Cisplatin Combination Chemotherapy Research Articles

Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer.

Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion. A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning. We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia. Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p<0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p=0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p=0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p<0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58). Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

Prognosis of patients with residual pathological disease after neoadjuvant docetaxel, cisplatin, and 5-fluorouracil therapy and surgery for esophageal squamous cell carcinoma: a retrospective cohort study.

Docetaxel, cisplatin, and 5-fluorouracil (DCF) combination chemotherapy has been established as one of the standard neoadjuvant therapies for locally advanced esophageal squamous cell carcinoma (ESCC). However, little is known about prognostic factors in patients with residual pathological disease after neoadjuvant DCF followed by surgery for locally advanced ESCC who are candidates for adjuvant nivolumab. This study aimed to investigate prognostic factors in patients with residual pathological disease after neoadjuvant DCF chemotherapy followed by surgery for locally advanced ESCC. This was a retrospective cohort study. This retrospective cohort study included patients who received neoadjuvant DCF followed by surgery for locally advanced ESCC between June 2014 and January 2020 at the National Cancer Center Hospital East. Among a total of 210 patients, 45 patients (21.4%) achieved a pathological complete response. The 3-year disease-free survival (DFS) rate was significantly lower in patients with residual pathological disease than in those with a pathological complete response [53.5% versus 74.5%; hazard ratio (HR): 2.09, 95% confidence interval (CI): 1.16-3.77, p = 0.01]. In patients with residual pathological disease (n = 165), multivariate analysis revealed that pathological node positivity (HR: 3.59, 95% CI: 1.92-6.71, p < 0.01), supraclavicular lymph node metastasis (HR: 2.15, 95% CI: 1.19-3.90, p = 0.01), and lymphovascular invasion (HR: 1.90, 95% CI: 1.14-3.17, p = 0.02) were significantly associated with poor DFS. In this largest-to-date cohort study, patients with residual pathological disease after neoadjuvant DCF followed by surgery for locally advanced ESCC had a poor prognosis. In these patients, pathological node positivity, including supraclavicular lymph node metastasis, and lymphovascular invasion were considered significant prognostic factors.

ARID5B promoted the histone demethylation of SORBS2 and hampered the metastasis of ovarian cancer

Ovarian cancer (OVCA) is the 4th most common female tumor after breast cancer, cervical cancer, and endometrial cancer, and now is mainly treated with debulking surgery and postoperative cisplatin and paclitaxel-based combination chemotherapy regimens. However, OVCA is insidious in its development and recurrence occurred in some patients after treatment. It is of great significance to study the pathogenesis of ovarian cancer and identify more biomarkers. Recently, the role of histone methyltransferase (HMT) and histone demethylase (HDM) in oncogenesis and development of malignant tumors has raised attention. Unlike other JMJC demethylases that have both JMJC and ARID domains in a single molecule, PHF2 requires assembly into a complex with a DNA-binding subunit (ARID5B) and exerts its enzymatic activity. Therefore, the aim of this manuscript is to investigate the role of histone demethylases ARID5B-PHF2 complex in the metastasis of OVCA. As result, we found ARID5B and PHF2 are both low expressed in OVCA tumor tissues and cell lines and associated with diagnosis and prognosis. Also, ARID5B suppressed rearrangement of the cytoskeleton in the process of EMT in OVCA cell lines. The role of PHF2 as a tumor suppressor was also confirmed both in vivo and in vitro. SORBS2 is low expressed in OVCA tumor tissues and cell lines and associated with diagnosis and prognosis. The expression of SORBS2 is positively corelated with the expression of ARID5B and PHF2. The promoter of SORBS2 is proved combined with ARID5B. The expression of SORBS2 was increased due to ARID5B-PHF2 complex promoted the histone demethylation by mainly binding in site H3K36me2 and therefore promoting the transcription of SORBS2. In conclusion, ARID5B-PHF2 complex promoted the histone demethylation of SORBS2 by mainly bind in site H3K36me2 and therefore promote the transcription of SORBS2 then hampered the process of EMT and tumor generation of OVCA. These results provided a new perspective on the molecular mechanisms of OVCA development and offered a new target of clinical diagnose and treatment of OVCA.

