Safety and efficacy of trastuzumab administered as a 30-min infusion in patients with HER2-positive advanced gastric cancer

Abstract

Purpose

To investigate the safety and efficacy of 30-min maintenance infusions of trastuzumab in advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2).

Methods

This was a retrospective study conducted across five Korean hospitals in patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with first-line, 3-weekly trastuzumab plus chemotherapy. The first dose of trastuzumab (8 mg/kg) was administered as a 90-min infusion, with all subsequent maintenance infusions (6 mg/kg) given over 30 min. The primary aim was to investigate infusion-related reactions and cardiac events with 30-min infusions of trastuzumab. Objective response rate, progression-free survival, and overall survival were secondary endpoints.

Results

The study included 128 patients (efficacy population), of whom 123 received both induction and maintenance infusions and formed the safety population. The median age was 63 years; 80% were presenting for the first time with metastatic disease, and 94% were treated with trastuzumab plus capecitabine/cisplatin. Infusion-related reactions were observed in 32 of 123 patients (26%). There were no cardiac events. The most frequent adverse events were anorexia and nausea, followed by vomiting, fatigue, mucositis, sensory neuropathy, and hand–foot syndrome. Most events were grade 1–2 and were manageable. No patient discontinued study treatment due to adverse events. The objective response rate was 63%, and included 6 complete responses.

Conclusions

Trastuzumab 30-min maintenance infusions were well tolerated with a good safety profile, and resulted in sustained efficacy in patients with HER2-positive advanced gastric cancer.

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A window-of-opportunity clinical trial of dasatinib in women with newly diagnosed endometrial cancer

Abstract

Objective

To determine the extent of dasatinib uptake and effect on Src kinase activity in tumor, normal adjacent tissue, and blood in newly diagnosed endometrial cancer patients.

Methods

Dasatinib was dosed at 100 or 200 mg PO BID at 32 and 8 h preoperatively. Blood and tissue were collected pre-treatment and at surgery to assess active (pY419) and total Src protein (pharmacodynamics [PD]) and pharmacokinetics (PK). Plasma PK and PD were also analyzed at 2, 4 and 8 h following the second dose.

Results

Ten patients completed the study, 5 at each dose level (DL). Average (median, standard deviation, range) 2 h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200 mg DL, respectively. Average ratio of 8 h normal and tumor tissue to plasma concentration overall was 3.6 (2.3, 3.4, 9.6) and 8.3 (3.2, 11.9, 38.7), respectively. Dasatinib concentration in tumor was higher than in plasma for both DL. Four patients displayed significant reductions in pTyr419Src at ≥ 1 time points in blood, and four patients satisfied the PD activity criteria in tissue, with reductions in pTyr419Src of ≥ 60%.

Conclusions

This is the first study to show PK and PD effects of dasatinib in tumor tissue, allowing evaluation of tissue PD markers as a function of tumor dasatinib concentration. Dasatinib tissue concentrations at 8 h after dosing were associated with modulation of pTyr419Src, total Src protein, and pTyr419Src/Src ratio. All patients had reduction in at least one Src parameter in either tissue or blood.

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Octreotide SC depot in patients with acromegaly and functioning neuroendocrine tumors: a phase 2, multicenter study

Abstract

Purpose

Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM.

Methods

Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0).

Results

Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders.

Conclusion

Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM.

ClinicalTrials.gov identifier

NCT02299089.

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A phase II trial of the effect of perindopril on hand–foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC

Abstract

Purpose

Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303–312, 2013), but comes with potential significant toxicities including grade 3 hand–foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237–246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR.

Patients and methods

In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03.

Results

A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%).

Conclusion

The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.

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MnO 2 -loaded microorganism-derived carbon for U(VI) adsorption from aqueous solution

Abstract

A low-cost industrial microorganism, Saccharomyces cerevisiae, was employed as a precursor to synthesize carbon/MnO₂ composites (MMCs) via an oxidation-reduction reaction and one-step carbonization method for U(VI) adsorption. Scanning electron microscopy and nitrogen adsorption measurement indicated that the microorganism's carbonization could form surface porous structure and increase the specific surface area. Batch experiments showed that the maximum U(VI) adsorption capacity of MMCs reached 207 mg g⁻¹ at [U(VI)]_initial = 25 mg L⁻¹ and pH_initial = 4.5. The obtained thermodynamic and kinetic parameters suggested that the process is endothermic, spontaneous, and chemisorption. FTIR and X-ray photoelectron spectroscopy demonstrated that the surface hydroxyl groups of composites might be the reactive adsorption sites for U(VI). Additionally, 0.5 mol L⁻¹ HNO₃ solution could desorb ~ 95% uranium from U(VI)-loaded MMCs, and materials exhibited good regenerated availability. This study suggests that MMCs can be a potential adsorbent for U(VI) preconcentration and removal from radioactive wastewater.

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The Results of a Crossover Placebo-Controlled Study of the Effect of Lavender Oil on Behavioral and Psychological Symptoms of Dementia

Rejuvenation Research, Ahead of Print.


