Why are patients with blood cancers more likely to die without hospice?

BACKGROUND

Although patients with blood cancers have significantly lower rates of hospice use than those with solid malignancies, data explaining this gap in end-of-life care are sparse.

METHODS

In 2015, we conducted a mailed survey of a randomly selected sample of hematologic oncologists in the United States to characterize their perspectives regarding the utility and adequacy of hospice for blood cancer patients, as well as factors that might impact referral patterns. Simultaneous provision of care for patients with solid malignancies was permitted.

RESULTS

We received 349 surveys (response rate, 57.3%). The majority of respondents (68.1%) strongly agreed that hospice care is helpful for patients with hematologic cancers; those with practices including greater numbers of solid tumor patients (at least 25%) were more likely to strongly agree (odds ratio, 2.10; 95% confidence interval, 1.26-3.52). Despite high levels of support for hospice in general, 46.0% felt that home hospice is inadequate for their patients' needs (as compared to inpatient hospice with round-the-clock care). Although more than half of the respondents reported that they would be more likely to refer patients to hospice if red cell and/or platelet transfusions were available, those who considered home hospice inadequate were even more likely to report that they would (67.3% vs 55.3% for red cells [P = .03] and 52.9% vs 39.7% for platelets [P = .02]).

CONCLUSIONS

These data suggest that although hematologic oncologists value hospice, concerns about the adequacy of services for blood cancer patients limit hospice referrals. To increase hospice enrollment for blood cancer patients, interventions tailoring hospice services to their specific needs are warranted. Cancer 2017. © 2017 American Cancer Society.

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Why are patients with blood cancers more likely to die without hospice?

BACKGROUND

Although patients with blood cancers have significantly lower rates of hospice use than those with solid malignancies, data explaining this gap in end-of-life care are sparse.

METHODS

In 2015, we conducted a mailed survey of a randomly selected sample of hematologic oncologists in the United States to characterize their perspectives regarding the utility and adequacy of hospice for blood cancer patients, as well as factors that might impact referral patterns. Simultaneous provision of care for patients with solid malignancies was permitted.

RESULTS

We received 349 surveys (response rate, 57.3%). The majority of respondents (68.1%) strongly agreed that hospice care is helpful for patients with hematologic cancers; those with practices including greater numbers of solid tumor patients (at least 25%) were more likely to strongly agree (odds ratio, 2.10; 95% confidence interval, 1.26-3.52). Despite high levels of support for hospice in general, 46.0% felt that home hospice is inadequate for their patients' needs (as compared to inpatient hospice with round-the-clock care). Although more than half of the respondents reported that they would be more likely to refer patients to hospice if red cell and/or platelet transfusions were available, those who considered home hospice inadequate were even more likely to report that they would (67.3% vs 55.3% for red cells [P = .03] and 52.9% vs 39.7% for platelets [P = .02]).

CONCLUSIONS

These data suggest that although hematologic oncologists value hospice, concerns about the adequacy of services for blood cancer patients limit hospice referrals. To increase hospice enrollment for blood cancer patients, interventions tailoring hospice services to their specific needs are warranted. Cancer 2017. © 2017 American Cancer Society.

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Cigarette Filter Ventilation and its Relationship to Increasing Rates of Lung Adenocarcinoma

The 2014 Surgeon General's Report on smoking and health concluded that changing cigarette designs have caused an increase in lung adenocarcinomas, implicating cigarette filter ventilation that lowers smoking machine tar yields. The Food and Drug Administration (FDA) now has the authority to regulate cigarette design if doing so would improve public health. To support a potential regulatory action, two weight-of-evidence reviews were applied for causally relating filter ventilation to lung adenocarcinoma. Published scientific literature (3284 citations) and internal tobacco company documents contributed to causation analysis evidence blocks and the identification of research gaps. Filter ventilation was adopted in the mid-1960s and was initially equated with making a cigarette safer. Since then, lung adenocarcinoma rates paradoxically increased relative to other lung cancer subtypes. Filter ventilation 1) alters tobacco combustion, increasing smoke toxicants; 2) allows for elasticity of use so that smokers inhale more smoke to maintain their nicotine intake; and 3) causes a false perception of lower health risk from "lighter" smoke. Seemingly not supportive of a causal relationship is that human exposure biomarker studies indicate no reduction in exposure, but these do not measure exposure in the lung or utilize known biomarkers of harm. Altered puffing and inhalation may make smoke available to lung cells prone to adenocarcinomas. The analysis strongly suggests that filter ventilation has contributed to the rise in lung adenocarcinomas among smokers. Thus, the FDA should consider regulating its use, up to and including a ban. Herein, we propose a research agenda to support such an effort.

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Cigarette Filter Ventilation and its Relationship to Increasing Rates of Lung Adenocarcinoma

The 2014 Surgeon General's Report on smoking and health concluded that changing cigarette designs have caused an increase in lung adenocarcinomas, implicating cigarette filter ventilation that lowers smoking machine tar yields. The Food and Drug Administration (FDA) now has the authority to regulate cigarette design if doing so would improve public health. To support a potential regulatory action, two weight-of-evidence reviews were applied for causally relating filter ventilation to lung adenocarcinoma. Published scientific literature (3284 citations) and internal tobacco company documents contributed to causation analysis evidence blocks and the identification of research gaps. Filter ventilation was adopted in the mid-1960s and was initially equated with making a cigarette safer. Since then, lung adenocarcinoma rates paradoxically increased relative to other lung cancer subtypes. Filter ventilation 1) alters tobacco combustion, increasing smoke toxicants; 2) allows for elasticity of use so that smokers inhale more smoke to maintain their nicotine intake; and 3) causes a false perception of lower health risk from "lighter" smoke. Seemingly not supportive of a causal relationship is that human exposure biomarker studies indicate no reduction in exposure, but these do not measure exposure in the lung or utilize known biomarkers of harm. Altered puffing and inhalation may make smoke available to lung cells prone to adenocarcinomas. The analysis strongly suggests that filter ventilation has contributed to the rise in lung adenocarcinomas among smokers. Thus, the FDA should consider regulating its use, up to and including a ban. Herein, we propose a research agenda to support such an effort.