Physical exercise in patients with testicular cancer treated with bleomycin, etoposide and cisplatin chemotherapy: pulmonary and vascular endothelial function—an exploratory analysis

PurposeBleomycin, etoposide, and cisplatin combination chemotherapy (BEP) improves the survival of patients with testicular cancer, but is associated with potentially life-threatening toxicities like pneumonitis and thromboembolic events. This study explored the effects of physical exercise in patients with testicular cancer during or after BEP-chemotherapy on pulmonary and vascular endothelial toxicity.MethodsIn this post hoc analysis of a multicenter randomized clinical trial (NCT01642680), patients with metastatic testicular cancer scheduled to receive BEP-chemotherapy were randomized to a 24-week exercise intervention, initiated during (group A) or after BEP-chemotherapy (group B). Endpoints were pulmonary function (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), lung transfer-coefficient and transfer factor for carbon monoxide (KCO, DLCO) and markers of vascular endothelial dysfunction (von Willebrand factor (vWF) and factor VIII).ResultsThirty patients were included. Post-chemotherapy, patients declined less in FVC, FEV1 and DLCO in group A compared to group B. Post-chemotherapy, vWF and factor VIII were significantly lower in group A compared to group B. After completion of exercise, started either during BEP-chemotherapy or thereafter, no between-group differences were found. At 1-year post-intervention, significant between-group differences were found in favour of group A in DLCO and KCO.ConclusionsPatients who exercised during BEP-chemotherapy better preserved FVC, FEV1 and DLCO, measured directly post-chemotherapy and 1-year post-intervention (DLCO, KCO). This coincided with less increase in vWF and factor VIII measured directly post-chemotherapy. These data support a beneficial role of a physical exercise intervention during BEP-chemotherapy on pulmonary and vascular damage in patients with testicular cancer.Trial registryOptimal Timing of Physical Activity in Cancer Treatment (ACT) Registry URL: https://clinicaltrials.gov/ct2/show/NCT01642680. Trial registration number: NCT01642680.

Revisiting targeted therapy and immunotherapy for advanced cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a rare and aggressive type of malignant tumor. In the past few years, there has been an increase in the incidence of CCA. Surgery is the only effective treatment but is only suitable for a small percentage of patients. Comprehensive treatment is the normal therapy for terminal CCA patients, depending basically on gemcitabine and cisplatin combination chemotherapy. In the past decade, the emergence of next-generation sequencing technology can be used for the identification of important molecular features of CCA, and several studies have demonstrated that different CCA subtypes have unique genetic aberrations. Targeting fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH) and epidermal growth factor receptor 2 (EGFR2) are emerging targeted therapies. In addition, researches have indicated that immunotherapy has a key function in CCA. There is ongoing research on programmed cell death protein 1 inhibitors (PD-1), chimeric antigen receptor T cells (CAR-T) and tumor-infiltrating leukocyte (TILs). Researches have shown that targeted therapy, immunotherapy, and conventional chemotherapy in CCA had certain mechanistic links, and the combination of those can greatly improve the prognosis of advanced CCA patients. This study aimed to review the research progress of targeted therapy and immunotherapy for CCA.

A More Biomimetic Cell Migration Assay with High Reliability and Its Applications.

Cell migration refers to the directional movement of cells to the surrounding cell-free zone in response to chemical and mechanical stimuli. A cell migration assay is an essential device for studying pharmaceutical and medical problems. In this paper, we present a novel approach to a cell migration assay on a chip with two merits, namely (i) simultaneous creation of many cell samples on the same condition and (ii) cells migrating while being stressed in a fluidic environment. The first merit has addressed the problem of poor reproducibility in experimental studies for medical problems such as wound healing, and the second merit has made the cell migration device, which is an in vitro environment, more biomimetic. The two merits are attributed to a novel mechanical method to simultaneously create many cell-free zones and to the design of a microfluidic process to create shear stress in cells uniformly. Two applications were studied on our device to explore its effectiveness. The first application is regarding the combination chemotherapy of cisplatin and doxorubicin (Adriamycin) on cervical cancer cells (HeLa). The second application is regarding inhibiting the migration of endothelial cells (HUVEC) in the process of anti-angiogenesis.