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Laryngeal temperature simulations during carbon dioxide laser irradiation delivered by a scanning micromanipulator

Abstract

We use scatter-limited phototherapy techniques to calculate the time-dependent temperature profiles of incisions made with a commercial carbon dioxide laser being used to make a 1-mm incision under computer control using the Digital Acublade™ and with incisions made with the same laser under manual control. The goal is to understand the differences in the amount of lateral thermal damage that is likely from the computer-controlled incisions versus the manually controlled incisions. The temperature profiles are calculated from the absorption and scatter of light in a homogeneous material. The resulting temperature profiles are presented as videos showing how the tissue heats up and cools down with the incident laser pulses. The time-dependent thermal distributions indicate that the computer-controlled laser incision could show as little as 210 μm of lateral thermal damage, whereas the manually controlled laser incisions could show as much as 375 μm of lateral thermal damage. The computer-controlled laser incision is able to control laser pulses fast enough that subsequent pulses can ablate away tissue with a significant amount of residual heat from the previous laser pulse. Using the scatter-limited phototherapy techniques, we can see how a computer-controlled laser can make incisions with less thermal damage by ablating away tissue holding a significant amount of heat from the previous pulse before it has time to diffuse through the tissue. This method of heat removal from laser incisions has not been previously described or demonstrated.

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5 natural ways to reduce breast size

Breast tissue is largely made up of fatty materials. Losing body fat is one effective way to reduce breast size naturally. In this article, we look at five methods people can use to reduce breast size, or the appearance of breasts.

https://ift.tt/2BWCJJn

Utilizing serum bicarbonate instead of venous pH to transition from intravenous to subcutaneous insulin shortens the duration of insulin infusion in pediatric diabetic ketoacidosis

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Long-acting intramuscular ACTH stimulation test for the diagnosis of secondary adrenal insufficiency in children

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


https://ift.tt/2G5Vxu6

Fatty pancreas in relation to insulin resistance and metabolic syndrome in children with obesity

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy

Publication date: Available online 7 December 2018

Source: Journal of Autoimmunity

Author(s): M. Saeed Qureshi, Jawaher Alsughayyir, Manu Chhabra, Jason M. Ali, Martin J. Goddard, Chris Devine, Thomas M. Conlon, Michelle A. Linterman, Reza Motallebzadeh, Gavin J. Pettigrew

Abstract

The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection.

In a MHC class II-mismatched murine model of chronic humoral rejection, we report that effector antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T-cells transferred within heart allografts. Consequently, grafts were rejected more rapidly, and with markedly augmented autoantibody responses, upon transplantation of hearts from donors previously primed against recipient. Nevertheless, rejection was dependent upon recipient T follicular helper (T_FH) cell differentiation and provision of cognate (peptide-specific) help for maintenance as long-lived GC reactions, which diversified to encompass responses against vimentin autoantigen. Heart grafts transplanted into stable donor/recipient mixed haematopoietic chimeras, or from parental strain donors into F1 recipients (neither of which can trigger host adaptive alloimmune responses), nevertheless provoked GC autoimmunity and were rejected chronically, with rejection similarly dependent upon host T_FH cell differentiation.

Thus, autoantibody responses contribute independently of host adaptive alloimmunity to graft rejection, but require host T_FH cell differentiation to maintain long-lived GC responses. The demonstration that one population of helper CD4 T-cells initiates humoral autoimmunity, but that a second population of T_FH cells is required for its maintenance as a GC reaction, has important implications for how autoimmune-related phenomena manifest.

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Poorly Differentiated Thyroid Cancer in the Context of the Revised 2015 American Thyroid Association Guidelines and the Updated American Joint Committee on Cancer/Tumor‐Node‐Metastasis Staging System (Eighth Edition)

SUMMARY

Objective

Poorly differentiated thyroid cancer (PDTC) is a rare, but aggressive thyroid cancer (TC) and a main cause of death from non‐anaplastic follicular cell‐derived TC. Assessing the risk of PDTC‐related death and the risk of recurrence is important for clinicians. The recent American Thyroid Association (ATA) 2015 guidelines and the updated 8^th edition of the American Joint Committee on Cancer/Tumor‐Node‐Metastasis (AJCC/TNM) staging system should support clinicians in the management approach to PDTC patients.

Patients

Forty‐six consecutive PDTC patients treated in a single oncologic center, 2000‐2017.

Measurements

Retrospective analysis of TNM stage, initial risk, response‐to‐therapy categories, follow‐up, and final disease status incorporating the ATA 2015 criteria and the 8^th AJCC/TNM staging system. Disease‐specific survival (DSS) using the Kaplan‐Meier method.

Results

Of the 46 PDTC 21 (45.6%) were ATA high risk (HR), 22 (47.8%), 17 (37%) and seven (15.2%) were TNM stage I, II, and III–IV, respectively. During a median follow‐up of 55.5 months, two (4.3%) patients were recurrent, 18 (39.1%) died of PDTC. The 5‐/10‐year DSS were 65/57%, respectively. According to the AJCC/TNM, the 5‐/10‐year DSS of I, II, and III‐IV stage were 83/83%; 77/55%, and 0/0%, respectively. According to the 2015 ATA initial risk, the 5‐/10‐year DSS were 91/72% for ATA intermediate risk, and 38/38% for ATA HR patients.