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Racial differences in colorectal cancer survival at a safety net hospital

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Umit Tapan, Shin Yin Lee, Janice Weinberg, Vijaya B. Kolachalama, Jean Francis, Marjory Charlot, Kevan Hartshorn, Vipul Chitalia
BackgroundWhile racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood.MethodsWe examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital's electronic medical record. Survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated.ResultsBlack patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.70, CI 1.01–2.90, p=0.0467) for death. Though response to therapy emerged as a strong predictor of survival (HR=0.4, CI=0.2-0.7, p=0.0021), it was comparable between Blacks and Whites.ConclusionsDespite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce findings from previous studies showing lower colorectal cancer survival in Black patients, and also point to the importance of investigating other factors such as genetic and pathologic differences.



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Racial differences in colorectal cancer survival at a safety net hospital

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Umit Tapan, Shin Yin Lee, Janice Weinberg, Vijaya B. Kolachalama, Jean Francis, Marjory Charlot, Kevan Hartshorn, Vipul Chitalia
BackgroundWhile racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood.MethodsWe examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital's electronic medical record. Survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated.ResultsBlack patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.70, CI 1.01–2.90, p=0.0467) for death. Though response to therapy emerged as a strong predictor of survival (HR=0.4, CI=0.2-0.7, p=0.0021), it was comparable between Blacks and Whites.ConclusionsDespite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce findings from previous studies showing lower colorectal cancer survival in Black patients, and also point to the importance of investigating other factors such as genetic and pathologic differences.



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Presence of new mutations in the TP53 gene in patients with low-risk myelodysplastic syndrome: two case reports

Myelodysplastic syndromes are heterogeneous disorders. Patients with myelodysplastic syndrome disease often have ineffective hematopoiesis, cytopenias, blood cell dysplasia in one or more cell types, and are a...

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Hashimoto’s Encephalopathy Presenting with Unusual Behavioural Disturbances in an Adolescent Girl

Hashimoto's encephalopathy (HE) is a rare autoimmune disorder with neurological and neuropsychiatric manifestations and elevated titres of anti-thyroid antibodies. Here we are reporting a case of HE in a 19-year-old girl who presented with seizure-like episodes, confusion, and behavioural disturbances with catatonic symptoms such as posturing, echopraxia, echolalia, and ambivalence. Patient did not respond to antipsychotics and anticonvulsants. On further investigation, patient was found to have high serum anti-TPO antibodies of about 1261 U/mL with euthyroid status, which supported a suspicion of HE. Our consultant neurologist confirmed the diagnosis and she was started on injection of methylprednisolone 750 mg OD. Since patient started showing clinical improvement, her antipsychotic medications were tapered off. On follow-up, patient has recovered and is functioning well. Since HE is a diagnosis of exclusion, very high anti-TPO antibodies and good response to steroids supported the diagnosis of HE in this patient after excluding other etiological possibilities. This case has been reported because the clinical presentation was predominantly neurobehavioural manifestations which is uncommon with HE.

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TRPS1 gene alterations in human subependymoma

Abstract

Subependymoma is a rare primary brain tumor, constituting 0.07–0.51% of brain tumors. Genetic alterations in subependymoma are largely unknown, but familial occurrences have been reported. Trichorhinophalangeal syndrome type 1 (TRPS1) is a rare hereditary malformation complex caused by mutations in a gene identified in the year 2000 on 8q24.12. We report two patients with TRPS I and surgically treated subependymomas, one of whom has a first degree relative, now deceased, who was affected and also had a subependymoma. We therefore sought a role for the TRPS1 gene in the molecular oncogenesis of subependymoma. Formalin fixed tumor specimens and saliva samples were obtained from the two index patients as well as tumor samples from six sporadic subependymoma surgical specimens. A heterozygous TRPS1 germ line mutation predicted to cause a frame shift leading to a premature stop codon was found in the first index patient and also present in the associated tumor. No germline mutation was found in the second index patient, but his tumor displayed copy number neutral loss of heterozygosity in TRPS1. TRPS1 mutation analysis of the sporadic subependymomas revealed genetic, mostly loss of function alterations in one-third (two of six) of samples. Genetic alterations in TRPS1 likely play a role in at least a subgroup of subependymomas. Confirmation and further (epi)genetic investigations, ideally in newly acquired, fresh-frozen tumor samples, are warranted.

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TRPS1 gene alterations in human subependymoma

Abstract

Subependymoma is a rare primary brain tumor, constituting 0.07–0.51% of brain tumors. Genetic alterations in subependymoma are largely unknown, but familial occurrences have been reported. Trichorhinophalangeal syndrome type 1 (TRPS1) is a rare hereditary malformation complex caused by mutations in a gene identified in the year 2000 on 8q24.12. We report two patients with TRPS I and surgically treated subependymomas, one of whom has a first degree relative, now deceased, who was affected and also had a subependymoma. We therefore sought a role for the TRPS1 gene in the molecular oncogenesis of subependymoma. Formalin fixed tumor specimens and saliva samples were obtained from the two index patients as well as tumor samples from six sporadic subependymoma surgical specimens. A heterozygous TRPS1 germ line mutation predicted to cause a frame shift leading to a premature stop codon was found in the first index patient and also present in the associated tumor. No germline mutation was found in the second index patient, but his tumor displayed copy number neutral loss of heterozygosity in TRPS1. TRPS1 mutation analysis of the sporadic subependymomas revealed genetic, mostly loss of function alterations in one-third (two of six) of samples. Genetic alterations in TRPS1 likely play a role in at least a subgroup of subependymomas. Confirmation and further (epi)genetic investigations, ideally in newly acquired, fresh-frozen tumor samples, are warranted.