NEO-GAP: A phase II single-arm prospective feasibility study of neoadjuvant gemcitabine/cisplatin/nab-paclitaxel for resectable high-risk intrahepatic cholangiocarcinoma.

4097 Background: Given a high recurrence rate, surgical resection for localized intrahepatic cholangiocarcinoma (IHCC) is curative in only 30-35% of patients. BILCAP has established a standard of care for adjuvant therapy with monotherapy capecitabine. Gemcitabine, cisplatin and nab-paclitaxel combination chemotherapy (GAP) was associated with a response rate of 45% in biliary cancer and 20% of patients who were previously inoperable underwent margin negative resection. Based on these data, we conducted a neoadjuvant study of GAP for resectable but high-risk IHCC. Methods: A multi-institutional prospective single-arm phase II trial was conducted for patients with resectable high-risk disease, as defined by tumor size &gt; 5cm, multiple tumors, presence of radiographic major vascular invasion, and lymph node involvement. Patients were administered 4 cycles (3 months) of preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2 and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of all therapy, including both preoperative chemotherapy and resection. Secondary endpoints were toxicity, radiologic response according to Response Evaluation Criteria in Solid Tumor (RECIST) criteria, RFS, and OS. Thirty evaluable patients provided 73% power to reject a null therapy completion rate of 50%, with a target completion rate of 70% using a one-sided exact test with a Type I error of 0.05. Results: Thirty-seven patients were screened and 30 evaluable patients were enrolled. The trial was sequentially activated at each of the 4 sites from 09/18-02/21 and the final patient was enrolled in 09/21. Median age was 60.5 years and 40% were female. Twenty-three patients (77%, 90% CI: 60.6-88.5%; p = 0.0026) completed all preoperative chemotherapy and underwent surgical resection. Ten patients (33%) experienced grade 3-4 treatment-related adverse events, the most common being neutropenia and diarrhea; 47% required at least one dose reduction. Partial response rate was 23% and disease control rate was 90% (PD: 10%, PR: 23%, SD: 67%). Of the 23 patients who successfully underwent surgical resection, 2 (9%) had minor postoperative complications. Median size of largest tumor was 5.5cm, median number of tumors was 3, and 39% were lymph node positive. Median length of hospital stay was 4 days. There was zero treatment related mortality. Conclusions: This study met its primary endpoint and demonstrated that neoadjuvant gemcitabine/cisplatin/nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes. Continued follow-up for RFS and OS with this treatment strategy is underway and larger validation studies are planned. Clinical trial information: NCT03579771.

Intraperitoneal perforation through lymph node metastases in a patient with esophageal squamous cell carcinoma during intensive chemotherapy: A case report with literature review.

IntroductionEsophageal fistula after treatment is a critical and fatal complication of esophageal cancer. A fistula forming from lower thoracic esophageal cancer to the peritoneum through lymph node metastases following chemotherapy has not been reported. We report a case of peritonitis due to lymph node perforation through the tumor ulcer after induction of biweekly docetaxel, cisplatin, and 5FU combined chemotherapy (Bi-DCF) for advanced esophageal squamous cell carcinoma (ESCC).Presentation of caseA 48-year-old woman was referred to us with a diagnosis of lower thoracic ESCC and thoracoabdominal aortic aneurysm. Esophagogastroduodenoscopy showed a circumferential type 3 tumor with stenosis in the lower thoracic esophagus. Contrast-enhanced computed tomography (CT) showed a thoracoabdominal aortic aneurysm and wall thickening of the lower thoracic esophagus that was suspicious of esophageal cancer. Lymph node metastases dumpling from around the tumor to abdominal cavity were also observed. The initial diagnosis was ESCC T3 N3 M1 (para-aortic lymph nodes and liver) Stage IVB. She was started on Bi-DCF (docetaxel 35 mg/m2 days 1/15, cisplatin 40 mg/m2 days 1/15, 5FU 400 mg/m2 days 1–5, 15–19) as the first-line regimen. The third day after starting chemotherapy, she felt strong abdominal pain, and internal necrosis of lymph nodes around the primary lesion and free air in the abdominal cavity were found. Peritonitis was diagnosed due to a fistula formed from the lower thoracic ESCC to the peritoneum through lymph node metastases. She underwent emergency laparoscopic drainage, omental filling, and jejunostomy. Postoperatively, her general condition and inflammatory findings improved within 10 days, and she could continue intensive chemotherapy as scheduled.DiscussionBecause of the risk of perforation and fistula in regimens that are expected to cause tumor shrinkage, careful observation may be required after starting chemotherapy.ConclusionWe report the first case of peritonitis caused by perforation through lymph node metastasis of thoracic esophageal cancer.