Conclusions

In PDTC patients, the updated AJCC/TNM staging system accurately predicts a high risk of death in stage III–IV, whereas it seems to be inadequate for predicting a very low or low risk of death expected for differentiated TC in stage I–II. The ATA initial HR may be also used to predict a high risk of PDTC‐related death.

This article is protected by copyright. All rights reserved.

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The healing of dental extraction sockets in insulin dependent diabetic patients: a prospective controlled observational study

Abstract

Background

The aim of this study was to determine whether there was a difference in delayed healing following dental extractions for insulin‐dependent diabetics as compared to non‐diabetic patients.

Methods

Prospective patients referred to the Adelaide Dental Hospital exodontia clinic for dental extractions were recruited into two groups: Known insulin‐dependent diabetics and healthy non‐diabetics. All had a random blood glucose level (BGL). Delayed healing cases were identified, and statistical evaluation performed.

Results

There were 56 insulin‐dependent diabetic patients (BGL 10.03, range 4.9‐26) and 49 non‐diabetic, age and sex matched, patients. Seven patients (12.5%) in the study group showed delayed healing following extraction, while only four patients (8.2%) in the control group suffered delayed healing. This difference was not statistically significant. Two of the study group developed post extraction infections, requiring incision, drainage, and antibiotics.

Conclusion

The study shows that Type 1 and insulin‐dependent Type 2 diabetic patients, if well controlled, tend to heal up well following dental extractions but with a small but not statistically different rate of post extraction complications including infection. This is contrary to what is usually taught. Clinicians should take great care with management of insulin dependent diabetic patients, as compared to non‐insulin dependent diabetics or non‐diabetic patients.

This article is protected by copyright. All rights reserved.

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Orofacial neuralgia associated with a middle cerebral artery aneurysm

Abstract

Chronic orofacial pain of neuropathic origin can present diagnostic and management dilemmas to dental practitioners and also affect the patient's quality of life. Intracranial aneurysms are a potential cause of stroke, with associated sub‐arachnoid haemorrhage leading to high rates of mortality and morbidity. A patient who had been previously managed for symptoms of temporomandibular joint disorder (TMD) presented with sharp, shooting pain of moderate intensity. It was precipitated by swallowing, and radiated to the right throat, posterior border of the mandible, ear and temporomandibular joint. Clinical and radiological investigations excluded odontogenic pain, TMD and other more common causes of facial pain. Magnetic resonance imaging revealed a 7 mm × 6 mm aneurysm in the right middle cerebral artery which was subsequently surgically clipped. Interestingly the facial pain resolved after this procedure. Compression of the insular region of the brain innervated by the trigeminal, glossopharyngeal and vagus nerves provides a plausible explanation for the pain. This is the first case of facial neuralgia associated with an aneurysm in the middle cerebral artery as far as we are aware, and it emphasizes the importance of a multidisciplinary approach in the diagnosis and management of unusual cases of chronic orofacial pain.

This article is protected by copyright. All rights reserved.

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Temporally Feathered Radiation Therapy (TFRT) for Head and Neck Squamous Cell Carcinoma

Condition:   Head and Neck Cancer
Intervention:   Radiation: Temporally Feathered Radiation Therapy (TFRT)
Sponsor:   Case Comprehensive Cancer Center
Not yet recruiting

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Assement of the Morphological Characteristics of the Hips and Correlating Them With the Pathology Found

Conditions:   Ischiofemoral Impingement;   Hip Pain Chronic;   Musculoskeletal Disease;   Femoral Anteversion
Intervention:   Radiation: MRI
Sponsor:   Universidad de Zaragoza
Not yet recruiting

https://ift.tt/2B1QEMP

Cetuximab in Head and Neck Cancer Patients

Conditions:   Head and Neck Cancer;   Squamous Cell Carcinoma
Intervention:   Drug: Cetuximab
Sponsors:   University of Wisconsin, Madison;   National Cancer Institute (NCI);   National Institute of Dental and Craniofacial Research (NIDCR)
Not yet recruiting

https://ift.tt/2UmuFcc

Proximal Femoral Fractures - Patient Population, Risk Factors, Surgical Performance and Outcome

Condition:   Proximal Femoral Fracture
Interventions:   Procedure: surgery for pertrochanteric femoral fracture;   Procedure: surgery for femoral neck fracture
Sponsor:   University Hospital, Basel, Switzerland
Recruiting

https://ift.tt/2UmuwWc

Tabelecleucel in Combination With Pembrolizumab in Subjects With EBV+ Nasopharyngeal Carcinoma (ATA129-NPC-202)

Conditions:   Nasopharyngeal Carcinoma;   Nasopharyngeal Neoplasms;   Epstein-Barr Virus Infections;   Epstein-Barr Viraemia
Interventions:   Biological: tabelecleucel;   Biological: pembrolizumab
Sponsors:   Atara Biotherapeutics;   Merck Sharp & Dohme Corp.
Recruiting

https://ift.tt/2Upqr3p