Pneumonitis and concomitant bacterial pneumonia in patients receiving pembrolizumab treatment: Three case reports and literature review.

RATIONALE: Pembrolizumab, a monoclonal antibody against the programmed cell death 1 (PD-1) protein, can induce a stable regression of some malignancies refractory to conventional chemotherapy. Despite such therapeutic benefits, pembrolizumab can induce immune-related adverse events, with pneumonitis being the most critical problem. PATIENT CONCERNS: All 3 patients complained of fever, cough, and dyspnea after a variable time interval (1-21 days) from pembrolizumab treatment. DIAGNOSES: Chest computed tomography invariably showed ground glass opacity. All tests for possible infectious agents were negative. Based on high procalcitonin level, one of 3 patients was diagnosed to have accompanying bacterial pneumonia. INTERVENTIONS: All patients received antibiotics and steroid treatments (methylprednisolone, 1 mg/kg). OUTCOMES: The 3 patients showed different clinical courses ranging from mild pneumonitis to rapidly progressing respiratory failure. Among the 3 patients, 2 fully recovered with steroid treatment; 1 died from superimposed bacterial pneumonia. LESSONS: The prognosis of pembrolizumab-induced pneumonitis with a superimposed bacterial pneumonia would be poor. It is important to distinguish pure pneumonitis from that with a superimposed bacterial pneumonia.

Serum level of CXCL10 is associated with inflammatory prognostic biomarkers in patients with diffuse large B-cell lymphoma.

Inflammatory biomarkers, such as the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and Glasgow Prognostic Score (GPS) have been proposed to predict prognosis in diffuse large B-cell lymphoma (DLBCL). C-X-C motif ligand 10 (CXCL10) is a chemokine released from inflammatory cells in the tumor microenvironment and is known to promote tumor cell migration and invasion. In this study, we investigated the clinical impact of pretreatment serum level of CXCL10 on the prognostic value of inflammatory biomarkers in 313 patients with DLBCL who were enrolled into a prospective cohort study. Serum level of CXCL10 was measured in archived pretreatment frozen samples. The high CXCL10 (>median value) group was significantly associated with high tumor burden status, including advanced stage (III-IV), elevated serum lactic dehydrogenase, and a higher risk International Prognostic Index. Progression-free survival of the high CXCL10 group was significantly worse than that of the low CXCL10 group, and secondary central nervous system involvement was more frequent in the high CXCL10 group. High CXCL10 was associated with high C-reactive protein level (r = 0.246), low albumin level (r = -0.289), low absolute lymphocyte count (r = -0.185), and risk stratification according to NLR, LMR, and GPS. C-X-C motif ligand 10 promoted cell migration of patient-derived cells and several DLBCL cell lines. However, the prognostic value of high CXCL10 was lost in the multivariate analyses. Nevertheless, we suggest serum CXCL10 may have clinical value if it can be more easily assessed because of its contribution to the prognostic value of NLR, LMR, and GPS in DLBCL.

Correlation of genetic polymorphisms with clinical outcomes in pemetrexed-treated advanced lung adenocarcinoma patients.

AIM: Pemetrexed is a commonly used chemotherapeutic agent for lung adenocarcinoma patients. We investigated the impact of the genetic polymorphisms on the therapeutic efficacy of pemetrexed in lung adenocarcinoma patients. MATERIALS & METHODS: We performed genotying of 51 polymorphisms of 13 genes in 243 lung adenocarcinoma patients treated with pemetrexed as a single agent for second or more line of therapy. RESULTS: Total 12 polymorphisms in six genes were showed statistical significances in univariate analysis. After a false-discovery rate correction, the associations between GGH rs16930092 (p = 0.034) and rs10464903 (p = 0.034), and progression-free survival (PFS) were still conserved. Two polymorphisms in ATIC and GGH genes were associated with therapeutic efficacy in multivariate analysis: ATIC rs12995526 for tumor response (p = 0.014) and for overall survival (p = 0.006), and GGH rs16930092 (p = 0.009) for PFS. CONCLUSION: This study shows that polymorphisms on genes related to the metabolic pathway of pemetrexed, especially, ATIC and GGH genes, would have a therapeutic implication in pemetrexed-treated patients with lung adenocarcinoma. Original submitted 10 May 2013; Revision submitted 27 June 2014.

