Family experience with palliative sedation therapy for terminally ill cancer patients

Symptomatic sedation is often required in terminally ill cancer patients, and could cause significant distress to their family. The aims of this study were to clarify the family experience during palliative sedation therapy, including their satisfaction and distress levels, and the determinants of family dissatisfaction and high-level distress. A multicenter questionnaire survey assessed 280 bereaved families of cancer patients who received sedation in 7 palliative care units in Japan. A total of 185 responses were analyzed (response rate, 73%). The families reported that 69% of the patients were considerably or very distressed before sedation. Fifty-five percent of the patients expressed an explicit wish for sedation, and 89% of families were clearly informed. Overall, 78% of the families were satisfied with the treatment, whereas 25% expressed a high level of emotional distress. The independent determinants of low levels of family satisfaction were: poor symptom palliation after sedation, insufficient information-giving, concerns that sedation might shorten the patient's life, and feelings that there might be other ways to achieve symptom relief. The independent determinants of high levels of family distress were: poor symptom palliation after sedation, feeling the burden of responsibility for the decision, feeling unprepared for changes in the patient's condition, feeling that the physicians and nurses were not sufficiently compassionate, and shorter interval to patient death. Palliative sedation therapy was principally performed to relieve severe suffering based on family and patient consent. Although the majority of families were comfortable with this practice, clinicians should minimize family distress by regular monitoring of patient distress and timely modification of sedation protocols, providing sufficient information, sharing the responsibility of the decision, facilitating grief, and providing emotional support.     

SARCOMATOUS VARIANT OF MALIGNANT HISTIOCYTOSIS; A CASE REPORT and REVIEW OF THE LITERATURE

The case is that of a 21-year-old female with mediastinal and subcutaneous, tumors composed of sarcomatous growth of poorly differentiated histiocytes defined by enzyme histochemical staining, ultrastructural observation and detection of surface markers. At autopsy neoplastic cells in the solid tumor became less cohesive and pleomorphic with erythrophagia, while features in the lymph node draining from the tumor was compatible with the criteria of malignant histiocytosis. The place where such a sarcomatous variant of malignant histiocytosis should be placed within other histiocytic tumors is discussed and the literature reviewed.     

A treatment for pulmonary metastases from colorectal cancer by pre-operative CPT-11/5'-DFUR combination therapy

There is no standardized consensus at each institution about a treatment for pulmonary metastases from colorectal cancer. A case of pulmonary radical resection can expect a good result. However, a result of a nonoperative case is extremely poor. A focal control until the time of operation to a metastatic lesion is very important. We want to have a safe and effective chemotherapy. We experienced a resectable case by CPT-11/5'-DFUR combination therapy.     

Efficacy of 5-FU hepatic arterial infusion with l-leucovorin for patients with unresectable colorectal liver metastasis

We investigated the efficacy of 5-FU hepatic artery infusion (HAI)for patients with unresectable colorectal liver metastasis. Fifteen patients who received HAI between June 2004 and December 2006 were studied. HAI was attempted as first-line chemotherapy in seven patients(Group A)and as second-line or more in eight(Group B). The response rate, time to progression, survival and toxicity were compared with those of 39 patients treated with systemic chemotherapy(18 as first-line: Group C, 21 as second-line or more: Group D). Response rate was 85.7%, 35.7%, 50.0%, and 4.8% in Groups A, B, C, and D, respectively. Time to progression was 12.5 months, 4.7 months, 5.8 months, and 2.3 months, in Groups A, B, C, and D, respectively, and significantly longer in Group A compared with Group C, as well as in Group B compared with Group D. Median survival was 15.4 months, 9.1 months, 11.3 months, and 8.0 months in Groups A, B, C, and D, respectively, and significantly longer in Group B compared with Group D. Grade 3 or 4 non-hematological toxicity was not observed in Group A and B. HAI was effective for the control of unresectable colorectal liver metastasis and improved survival as second-line chemotherapy or more.     

Regulation of angiogenesis and angiogenic factors by cardiovascular medications

Coronary artery disease (CAD) is the most important cause of death in the industrialized world. After experimental myocardial infarction, numerous dilated vessels appear in the border zone between the infarct and noninfarct areas. Angiogenic therapy has been widely regarded as an attractive approach for both treating CAD and enhancing arterioprotective functions of the endothelium. In this report, we critically review the evidence supporting the regulation of angiogenesis and angiogenic factors by cardiovascular medications such as statins, cholesterol ester transfer protein inhibitor, angiotensin II type 1 receptor blocker, angiotensin-converting enzyme inhibitor and calcium channel blocker, etc. Furthermore, in patients with CAD, vascular growth (vasculogenesis), capillary network growth (angiogenesis) and collateral artery growth (arteriogenesis), may be important. Current evidence from clinical trials on these therapies suggests that the development of coronary collateral circulation is likely to be a viable therapeutic strategy for CAD, while adaptation to chronic coronary stenosis can proceed. Many studies have suggested that newly developed strategies which include the administration of angiogenic growth factors and the transplantation of bone marrow-derived angioblasts are beneficial for the ischemic heart. Our assessment of the evidence in this review leads us to conclude that the development of collateral circulation using conventional cardiovascular medications may also play a critical role and needs to be reconsidered in the treatment of patients with CAD.     

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.     

Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death

Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the proband's maternal aunt revealed endocardial and subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor-acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death.