Feasibility and safety of exercise during chemotherapy in people with gastrointestinal cancers: a pilot study.

PURPOSE: Sarcopenia is a poor prognostic factor in cancer patients, and exercise is one of the treatments to improve sarcopenia. However, there is currently insufficient evidence on whether exercise can improve sarcopenia in patients with advanced cancers. This study examined the feasibility of exercise in advanced gastrointestinal (GI) cancer patients treated with palliative chemotherapy. METHODS: Between 2020 and 2021, 30 patients were enrolled in a resistance and aerobic exercise program for six weeks. The exercise intervention program (EIP) consisted of low, moderate, and high intensity levels. Patients were asked to select the intensity level according to their ability. The primary endpoint was the feasibility of the EIP measured by compliance during the six weeks. A compliance of over 50% was considered acceptable. The secondary endpoints were changes in weight and muscle mass, safety, quality of life (QoL) and overall survival (OS). RESULTS: The median age of the study's participants was 60 (30-77). The total compliance to the EIP was 63.3% (19/30 patients). Sixteen (53.3%) patients had a compliance of over 80%. The attrition rate was 30.0% (9/30). The mean exercise time was 41.4 min, and the aerobic exercise was 92.3% and the resistant exercise was 73.7%, and both exercise was 66.5%. Most patients performed the moderate intensity level exercises at home or near their home. The mean skeletal muscle index (SMI) was 43.5 cm2/m2 pre-chemotherapy and 42.2 cm2/m2 after six weeks of chemotherapy, with a decrease of -1.2 ± 2.8 cm2/m2 (-3.0%) (p = 0.030). In the poor compliance group, the mean SMI decrease was -2.8 ± 3.0 cm2/m2 which was significantly different (p = 0.033); however, in the good compliance group, the mean SMI decrease was -0.5 ± 2.5 cm2/m2 which was maintained over the six weeks (p = 0.337). The good compliance group had a significantly longer median OS compared with the poor compliance group (25.3 months vs. 7.9 months, HR = 0.306, 95% CI = 0.120-0.784, p = 0.014). The QoL showed a better score for insomnia (p = 0.042). There were no serious adverse events. CONCLUSIONS: The EIP during palliative chemotherapy in advanced GI cancer patients showed good compliance. In the good compliance group, muscle mass and physical functions were maintained for six weeks. The EIP was safe, and the QoL was maintained. Based on this study, further research in exercise intervention in advanced cancer patients is needed. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is KCT 0005615 (CRIS, https://cris.nih.go.kr/cris/en/ ); registration date, 23rd Nov 2020.

A Multicenter, Prospective, Observational Study to Evaluate Ethanol-Induced Symptoms in Patients Receiving Docetaxel Chemotherapy.

PURPOSE: Several previous studies and case reports have reported ethanol-induced symptoms in patients receiving anticancer drugs containing ethanol. Most docetaxel formulations contain ethanol as a solvent. However, there are insufficient data on ethanol-induced symptoms when docetaxel-containing ethanol is administered. The primary purpose of this study was to investigate the frequency and pattern of ethanol-induced symptoms during and after docetaxel administration. The secondary purpose was to explore the risk factors for ethanol-induced symptoms. MATERIALS AND METHODS: This was a prospective, multicenter, observational study. The participants filled out ethanol-induced symptom questionnaire on the day of chemotherapy and the following day. RESULTS: Data from 451 patients were analyzed. The overall occurrence rate of ethanol-induced symptoms was 44.3% (200/451 patients). The occurrence rate of facial flushing was highest at 19.7% (89/451 patients), followed by nausea in 18.2% (82/451 patients), and dizziness in 17.5% (79/451 patients). Although infrequent, unsteady walking and impaired balance occurred in 4.2% and 3.3% of patients, respectively. Female sex, presence of underlying disease, younger age, docetaxel dose, and docetaxel-containing ethanol amount were significantly associated with the occurrence of ethanol-induced symptoms. CONCLUSION: The occurrence of ethanol-induced symptoms was not low in patients receiving docetaxel-containing ethanol. Physicians need to pay more attention to the occurrence of ethanol-induced symptoms and prescribe ethanol-free or low-ethanol-containing formulations to high-risk patients.

Tumor-Infiltrating Lymphocytes in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Neoadjuvant Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab.

