Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen

Subcutaneous (sc) rather than intravenous administration of bortezomib (Bor) is becoming more common for treating multiple myeloma (MM) because scBor results in lower incidence and severity of peripheral neuropathy and has equivalent efficacy. Bor is an irritant cytotoxic agent when it leaks out; therefore, it is recommended that injections of scBor should be rotated among eight different sites on the abdomen and thigh. However, detailed information about injection site reaction (ISR) has not been sufficiently documented. We retrospectively analyzed the incidence and severity of ISR following scBor administration in 15 Japanese patients with MM. Grade 1 ISR occurred following 40 of 158 (25.3%) scBor injections in ten patients, whereas grade 2 ISRs occurred following seven injections (4.4%) in five patients. Five patients did not develop ISR. Of note, grade 2 ISR was documented in 6 of 65 (9.2%) thigh injections but only in 1 of 93 (1.1%) abdominal injections. These data show that grade 2 ISRs were more common in the thigh compared with the abdomen possibly because the thigh contains lesser adipose tissue than the abdomen. Grade 2 ISRs resolved without any sequela within a median of 7 d. scBor administration on the abdomen instead of the thigh should be considered, especially for emaciated patients, because ISR rapidly resolves within the interval before the next injection even if it occurs.     

Early coagulation disorder after allogeneic stem cell transplantation is a strong prognostic factor for transplantation-related mortality, and intervention with recombinant human thrombomodulin improves the outcome: a single-center experience

We retrospectively analyzed 60 cases of pediatric patients who received allogeneic stem cell transplantation (SCT) between 2000 and 2008, using the tentative scoring system for evaluation of early (<30 days) coagulation disorders. In the 41 patients who survived, d-dimer levels showed a transient increase 2 weeks after SCT and normalized thereafter, but these levels were persistently elevated in the 19 patients who died. Of 19 patients with a positive score, 11 died of transplantation-related complications [transplantation-related mortality (TRM) = 0.579] within 1 year, while none of the 41 with a negative score died during the same period. Since 2009, 12 of 30 patients had positive scores within 30 days after SCT. Intervention with recombinant human thrombomodulin (rhTM) was introduced for patients with a positive score, and 10 of these patients survived (TRM = 0.167) along with a dramatic improvement of d-dimer level. Although the effects of this treatment were observed in a limited number of patients, our observations suggest that early coagulation disorder after allogeneic SCT is a strong prognostic factor for TRM, and that intervention with rhTM improves TRM.     

Right atrial volume and phasic function in pulmonary hypertension

Background

Few studies have focused on right atrial (RA) structure and function in pulmonary hypertension (PH). We sought to evaluate RA volume and phasic function using cardiac magnetic resonance (CMR), and to examine their clinical relevance in PH.

Methods

We prospectively studied 50 PH patients and 21 control subjects. RA volume and indices of phasic function (reservoir volume, ejection fraction [EF], and conduit volume) were evaluated by CMR.

Results

Maximum RA volume index was significantly higher in PH patients (56 [44–70] ml/m²) than in controls (40 [30–48] ml/m²) (p < 0.001). Reservoir volume index was significantly lower in PH than in controls (p < 0.001), but conduit volume index was higher in PH than in controls (p = 0.008). RA EF was similar when comparing the two groups (p = 0.925). Interestingly, RA EF was increased in PH patients with WHO functional class III patients as compared with controls (p < 0.001) but was reduced in advanced PH patients with WHO functional class IV (p < 0.01). Maximum RA volume and RA EF significantly correlated with pulmonary hemodynamic indices, atrial and brain natriuretic hormone levels, and CMR-derived right ventricular indices. By contrast, RA reservoir volume correlated with cardiac index and 6-minute walk distance.

Conclusions

PH is associated with increased size, decreased reservoir function, and increased conduit function of the right atrium. RA systolic function indicated by RA EF increases in patients with mild to moderate PH but decreases in patients with advanced PH. Varying associations between RA indices and conventional PH indices suggest their unique role in the management of PH.     