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A Constellation of Rare Findings in a Case of Goldenhar Syndrome

An 18-month-old child presented with right macrostomia, bilateral preauricular skin tags, bilateral CTEV, squint in bilateral eyes, thoracic vertebral anomalies, right sided aortic arch, and associated left pulmonary agenesis. The patient did not have any associated respiratory symptoms. Ipsilateral pulmonary agenesis is considered as a rare association with Goldenhar syndrome and a case of contralateral pulmonary aplasia has been described as an even rarer association.

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The Current Value Of Determining The Mismatch Repair Status Of Colorectal Cancer: A Rationale For Routine Testing

Publication date: Available online 20 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): E. Ryan, K. Sheahan, B. Creavin, H.M. Mohan, D.C. Winter
Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumour screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumors have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC.



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Brain metastases from Non-Small Cell Lung Carcinoma: changing concepts for improving patients’ outcome

Publication date: Available online 20 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Chloé Rancoule, Alexis Vallard, Jean-Baptiste Guy, Sophie Espenel, Peng Diao, Cyrus Chargari, Nicolas Magné
The management of Non Small Cell Lung Cancer (NSCLC) brain metastases is challenging, as this frequent complication negatively impacts patients' quality of life, and can be a life-threatening event.Through a review of the literature, we discuss the main therapeutic options and the recent developments that improved (and complicated) the management of NSCLC brain metastases patients. Most current validated approaches are local with exclusive or combined surgery, whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRT). At the same time, there is a growing role for systemic treatments that might significantly postpone WBRT. Targeted therapies efficacy/toxicity profile remains to be defined but predictive and prognostic molecular factors integration could help to select treatments fully adapted to life expectancy and progression risk.



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The Current Value Of Determining The Mismatch Repair Status Of Colorectal Cancer: A Rationale For Routine Testing

Publication date: Available online 20 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): E. Ryan, K. Sheahan, B. Creavin, H.M. Mohan, D.C. Winter
Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumour screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumors have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC.



http://ift.tt/2rEMhln

Brain metastases from Non-Small Cell Lung Carcinoma: changing concepts for improving patients’ outcome

Publication date: Available online 20 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Chloé Rancoule, Alexis Vallard, Jean-Baptiste Guy, Sophie Espenel, Peng Diao, Cyrus Chargari, Nicolas Magné
The management of Non Small Cell Lung Cancer (NSCLC) brain metastases is challenging, as this frequent complication negatively impacts patients' quality of life, and can be a life-threatening event.Through a review of the literature, we discuss the main therapeutic options and the recent developments that improved (and complicated) the management of NSCLC brain metastases patients. Most current validated approaches are local with exclusive or combined surgery, whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRT). At the same time, there is a growing role for systemic treatments that might significantly postpone WBRT. Targeted therapies efficacy/toxicity profile remains to be defined but predictive and prognostic molecular factors integration could help to select treatments fully adapted to life expectancy and progression risk.



http://ift.tt/2r5NnJK

Prostate cancer-related anxiety in long-term survivors after radical prostatectomy

Abstract

Purpose

Knowledge of the psychological distress of long- and very long-term (>10 years) prostate cancer (PC) survivors is limited. This study intended to examine the parameters influencing anxiety related to prostate-specific antigen (PSA) and PC in long-term survivors after radical prostatectomy.

Methods

We surveyed 4719 PC survivors from the German multicenter prospective database "Familial Prostate Cancer." We evaluated the association of PC-related anxiety (MAX-PC) with sociodemographic characteristics, family history of PC, global health status/quality of life (EORTC QLQ-C30), depression and anxiety (PHQ-2; GAD-2), latest PSA level, time since radical prostatectomy, and current therapy.

Results

The survey participants' mean age was 75.2 years (SD = 6.5). Median follow-up was 11.5 years, and 19.5% of participants had survived more than 15 years since the initial treatment. The final regression analysis found that younger age, lower global health status/quality of life, higher depression and anxiety scores, higher latest PSA level, and shorter time since radical prostatectomy predicted increased PSA-related anxiety and PC anxiety. Familial PC was predictive only of PSA anxiety (all p < 0.05). The final model explained 12% of the variance for PSA anxiety and 24% for PC anxiety.

Conclusions

PC-related anxiety remained relevant many years after prostatectomy and was influenced by younger age, psychological status, rising PSA level, and shorter time since initial treatment.

Implications for Cancer Survivors

Survivors with these characteristics are at increased risk of PC-related anxieties, which should be considered by the treating physician during follow-up.

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Prostate cancer-related anxiety in long-term survivors after radical prostatectomy

Abstract

Purpose

Knowledge of the psychological distress of long- and very long-term (>10 years) prostate cancer (PC) survivors is limited. This study intended to examine the parameters influencing anxiety related to prostate-specific antigen (PSA) and PC in long-term survivors after radical prostatectomy.