PURPOSE: The tumor-infiltrating lymphocytes (TILs) expression in breast cancer is a positive prognostic marker for certain breast cancer subtypes. We evaluated the efficacy of dual anti-human epidermal growth factor receptor 2 (HER2) blockade in HER2-positive breast cancer and hypothesized that high TILs tumors are associated with better outcomes. METHODS: A total of 176 patients who were treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) between December 2015 and December 2018 were reviewed. They were grouped based on a cut-off value of the stromal TILs grade (≤ 20% TILs, > 20% TILs). RESULTS: In total, 107 patients (60.8%) achieved pathological complete response (pCR). Hormone receptor (HR)-negativity (p = 0.001) and a high TILs grade (p = 0.022) were independent predictors of pCR. Among the HR-negative patients, high TILs tumors were significantly associated with pCR (p = 0.035). CONCLUSION: HR status and the TILs grade are significantly correlated with pCR in dual anti-HER2 neoadjuvant therapy. The evaluation of the TILs at baseline may be beneficial for predicting pCR in HER2-positive breast cancer.

Superiority of Epstein-Barr Virus DNA in the Plasma Over Whole Blood for Prognostication of Extranodal NK/T Cell Lymphoma.

BACKGROUND: Extranodal natural killer T cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma with invariable infection of lymphoma cells with Epstein-Barr virus (EBV), and the presence of EBV-DNA in the blood is a well-known prognosticator. However, there is no consensus on which blood compartment is more optimal for predicting survival outcomes. METHODS: We analyzed 60 patients who were newly diagnosed with ENKTL from a prospectively collected database. EBV-DNA was measured in the whole-blood (WB) and plasma at the time of diagnosis and after treatment completion. RESULTS: EBV-DNA was detected in pre-treatment WB and plasma in 37 (61.7%) and 23 (38.3%) patients, respectively. The presence of pre-treatment plasma EBV-DNA was significantly associated with advanced stage while presence of WB EBV-DNA did not. Positivity of pre-treatment plasma-EBV, but not WB EBV-DNA, was independently associated with poor PFS (HR, 4.22;95% CI, 1.79-9.97; P=0.001) and OS (HR, 8.38; 95% CI, 3.03-23.19; P<0.001) in the multivariate analysis. After treatment completion, positivity of plasma-EBV was independently associated with poor PFS (HR, 9.41; 95% CI, 2.27-39.02; P=0.002) and OS (HR, 32.38; 95% CI, 3.25-322.56; P=0.003), whereas no significant association was observed between WB-EBV status and survival outcomes. CONCLUSIONS: Our results suggest that EBV-DNA in the plasma has better prognostic values than WB in patients with ENKTL.

Blockade of CCL2 expression overcomes intrinsic PD-1/PD-L1 inhibitor-resistance in transglutaminase 2-induced PD-L1 positive triple negative breast cancer.

Anti-PD-1/PD-L1 immunotherapy, as a treatment for many tumors, has shown good efficacy. However, responses to immunotherapy did not always occur or last long., i.e. primary or acquired resistance, even tumors were PD-L1 positive. Several oncogenic pathways, including PI3K/AKT activation by PTEN loss and NF-κB activation, induce PD-L1 expression and PD-L1 inhibitor-resistance. They also induce expression of CCL2, an inhibitory chemokine that blocks T cell tracking into the tumor by binding to CCR2 on the T cell surface. In this study, we showed that transglutaminase 2 (TG2), a post-translational modification enzyme, induced ubiquitin-proteasome dependent degradation of tumor suppressors including PTEN and IκBα by peptide cross-linking, inducing CCL2 as well as PD-L1 expression via PI3K/AKT and NF-κB activation. It also induced PD-L1 inhibitor-resistance because CCL2 was expressed despite increased PD-L1, which was blocked by PD-L1 inhibitor. We also revealed that inhibition of TG2, instead of PD-L1, restored T cell-dependent killing effect by blocking expression of both PD-L1 and CCL2 in PD-L1(+) triple negative breast cancer (TNBC) cells. In addition, the TG2-expressing TNBC patient group showed higher PD-L1 expression incidence than did the TG2-negative TNBC patient group. In conclusion, TG2 induces primary PD-1/PD-L1 inhibitor-resistance by inducing CCL2 expression. TG2 blockade can be utilized as an excellent therapeutic strategy to overcome PD-L1 inhibitor-resistance in PD-L1(+) TNBC patients. Our study suggested that PD-L1 expression alone might not always be a predictive biomarker for PD-L1(+) TNBC, but TG2 could be a useful predictive marker to select PD-L1 inhibitor-resistant TNBC patients.

The clinical outcomes of rituximab biosimilar CT-P10 (Truxima®) with CHOP as first-line treatment for patients with diffuse large B-cell lymphoma: real-world experience.