Impact of dose modification on intravenous bortezomib-induced peripheral neuropathy in multiple myeloma patients.

PURPOSE: Patients discontinue bortezomib treatment despite good response to the therapy because of bortezomib-induced neuropathy. Early and active dose reduction is recommended for efficacy of treatment. This study evaluates patterns of bortezomib-associated neuropathy and examines the effectiveness of dose modification on symptom management and treatment compliance. METHODS: This is a retrospective cohort study of multiple myeloma patients who received bortezomib intravenously from 2009 to 2012 at Samsung Medical Center, Seoul, Korea. Peripheral neuropathy was assessed using neurotoxicity subscale of the FACT/GOG-Ntx at daily clinical practice; physicians modified the dosage and schedule of bortezomib treatment. Mixed-effect models were used for evaluating changes of neuropathy symptoms over time. Linear spline models and multivariate logistic regression were used for testing the effectiveness of interventions. RESULTS: There were 1,060 visits of 55 multiple myeloma patients during the study period. Patients were most likely to have numbness of feet, painful burning in feet, muscle weakness, and the symptoms worsened over time (P < 0.05). For patients who received intervention (n = 32, 58.1 %), neuropathy symptoms were significantly decreased after the intervention (coefficient, -0.1 (95 % confidence interval (CI), -0.8, 0.6)). The intervention group had on average 5.19 (95 % CI, 3.79, 6.59) more bortezomib administrations and was 1.4 times more likely to complete the treatment (odds ratio, 1.40 (95 % CI, 0.31, 6.32)) than the nonintervention group. CONCLUSION: Close monitoring of peripheral neuropathy in patients receiving bortezomib is a feasible and useful way to manage neuropathy in the real world.

A retrospective comparison of adjuvant chemotherapeutic regimens for non-small cell lung cancer (NSCLC): paclitaxel plus carboplatin versus vinorelbine plus cisplatin.

BACKGROUND: Adjuvant chemotherapy with vinorelbine plus cisplatin (NP) has been demonstrated to increase overall survival in patients with stage II or IIIA non-small cell lung cancer (NSCLC). Although paclitaxel plus carboplatin (PC) failed to demonstrate efficacy in patients with stage IB NSCLC, an exploratory analysis suggested that patients with large tumors can benefit from adjuvant PC therapy. METHODS: Clinical outcomes of patients who received adjuvant NP or PC regimens after complete resection for their NSCLC were retrospectively compared. RESULTS: Of the 438 patients with completely resected NSCLC, 207 received PC and 231 patients received NP. The median relapse-free survival (RFS) was not significantly different, with 63.6 months for the PC group and 54.8 months for the NP group (P=.68). Overall survival also did not differ significantly between the two groups. The five-year overall survival rates were 73% (95% confidence interval (CI), 66-80%) in PC group and 71% (95% CI, 64-78%) in NP group (P=.71). In the subgroup analysis, RFS was comparable between the two groups across all variables. Analysis of the adverse events indicated that sensory neuropathy, alopecia, and myalgia are more frequent in the PC, while anemia, neutropenia, fatigue, anorexia, and vomiting are more common in the NP. CONCLUSION: Although the adverse event profiles were different, the efficacy was comparable between the PC and NP regimens as adjuvant chemotherapy for NSCLC. While there is lack of prospective data, our retrospective data suggest that PC regimen can be considered as adjuvant chemotherapy for resected NSCLC.

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation.

PURPOSE: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined. METHODS: We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR. RESULTS: Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4 %). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n = 6) or erlotinib (n = 6). The most common mutation was exon 19 deletion (n = 7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75 %, respectively. The median PFS was 3.67 months (95 % CI: 1.34-5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53 months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83 months) who were treated with EGFR TKIs. CONCLUSIONS: The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.

The impact of baseline and interim PET/CT parameters on clinical outcome in patients with diffuse large B cell lymphoma.