Methods

We surveyed 4719 PC survivors from the German multicenter prospective database "Familial Prostate Cancer." We evaluated the association of PC-related anxiety (MAX-PC) with sociodemographic characteristics, family history of PC, global health status/quality of life (EORTC QLQ-C30), depression and anxiety (PHQ-2; GAD-2), latest PSA level, time since radical prostatectomy, and current therapy.

Results

The survey participants' mean age was 75.2 years (SD = 6.5). Median follow-up was 11.5 years, and 19.5% of participants had survived more than 15 years since the initial treatment. The final regression analysis found that younger age, lower global health status/quality of life, higher depression and anxiety scores, higher latest PSA level, and shorter time since radical prostatectomy predicted increased PSA-related anxiety and PC anxiety. Familial PC was predictive only of PSA anxiety (all p < 0.05). The final model explained 12% of the variance for PSA anxiety and 24% for PC anxiety.

Conclusions

PC-related anxiety remained relevant many years after prostatectomy and was influenced by younger age, psychological status, rising PSA level, and shorter time since initial treatment.

Implications for Cancer Survivors

Survivors with these characteristics are at increased risk of PC-related anxieties, which should be considered by the treating physician during follow-up.

http://ift.tt/2pYyFEe

Hemodialysis does not impact axitinib exposure: clinical case of a patient with metastatic renal cell carcinoma

Abstract

Axitinib is approved with indication in patients with advanced renal cell carcinoma (RCC). Due to the localization of this cancer, physicians sometimes have to deal with hemodialyzed patients. Data exploring hemodialysis (HD) impact on axitinib pharmacokinetic (PK) or safety are lacking. To date, no data have been published on that problematic. This is the first publication discussing the assessment of axitinib PK for a patient undergoing HD. Our results suggest that there is no influence of HD on axitinib blood concentration. Interestingly, the membranes used are common and represent around 90% of the membranes used in routine for HD. Our data are also reassuring both from activity and from safety perspectives. In that case, axitinib administered at a dose of 6 mg twice a day was well tolerated and allowed 12 months of disease control. These results are in line with previous publications discussing other anti-angiogenic tyrosine kinase inhibitors pharmacokinetics, safety and activity among patients with metastatic RCC undergoing hemodialysis.

http://ift.tt/2qCWCQ1

The incidence and risk factors of febrile neutropenia in chemotherapy-naïve lung cancer patients receiving etoposide plus platinum

Abstract

Purpose

This study was to determine the incidence and risk factors of febrile neutropenia in chemotherapy-naïve Japanese patients treated systemically with etoposide plus platinum for lung cancer.

Methods

The study was a retrospective analysis of 244 patients who were monitored for febrile neutropenia through multiple cycles of the combination of etoposide with platinum, and the associations between incidence of febrile neutropenia and patient characteristics were evaluated.

Results

Eighty-eight patients were treated with etoposide plus cisplatin and 156 were treated with etoposide plus carboplatin. Of the 244 patients treated, 198 (81.1%) completed 4 cycles for chemotherapy. Febrile neutropenia was observed in 48 of 244 patients (19.7%), including 18 of 88 (20.5%) patients who received etoposide plus cisplatin and 30 of 156 (19.2%) patients who received etoposide plus carboplatin. Grade 3 or 4 of neutropenia was experienced by a total of 208 patients (85.2%); 79 of 88 (89.8%) receiving etoposide plus cisplatin and 129 of 156 (82.7%) receiving etoposide plus carboplatin. Male gender and previous radiotherapy were identified by multivariate analysis as independent risk factors for febrile neutropenia.

Conclusions

These results contrast with findings in Western patients and suggest that ethnic differences exist in the incidence of febrile neutropenia in patients receiving etoposide plus platinum chemotherapy. In addition, our results suggest that primary prophylaxis with granulocyte colony-stimulating factor should be considered for patients with these risk factors for febrile neutropenia prior to treatment with etoposide plus platinum.

http://ift.tt/2q898nd

Enhancing the therapeutic range of a targeted small-molecule tubulysin conjugate for folate receptor-based cancer therapy

Abstract

Purpose

EC0305 represents a folate-tubulysin B construct capable of specifically eradicating folate receptor (FR)-positive subcutaneous tumors from mice (Leamon et al., Cancer Res 68:9839–9844, 8). Herein we report on the use of multiple polar carbohydrate segments (e.g. 1-amino-1-deoxy-glucitolyl-γ-glutamate) placed in-between the folate and tubulysin B moieties of EC0305 creating a new conjugate, herein referred to as EC0531, with more desirable biological properties.

Methods

The synthesis of EC0531 and its tritium-labeled counterpart are described. EC0531's affinity for FR binding and specific cytotoxic activity was assessed using standard in vitro assays. Human tumor xenografts were used to directly compare EC0305 and EC0531's antitumor activity. Finally, bile duct cannulated, female Sprague–Dawley rats were used to compare hepatobiliary clearance of these two targeted chemotherapeutic agents.

Results

EC0531 tightly binds to the FR with an affinity about half that of folic acid. It was found to specifically inhibit the growth of FR⁺ cells (IC₅₀ of ~2 nM) in a dose-dependent manner. Using ³H-labeled compounds, more than a 12-fold higher amount of tubulysin was measured in a FR + human tumor xenograft compared to the unconjugated drug, a finding that explains, in part, why EC0531 displays curative activity, whereas the unconjugated tubulysin agent is essentially inactive. EC0531 was found to produce greater FR-specific anti-tumor activity at lower dose levels than EC0305; furthermore, EC0531's maximum tolerated dose level was significantly higher than that of EC0305, likely because EC0531's saccharopeptidic-based spacer allows for ~sixfold reduction in hepatic clearance.