Phospholipase D1 and choline kinase-α are interactive targets in breast cancer

A consistent metabolic hallmark observed in multiple cancers is the increase of cellular phosphocholine (PC) and total choline-containing compounds (tCho), which is closely related to malignant transformation, invasion, and metastasis. Enzymes in choline phospholipid metabolism present attractive targets to exploit for treatment, but require a clear understanding of the mechanisms underlying the altered choline phospholipid metabolism observed in cancer. Choline kinase-α (Chk-α) is an enzyme in the Kennedy pathway that phosphorylates free choline (Cho) to PC, and its upregulation in several cancers is a major contributor to increased PC levels. Similarly, increased expression and activity of phospholipase D1 (PLD1), which converts phosphatidylcholine (PtdCho) to phosphatidic acid (PA) and Cho, has been well documented in gastric, ovarian and breast cancer. Here we report a strong correlation between expression of Chk-α and PLD1 with breast cancer malignancy. Data from patient samples established an association between estrogen receptor (ER) status and Chk-α and PLD1 expression. In addition, these two enzymes were found to be interactive. Downregulation of Chk-α with siRNA increased PLD1 expression, and downregulation of PLD1 increased Chk-α expression. Simultaneous silencing of PLD1 and Chk-α in MDA-MB-231 cells increased apoptosis as detected by the TUNEL assay. These data provide new insights into choline phospholipid metabolism of breast cancer, and support multiple targeting of enzymes in choline phospholipid metabolism as a strategy for treatment.     

Long-term outcomes of 3 surgical adjuvants used for internal limiting membrane peeling in idiopathic macular hole surgery

Purpose

Indocyanine green (ICG), an adjuvant used for peeling of the internal limiting membrane (ILM) during vitreous surgery for idiopathic macular hole (MH), has been reported to be toxic, possibly affecting postoperative visual acuity. We compared the long-term outcomes (within 2 years) of brilliant blue G (BBG), ICG, and triamcinolone acetonide (TA).

Patients and methods

This study involved 97 eyes of 94 patients who underwent vitreous surgery for MH at the Yamagata University Hospital between June 2002 and November 2010. The surgical adjuvants used were BBG for 15 eyes, ICG for 61 eyes, and TA for 21 eyes. We compared the postoperative visual acuities, initial closure rates, final closure rates, and complications of the 3 groups.

Results

In all 3 groups, the visual acuity significantly improved after surgery. The magnitude of the improvement at 2 years after surgery was significantly better in the BBG group than in the ICG group (Mann–Whitney test, P = 0.020). The postoperative visual acuity did not significantly differ between the BBG and TA groups (P = 0.627) or between the ICG and TA groups (P =0 .137). Thus, the surgery using BBG resulted in a significantly better outcome in visual acuity than did the surgery using ICG. The 3 groups did not differ in initial or final closure rates or in incidence of complications.

Conclusion

Analysis of the long-term outcomes of vitreous surgeries provided evidence that BBG is a useful adjuvant for ILM peeling.     

The Predictive Value for Pulmonary Infection by Area Over the Neutrophil Curve (D-index) in Patients Who Underwent Reduced Intensity Hematopoietic Stem Cell Transplantation

We evaluated the predictive value of the D-index for pulmonary infection in the early phase of reduced intensity stem cell transplantation (RIST). Out of 68 patients, ten patients developed a pulmonary infection within 100 days after RIST. Both the D-index and the cD-index were higher in the patients with pulmonary infection than in the control group (P?=?0.009, P?=?0.042, respectively). The best sensitivity and specificity, calculated with receiver operating characteristic curves, showed that the D-index was superior to the duration of neutropenia in predicting pulmonary infection. We also evaluated the utility of a cumulative D-index until 21 days after RIST (D21-index). The D21-index was higher in the patients with pulmonary infection (P?=?0.047). The cutoff value of the D21-index was lower than that of the D-index (8650 vs. 11000) with comparable sensitivity and specificity. Our results demonstrate that the D21-index, as well as the D-index, are useful tools for the prediction of pulmonary infection in RIST.     

Targeting DNA damage response in cancer therapy

Cancer chemotherapy and radiotherapy are designed to kill cancer cells mostly by inducing DNA damage. DNA damage is normally recognized and repaired by the intrinsic DNA damage response machinery. If the damaged lesions are successfully repaired, the cells will survive. In order to specifically and effectively kill cancer cells by therapies that induce DNA damage, it is important to take advantage of specific abnormalities in the DNA damage response machinery that are present in cancer cells but not in normal cells. Such properties of cancer cells can provide biomarkers or targets for sensitization. For example, defects or upregulation of the specific pathways that recognize or repair specific types of DNA damage can serve as biomarkers of favorable or poor response to therapies that induce such types of DNA damage. Inhibition of a DNA damage response pathway may enhance the therapeutic effects in combination with the DNA‐damaging agents. Moreover, it may also be useful as a monotherapy when it achieves synthetic lethality, in which inhibition of a complementary DNA damage response pathway selectively kills cancer cells that have a defect in a particular DNA repair pathway. The most striking application of this strategy is the treatment of cancers deficient in homologous recombination by poly(ADP‐ribose) polymerase inhibitors. In this review, we describe the impact of targeting the cancer‐specific aberrations in the DNA damage response by explaining how these treatment strategies are currently being evaluated in preclinical or clinical trials.