We evaluated real-world effectiveness and safety of CT-P10 (Truxima®) compared with originator rituximab in diffuse large B-cell lymphoma (DLBCL) treatment. Before and after the introduction of CT-P10 to our institute (November 2017), 221 newly-diagnosed DLBCL patients received rituximab with standard cyclophosphamide, vincristine, doxorubicin and prednisone. Patients received originator rituximab throughout (n = 95), switched from originator rituximab to CT-P10 (n = 36), or received CT-P10 throughout (n = 90). There were no significant differences between groups in overall response rate (91.6% vs 94.4% vs 96.7%, respectively; p = 0.403) or complete response rate (84.2% vs 77.8% vs 86.7%, respectively; p = 0.467). Kaplan-Meier survival curves also showed no significant differences in progression-free survival and overall survival between groups (log-rank p = 0.794 and p = 0.955, respectively). Safety profiles were comparable between treatment groups. These data support the ability of CT-P10 to successfully replace originator rituximab in DLBCL treatment and, given the lowered financial barrier, to improve the overall prognosis for DLBCL patients.

Transglutaminase 2 induces intrinsic EGFR-TKI resistance in NSCLC harboring EGFR sensitive mutations.

The non-small cell lung cancer (NSCLC) patients with EGFR-sensitive mutations can be therapeutically treated by EGFR-TKI such as erlotinib and gefitinib. However, about 40% of individuals harboring EGFR-TKI sensitive mutations are still resistant to EGFR-TKI. And, it has been reported that both PTEN loss and NF-κB activation contribute to intrinsic EGFR-TKI resistance in EGFR-mutant lung cancer. Transglutaminse 2 (TG2) is post-translational modification enzyme and known to induce degradation of tumor suppressors including PTEN and IκBα with peptide cross-linking activity. Because TG2 was known as a regulator of PTEN and IκBα (NF-κB inhibitor) level in cytosol, we have explored if TG2 can be another key regulator to the intrinsic resistance of EGFR-TKI in the intrinsic EGFR-TKI resistant NSCLC cell. We first found that higher TG2 expression level and lower PTEN and IκBα expression levels in the intrinsic EGFR-TKI resistant NSCLC compare with EGFR-TKI sensitive NSCLC. TG2 stably expressing EGFR-TKI sensitive NSCLC cells harboring EGFR mutations showed reduction of both PTEN and IκBα and exhibited EGFR-TKI resistance. In reverse, When TG2 is downregulated by TG2 inhibitor in H1650, intrinsic EGFR-TKI resistant NSCLC cell harboring EGFR sensitive mutation, reversed EGFR-TKI resistance via IκBα restoration. Moreover, combination treatment of TG2 inhibitor and EGFR-TKI decreased the tumor growth in mouse xenograft models of EGFR mutant NSCLCs. Therefore, we have demonstrated that TG2 elicits the intrinsic EGFR-TKI resistance via PTEN loss and activation of NF-κB pathway. These results suggest that TG2 may be a useful predictive marker and also be a target for overcoming the resistance.

A case report of recurrent Merkel cell carcinoma with synchronous metastases to the heart and stomach.

RATIONALE: Merkel cell carcinoma (MCC) is an aggressive, rare neuroendocrine skin cancer. MCC metastasis to the heart is exceedingly rare and gastric metastases from MCC have rarely been reported. PATIENT CONCERNS: We described the case of an 82-year-old man diagnosed with recurrent MCC with cardiac and gastric metastasis who presented with poor oral intake and severe weight loss. The patient was diagnosed with MCC 3 years ago and treated with surgical resection and radiation. INTERVENTIONS: We performed stomach biopsy in edematous lesion. And fluoroscopy and ultrasound guided biopsy of the cardiac mass was performed. DIAGNOSES: MCC with synchronous metastases to the heart and stomach. OUTCOMES: The primary lesion had complete resolution and the patient remained disease free on regular follow-up every 6 months for 2 and half years. After MCC recurred, palliative anti-cancer therapy was considered but could not be performed due to the patient's poor performance status involved elderly, combined recurrent pneumonia. LESSONS: To our best knowledge, this is the first report of synchronous cardiac and gastric metastasis from cutaneous MCC worldwide. Although uncommon, MCC should be considered in clinical cases of synchronous metastasis.

Choroidal and skin metastases from colorectal cancer.

Choroidal and skin metastasis of colon cancer is rare. In women, the frequency of cutaneous metastasis from colon cancer as the primary lesion in is 9% and skin metastasis occurs in 0.81% of all colorectal cancers. We report a patient with colonic adenocarcinoma who presented with visual disorder in her right eye and scalp pain as her initial symptoms. Contrast-enhance orbital magnetic resonance imaging with fat suppression revealed an infrabulbar mass, and skin biopsy of the posterior parietal scalp confirmed adenocarcinoma. These symptoms were diagnosed as being caused by choroidal and skin metastases of colonic adenocarcinoma. We started palliative chemotherapy with oral capecitabine (1000 mg/m2, twice a day, on days 1-14) every 3 wk, which was effective at shrinking the brain masses and improving the visual disorder. This is the first report that capecitabine is effective at reducing a choroidal and cutaneous metastatic lesion from right-sided colorectal cancer.