Conclusions

These data provide additional evidence that the therapeutic range of targeted small-molecule drug conjugates can be favorably increased using molecular spacers constructed with 1-amino-1-deoxy-glucitolyl-γ-glutamate residues.

http://ift.tt/2qDjy1P

Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese

Abstract

Purpose

Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer.

Methods

Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN.

Results

Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991–4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively).

Conclusions

ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.

http://ift.tt/2q83VvP

Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue

Abstract

Purpose

To challenge the view that the dose of folinic acid rescue after high-dose methotrexate (MTX) has no significance in the prevention of neurotoxicity and to present the minority view that neurotoxicity can be prevented by an adequate dose of folinic acid, without compromising treatment results. Several fallacies that led to the misunderstanding of post MTX neurotoxicity are presented.

Methods

Data mining using search engines was used to find relevant publications, and an e-mail survey of more than 60 authors of articles in this field was performed. All relevant articles identified were read in their entirety.

Results

Examples of clinical studies with neurotoxicity following inadequate rescue are given. Some studies demonstrated no neurotoxicity when adequate doses of folinic acid rescue were started 24–36 h after the start of HDMTX rescue even after mega doses of MTX. Rescue started after 42 h was associated with neurotoxicity except in patients with low serum MTX levels after 24 and 36 h. ALL protocols with neurotoxicity, especially BFM-like protocols, are presented. Protocol is reported in which single protocol changes prevented neurotoxicity.

Conclusions

From the published data, when folinic acid rescue is given in a sufficiently high enough dose and is started 24–36 h after the beginning of the methotrexate exposure, and virtually all forms of post MTX neurotoxicity can be prevented without compromising therapeutic results.

http://ift.tt/2qCZHj6

Phase II study of S-1 plus bevacizumab combination therapy for patients previously treated for non-squamous non-small cell lung cancer

Abstract

Purpose

To assess the efficacy and toxicity of S-1 and bevacizumab combination therapy for patients previously treated for advanced non-squamous non-small cell lung cancer (NSCLC).

Methods

This was a prospective, multi-center, single-arm phase II study. Patients with non-squamous NSCLC who had experienced progression after cytotoxic chemotherapy were enrolled. Oral S-1 was administered on days 1–14 of a 21-day cycle, and bevacizumab (15 mg/kg) was given intravenously on day 1. Patients received S-1 adjusted on the basis of their creatinine clearance and body surface area. The primary endpoint was response rate (RR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

Results

We enrolled 30 patients. One patient had never received platinum-based therapy. Five patients had activating mutations of the epidermal growth factor receptor gene, of whom four had received tyrosine kinase inhibitors before this study. The RR was 6.7% [95% confidence interval (CI) 1.8–21.3%], and the disease control rate (DCR) was 80% (95% CI 62.7–90.5%). Median PFS was 4.8 months (95% CI 2.7–6.4 months], and median OS was 13.8 months (95% CI 8.4 months–not applicable). Patients did not experience any Grade 4 toxicity or treatment-related death. Grade 3 hematologic toxicity (anemia) occurred in one patient (3.3%). The main Grade 3 non-hematologic toxicities were anorexia (10%), infection (10%), and diarrhea (6.7%).

Conclusion

The addition of bevacizumab to S-1 was tolerable, but not beneficial for patients with previously treated non-squamous NSCLC. We do not recommend further study of this regimen.

http://ift.tt/2q80uFd

MITF suppression by CH5552074 inhibits cell growth in melanoma cells

Abstract

Purpose

Although treatment of melanoma with BRAF inhibitors and immune checkpoint inhibitors achieves a high response rate, a subset of melanoma patients with intrinsic and acquired resistance are insensitive to these therapeutics, so to improve melanoma therapy other target molecules need to be found. Here, we screened our chemical library to identify an anti-melanoma agent and examined its action mechanisms to show cell growth inhibition activity.

Methods

We screened a chemical library against multiple skin cancer cell lines and conducted ingenuity pathway analysis (IPA) to investigate the mechanisms of CH5552074 activity. Suppression of microphthalmia-associated transcription factor (MITF) expression levels was determined in melanoma cells treated with CH5552074. Cell growth inhibition activity of CH5552074 was evaluated in MITF-dependent melanoma cell lines.

Results

We identified an anti-melanoma compound, CH5552074, which showed remarkable cell growth inhibition activity in melanoma cell lines. The IPA results suggested that CH5552074-sensitive cell lines had activated MITF. In further in vitro studies in the melanoma cell lines, a knockdown of MITF with siRNA resulted in cell growth inhibition, which showed that CH5552074 inhibited cell growth by reducing the expression level of MITF protein.

Conclusions

These results suggest that CH5552074 can inhibit cell growth in melanoma cells by reducing the protein level of MITF. MITF inhibition by CH5552074 would be an attractive option for melanoma treatment.

http://ift.tt/2qDfTBd

In vitro and in vivo assessments of two novel hydrazide compounds against breast cancer as well as mammary tumor cells

Abstract

Purpose

The hydrazide backbone is a well-known structural core system found in a broad range of biologically activated compounds. Among which, the compounds with anticancer activity have been cited in a number of studies. With this object in mind, we focused on the in vitro and in vivo anticancer potential of two novel hydrazide derivatives bearing furan or thiophen substituents (compounds 1 and 2).

Methods

The cytotoxic property was evaluated using MTT assay against MCF-7 human breast adenocarcinoma cell line, while the in vivo antitumor activity was investigated in BALB/c mice bearing 4T1 mammary carcinoma cells. Flow cytometry was used for cell cycle analysis, and detection of apoptosis was examined by Annexin-V-FLUOS/PI assay. Protein expression of Bax, Bcl-2 and procaspase-3 was estimated by Western blotting.

