term outcomes of radiation-induced CNS tumors have been documented in four case series, which did not conclusively demonstrate that secondary CNS tumors fared worse than primary CNS tumors. Radiation-induced CNS tumors remain a rare occurrence that should not by itself impede radiation treatment. Additional investigation is needed on the risk of radiation-induced tumors in adults and the long-term outcomes of these tumors.

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