Taking a step forward from the IPI, attention is focused on the role of 18F-FDG PET/CT as a tool for guidance in risk stratification in patients with aggressive non-Hodgkin's lymphoma (NHL). Here, we analyzed the predictive value of various PET/CT parameters in patients with DLBCL. Particularly, we were interested in patients with an IPI score of 1, 2, or 3, whose prognosis are confusing. Between Jul 2008 and Feb 2010, a total of 100 patients (including 57 patients with an IPI score of 1-3) who were treated with R-CHOP for DLBCL, and had assessable PET/CT parameters were analyzed in this study. Absolute value of SUVmax, SUVsum(sum of SUVmax) and TLGsum(SUVmean x Volumemeta) from baseline and interim PET/CT, and ΔSUVsum, ΔSUVmax, and ΔTLGsum between baseline and interim PET/CT were selected as PET/CT parameters. The median number of R-CHOP cycles was 6, and interim PET/CT was performed after 2 or 3 cycles. None of the parameters which showed percentile change between initial and interim PET/CT were associated with prognosis. Instead, absolute value of SUVsum from baseline PET/CT, and SUVmax and SUVsum from interim PET/CT were significantly relevant to PFS in all patients, and in patients with an IPI score of 1­3.

Implications of different CA 15-3 levels according to breast cancer subtype at initial diagnosis of recurrent or metastatic breast cancer.

BACKGROUND: CA 15-3 is derived from proteolytic shedding of the extracellular domain of mucin 1 (MUC1) glycoprotein. Luminal subtype breast cancer shows a higher expression in MUC1 genes, and a positive relationship between MUC1 expression and estrogen receptor (ER) expression has been reported. In this study, we attempted to determine the difference of CA 15-3 level according to the subtype of breast cancer. METHODS: From January 2000 to December 2009, a total of 707 patients who were diagnosed with metastatic or recurrent breast cancer at Samsung Medical Center were included in this study. Among these, 536 patients with available clinical data including pretreatment CA 15-3 and immunohistochemistry for ER, progesterone receptor (PgR) and hormone receptor 2 (HER2) were analyzed in this study. Patients were classified into 3 groups according to their receptor status: ER-positive (ER+) and/or PgR+ irrespective of HER2 (HR+), ER-/PgR-/HER2+ (HER2-enriched) and ER-/PgR-/HER2- (triple negative, TN). RESULTS: The supranormal values of CA 15-3 were frequently observed in HR+ breast cancer compared to other types (45.6% for HR+, 24.4% for HER2-enriched and 28.8% for TN; p < 0.001). The increase of marker levels differed significantly among the 3 groups (24 U/ml for HR+, 13 U/ml for HER2-enriched and 18 U/ml for TN; p < 0.001). CONCLUSIONS: The increase of both marker levels and the frequency of supranormal values of CA 15-3 were more frequently observed in HR+ breast cancer, which is positively associated with MUC1 expression. These results could potentially serve as a basis for expanding the clinical implications of CA 15-3 in the field of clinical trials for novel targeted therapies in breast cancer.

Impact of previous invasive pulmonary aspergillosis on the outcome of allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is one of the major complications encountered by patients receiving chemotherapy for hematologic malignancies. The prolonged period of intense immunosuppression following allogeneic hematopoietic stem cell transplantation (HSCT) may increase the risk of IPA recurrence in patients with a history of IPA. We evaluated the impact of a history of IPA on allogeneic HSCT outcome, and examined the incidence of IPA after HSCT. METHODS: This retrospective study included 22 patients with a history of IPA prior to receiving allogeneic HSCT at the Samsung Medical Center from 1995 to 2007. Diagnosis of IPA was defined as proven (N=5), probable (N=0), or possible (N=17). RESULTS: All 22 patients received amphotericin-based regimens to treat pre-transplant IPA. Secondary antifungal prophylaxis was administered to 10 patients during HSCT. The development of post-transplant IPA was observed in 2 patients. One of the patients died from septic shock within 2 days of the diagnosis of possible IPA. The other patient recovered from IPA, but eventually had a relapse of the primary disease. Of the 22 patients, the overall 2-year survival rate was 63% (95% confidence interval [CI]: 41-85), and the transplant-related mortality rate was 19% (95% CI: 0-38). CONCLUSION: Our results suggest that a history of IPA prior to HSCT does not have an adverse impact on transplant outcomes, although the small number of cases was a limitation in this study. Future studies involving a larger number of cases are needed to further examine this issue.