Results

Compounds 1 and 2 were found to be cytotoxic towards breast cancer cells presenting IC₅₀ values of 0.7 and 0.18 µM, respectively, and selectivity over normal fibroblast cells. Our findings further indicated that 2 × IC₅₀ concentrations of both compounds induce early stage apoptosis and increase percentage of sub-G1 population in MCF-7 cells at 48 h. An elevation in Bax/Bcl-2 ratio and caspase-3 cleavage suggested that apoptosis induced by the two compounds is through a caspase- and mitochondrial-dependent pathway. In the in vivo study, compounds 1 and 2 at doses of 10 and 1 mg/Kg/day, respectively, significantly hindered the growth of tumor after 3 weeks of i.p. administration, when compared to vehicle-treated mice.

Conclusion

Collectively, the great potential exhibited by compound 2 could make it a promising chemotherapeutic candidate for human cancers, especially for breast cancer.

http://ift.tt/2qDeuKZ

Adjuvant concurrent chemoradiotherapy with low-dose daily cisplatin for extrahepatic bile duct cancer

Abstract

Purpose

We aimed to present the clinical outcomes of adjuvant concurrent chemoradiotherapy (CCRT) with low-dose daily cisplatin regimen compared to the conventional 5-fluorouracil (5-FU)-based regimen for extrahepatic bile duct cancer (EHBDC).

Methods

From October 1994 to April 2013, 41 patients received adjuvant CCRT with low-dose daily regimen or 5-FU-based regimens. Nineteen patients received low-dose of cisplatin just before every delivery of radiation therapy, and 21 patients received two cycles of 5-FU-based regimen during radiotherapy. We compared the clinical outcomes between two adjuvant CCRT regimens.

Results

Adjuvant CCRT with low-dose daily cisplatin showed comparable toxicity profiles compared with that of a 5-FU-based regimen. The median follow-up time was 33 months (range, 5–205), and the 5-year overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 34.2, 50.8, and 49.7%, respectively. Univariable analyses showed no significant differences in OS, LRRFS, and DMFS between the groups with two regimens. In multivariable analyses, chemotherapeutic regimen was a significant prognostic factor for OS, favoring the low-dose daily cisplatin regimen (HR = 2.491, p = 0.036) over 5-FU-based regimen, though not for LRRFS (p = 0.642) and DMFS (p = 0.756).

Conclusions

Adjuvant CCRT with low-dose daily cisplatin regimen showed acceptable toxicities and survivals compared to those of the 5-FU-based regimen. Low-dose daily cisplatin can be one of the feasible regimens for adjuvant CCRT for EHBDC.

http://ift.tt/2q84Wns

Hemodialysis does not impact axitinib exposure: clinical case of a patient with metastatic renal cell carcinoma

Abstract

Axitinib is approved with indication in patients with advanced renal cell carcinoma (RCC). Due to the localization of this cancer, physicians sometimes have to deal with hemodialyzed patients. Data exploring hemodialysis (HD) impact on axitinib pharmacokinetic (PK) or safety are lacking. To date, no data have been published on that problematic. This is the first publication discussing the assessment of axitinib PK for a patient undergoing HD. Our results suggest that there is no influence of HD on axitinib blood concentration. Interestingly, the membranes used are common and represent around 90% of the membranes used in routine for HD. Our data are also reassuring both from activity and from safety perspectives. In that case, axitinib administered at a dose of 6 mg twice a day was well tolerated and allowed 12 months of disease control. These results are in line with previous publications discussing other anti-angiogenic tyrosine kinase inhibitors pharmacokinetics, safety and activity among patients with metastatic RCC undergoing hemodialysis.

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The incidence and risk factors of febrile neutropenia in chemotherapy-naïve lung cancer patients receiving etoposide plus platinum

Abstract

Purpose

This study was to determine the incidence and risk factors of febrile neutropenia in chemotherapy-naïve Japanese patients treated systemically with etoposide plus platinum for lung cancer.

Methods

The study was a retrospective analysis of 244 patients who were monitored for febrile neutropenia through multiple cycles of the combination of etoposide with platinum, and the associations between incidence of febrile neutropenia and patient characteristics were evaluated.

Results

Eighty-eight patients were treated with etoposide plus cisplatin and 156 were treated with etoposide plus carboplatin. Of the 244 patients treated, 198 (81.1%) completed 4 cycles for chemotherapy. Febrile neutropenia was observed in 48 of 244 patients (19.7%), including 18 of 88 (20.5%) patients who received etoposide plus cisplatin and 30 of 156 (19.2%) patients who received etoposide plus carboplatin. Grade 3 or 4 of neutropenia was experienced by a total of 208 patients (85.2%); 79 of 88 (89.8%) receiving etoposide plus cisplatin and 129 of 156 (82.7%) receiving etoposide plus carboplatin. Male gender and previous radiotherapy were identified by multivariate analysis as independent risk factors for febrile neutropenia.

Conclusions

These results contrast with findings in Western patients and suggest that ethnic differences exist in the incidence of febrile neutropenia in patients receiving etoposide plus platinum chemotherapy. In addition, our results suggest that primary prophylaxis with granulocyte colony-stimulating factor should be considered for patients with these risk factors for febrile neutropenia prior to treatment with etoposide plus platinum.

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Enhancing the therapeutic range of a targeted small-molecule tubulysin conjugate for folate receptor-based cancer therapy

Abstract

Purpose

EC0305 represents a folate-tubulysin B construct capable of specifically eradicating folate receptor (FR)-positive subcutaneous tumors from mice (Leamon et al., Cancer Res 68:9839–9844, 8). Herein we report on the use of multiple polar carbohydrate segments (e.g. 1-amino-1-deoxy-glucitolyl-γ-glutamate) placed in-between the folate and tubulysin B moieties of EC0305 creating a new conjugate, herein referred to as EC0531, with more desirable biological properties.

Methods

The synthesis of EC0531 and its tritium-labeled counterpart are described. EC0531's affinity for FR binding and specific cytotoxic activity was assessed using standard in vitro assays. Human tumor xenografts were used to directly compare EC0305 and EC0531's antitumor activity. Finally, bile duct cannulated, female Sprague–Dawley rats were used to compare hepatobiliary clearance of these two targeted chemotherapeutic agents.

Results

EC0531 tightly binds to the FR with an affinity about half that of folic acid. It was found to specifically inhibit the growth of FR⁺ cells (IC₅₀ of ~2 nM) in a dose-dependent manner. Using ³H-labeled compounds, more than a 12-fold higher amount of tubulysin was measured in a FR + human tumor xenograft compared to the unconjugated drug, a finding that explains, in part, why EC0531 displays curative activity, whereas the unconjugated tubulysin agent is essentially inactive. EC0531 was found to produce greater FR-specific anti-tumor activity at lower dose levels than EC0305; furthermore, EC0531's maximum tolerated dose level was significantly higher than that of EC0305, likely because EC0531's saccharopeptidic-based spacer allows for ~sixfold reduction in hepatic clearance.

Conclusions

These data provide additional evidence that the therapeutic range of targeted small-molecule drug conjugates can be favorably increased using molecular spacers constructed with 1-amino-1-deoxy-glucitolyl-γ-glutamate residues.

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Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese

Abstract

Purpose

Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer.

Methods

Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN.

Results

Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991–4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively).

Conclusions

ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.

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Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue

Abstract

Purpose

To challenge the view that the dose of folinic acid rescue after high-dose methotrexate (MTX) has no significance in the prevention of neurotoxicity and to present the minority view that neurotoxicity can be prevented by an adequate dose of folinic acid, without compromising treatment results. Several fallacies that led to the misunderstanding of post MTX neurotoxicity are presented.

Methods

Data mining using search engines was used to find relevant publications, and an e-mail survey of more than 60 authors of articles in this field was performed. All relevant articles identified were read in their entirety.

Results

Examples of clinical studies with neurotoxicity following inadequate rescue are given. Some studies demonstrated no neurotoxicity when adequate doses of folinic acid rescue were started 24–36 h after the start of HDMTX rescue even after mega doses of MTX. Rescue started after 42 h was associated with neurotoxicity except in patients with low serum MTX levels after 24 and 36 h. ALL protocols with neurotoxicity, especially BFM-like protocols, are presented. Protocol is reported in which single protocol changes prevented neurotoxicity.

Conclusions

From the published data, when folinic acid rescue is given in a sufficiently high enough dose and is started 24–36 h after the beginning of the methotrexate exposure, and virtually all forms of post MTX neurotoxicity can be prevented without compromising therapeutic results.

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Phase II study of S-1 plus bevacizumab combination therapy for patients previously treated for non-squamous non-small cell lung cancer

Abstract

Purpose

To assess the efficacy and toxicity of S-1 and bevacizumab combination therapy for patients previously treated for advanced non-squamous non-small cell lung cancer (NSCLC).

Methods

This was a prospective, multi-center, single-arm phase II study. Patients with non-squamous NSCLC who had experienced progression after cytotoxic chemotherapy were enrolled. Oral S-1 was administered on days 1–14 of a 21-day cycle, and bevacizumab (15 mg/kg) was given intravenously on day 1. Patients received S-1 adjusted on the basis of their creatinine clearance and body surface area. The primary endpoint was response rate (RR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

Results

We enrolled 30 patients. One patient had never received platinum-based therapy. Five patients had activating mutations of the epidermal growth factor receptor gene, of whom four had received tyrosine kinase inhibitors before this study. The RR was 6.7% [95% confidence interval (CI) 1.8–21.3%], and the disease control rate (DCR) was 80% (95% CI 62.7–90.5%). Median PFS was 4.8 months (95% CI 2.7–6.4 months], and median OS was 13.8 months (95% CI 8.4 months–not applicable). Patients did not experience any Grade 4 toxicity or treatment-related death. Grade 3 hematologic toxicity (anemia) occurred in one patient (3.3%). The main Grade 3 non-hematologic toxicities were anorexia (10%), infection (10%), and diarrhea (6.7%).

Conclusion

The addition of bevacizumab to S-1 was tolerable, but not beneficial for patients with previously treated non-squamous NSCLC. We do not recommend further study of this regimen.

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MITF suppression by CH5552074 inhibits cell growth in melanoma cells

Abstract

Purpose

Although treatment of melanoma with BRAF inhibitors and immune checkpoint inhibitors achieves a high response rate, a subset of melanoma patients with intrinsic and acquired resistance are insensitive to these therapeutics, so to improve melanoma therapy other target molecules need to be found. Here, we screened our chemical library to identify an anti-melanoma agent and examined its action mechanisms to show cell growth inhibition activity.

Methods

We screened a chemical library against multiple skin cancer cell lines and conducted ingenuity pathway analysis (IPA) to investigate the mechanisms of CH5552074 activity. Suppression of microphthalmia-associated transcription factor (MITF) expression levels was determined in melanoma cells treated with CH5552074. Cell growth inhibition activity of CH5552074 was evaluated in MITF-dependent melanoma cell lines.

Results

We identified an anti-melanoma compound, CH5552074, which showed remarkable cell growth inhibition activity in melanoma cell lines. The IPA results suggested that CH5552074-sensitive cell lines had activated MITF. In further in vitro studies in the melanoma cell lines, a knockdown of MITF with siRNA resulted in cell growth inhibition, which showed that CH5552074 inhibited cell growth by reducing the expression level of MITF protein.

Conclusions

These results suggest that CH5552074 can inhibit cell growth in melanoma cells by reducing the protein level of MITF. MITF inhibition by CH5552074 would be an attractive option for melanoma treatment.

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via IFTTT

In vitro and in vivo assessments of two novel hydrazide compounds against breast cancer as well as mammary tumor cells

Abstract

Purpose

The hydrazide backbone is a well-known structural core system found in a broad range of biologically activated compounds. Among which, the compounds with anticancer activity have been cited in a number of studies. With this object in mind, we focused on the in vitro and in vivo anticancer potential of two novel hydrazide derivatives bearing furan or thiophen substituents (compounds 1 and 2).

Methods

The cytotoxic property was evaluated using MTT assay against MCF-7 human breast adenocarcinoma cell line, while the in vivo antitumor activity was investigated in BALB/c mice bearing 4T1 mammary carcinoma cells. Flow cytometry was used for cell cycle analysis, and detection of apoptosis was examined by Annexin-V-FLUOS/PI assay. Protein expression of Bax, Bcl-2 and procaspase-3 was estimated by Western blotting.

Results

Compounds 1 and 2 were found to be cytotoxic towards breast cancer cells presenting IC₅₀ values of 0.7 and 0.18 µM, respectively, and selectivity over normal fibroblast cells. Our findings further indicated that 2 × IC₅₀ concentrations of both compounds induce early stage apoptosis and increase percentage of sub-G1 population in MCF-7 cells at 48 h. An elevation in Bax/Bcl-2 ratio and caspase-3 cleavage suggested that apoptosis induced by the two compounds is through a caspase- and mitochondrial-dependent pathway. In the in vivo study, compounds 1 and 2 at doses of 10 and 1 mg/Kg/day, respectively, significantly hindered the growth of tumor after 3 weeks of i.p. administration, when compared to vehicle-treated mice.

Conclusion

Collectively, the great potential exhibited by compound 2 could make it a promising chemotherapeutic candidate for human cancers, especially for breast cancer.

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Adjuvant concurrent chemoradiotherapy with low-dose daily cisplatin for extrahepatic bile duct cancer

Abstract

Purpose

We aimed to present the clinical outcomes of adjuvant concurrent chemoradiotherapy (CCRT) with low-dose daily cisplatin regimen compared to the conventional 5-fluorouracil (5-FU)-based regimen for extrahepatic bile duct cancer (EHBDC).

Methods

From October 1994 to April 2013, 41 patients received adjuvant CCRT with low-dose daily regimen or 5-FU-based regimens. Nineteen patients received low-dose of cisplatin just before every delivery of radiation therapy, and 21 patients received two cycles of 5-FU-based regimen during radiotherapy. We compared the clinical outcomes between two adjuvant CCRT regimens.

Results

Adjuvant CCRT with low-dose daily cisplatin showed comparable toxicity profiles compared with that of a 5-FU-based regimen. The median follow-up time was 33 months (range, 5–205), and the 5-year overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 34.2, 50.8, and 49.7%, respectively. Univariable analyses showed no significant differences in OS, LRRFS, and DMFS between the groups with two regimens. In multivariable analyses, chemotherapeutic regimen was a significant prognostic factor for OS, favoring the low-dose daily cisplatin regimen (HR = 2.491, p = 0.036) over 5-FU-based regimen, though not for LRRFS (p = 0.642) and DMFS (p = 0.756).

Conclusions

Adjuvant CCRT with low-dose daily cisplatin regimen showed acceptable toxicities and survivals compared to those of the 5-FU-based regimen. Low-dose daily cisplatin can be one of the feasible regimens for adjuvant CCRT for EHBDC.

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Comparing the Vitex-castus extract and cabergoline effects on estrous induction in female dogs

Abstract

Cabergoline is used to induce estrus, stop lactation, and induce abortion in small animals. The specific doses of Vitagnus extract have almost identical properties of cabergoline that reduce prolactin and increase the concentration of FSH hormone. The aim of this study was to compare the effect of Vitex agnus-castus extract and cabergoline on prolactin concentration and hormonal changes associated with the onset of estrous cycle in dogs. Twelve healthy adult cyclic female-mix breed dogs were selected and randomly aligned in treatment (6 dogs, Vitagnus extract 1.5 ml daily for 5 weeks, 80–90 mg/ml, PO) and control groups (6 dogs, cabergoline, daily for 5 weeks, 5 μg/kg, PO). Blood sampling and vaginal smears were taken weekly. Serum samples were stored at −20 °C until prolactin, estradiol, and progesterone were measured by ELISA method. Based on vaginal cytology results, four (cabergoline) and three (Vitagnus) dogs were in the estrous phase after 5 weeks of treatment. The average concentration of the prolactin was not changed during 5 weeks and between two groups. There was no significant difference in progesterone and estradiol levels between groups. The changes of estradiol concentration were significant during the 5 weeks (p < 0.01). The mean concentration of this hormone changed significantly between weeks 2 and 3 (p < 0.01), 2 and 5 (p < 0.05), and 3 and 4 (p < 0.05). In conclusion, Vitagnus extract had hormonal effects similar to those of cabergoline for induction of estrus in bitches.

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