Characterization of the nucleotide excision repair pathway and evaluation of compounds for overcoming the cisplatin resistance of non‑small cell lung cancer cell lines.

Lung cancer has been reported to be the leading cause of cancer‑related mortality worldwide. Cisplatin combination chemotherapy is a standard therapeutic strategy for patients with non‑small cell lung cancer (NSCLC) lacking driver mutations. However, the development of cisplatin resistance is a major obstacle to effective cancer treatment. The cellular mechanisms underlying cisplatin resistance have been previously revealed to be multifunctional. Accordingly, mechanistic analysis and the development of novel therapeutic strategies for cisplatin‑resistant NSCLC are urgently required. The present study mainly focused on the DNA repair mechanisms in cisplatin‑resistant NSCLC cells. Additionally, the effects of an Ecteinascidin (Et) derivative on cisplatin‑resistant cell lines were examined, by using a cisplatin‑resistant NSCLC cell line subjected to nucleotide excision repair (NER) pathway alterations. The results revealed that xeroderma pigmentosum group F‑complementing protein (XPF) mRNA expression was strongly associated with cisplatin resistance in cisplatin‑resistant NSCLC cell lines. XPF silencing significantly restored the sensitivity of cisplatin‑resistant PC‑14/CDDP cells to the drug. A potent anticancer effect of Et was observed in the cisplatin‑resistant cell line (PC‑14/CDDP), in which the NER pathway was altered. On the whole, these findings revealed that the expression levels of NER pathway‑related genes, including XPF, may have potential as biomarkers of cisplatin resistance. It was also suggested that Et may be a very promising compound for the development of novel anticancer drugs for the treatment of cisplatin‑resistant lung cancer.

YpN0 in Patients With Definitive cN-positive Status After Preoperative Treatment Is a Prognostic Factor in Esophageal Cancer

Histopathological tumor regression grade is applied not to lymph nodes but primary tumors modified by preoperative treatments. This study focused on patients whose pathological examination at the time of surgery showed no residual tumor after chemo(radio)therapy in the primary lesion (ypT0) or lymph nodes (ypN0). A total of 87 patients with clinical stage II/III thoracic esophageal cancer underwent esophagectomy following preoperative treatments to evaluate significances between pathological response and clinical outcomes; 51 patients with clinically definitive lymph node metastasis (cN+) were analyzed as a subgroup. ypT0 rates were 20.7% and 23.5%, and ypN0 rates were 47.1% and 27.5% in the whole cohort and in the cN+ subgroup, respectively. Disease-free survival, from surgery to relapse or death, was significantly influenced by ypN status (p=0.035) but not by ypT status in the 51 patients with definitive cN+ disease. Preoperative chemoradiation was an independent favorable factor for achievement of ypN0 in the 51 patients (odds ratio=0.09; p=0.007). ypN status was a predictive factor for DFS in patients treated with docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy, superior to ypT status, especially in patients with definitive cN+ disease.

Weekly Cisplatin vs. Triweekly Docetaxel Plus Cisplatin With Concurrent Chemoradiation in Post-Operative Treatment for Cervical Cancer With High-Risk Pathological Factors: A Randomized Controlled Phase III Trial From a Single Institution

After radical surgery, patients with high-risk factors were recommended adjuvant concurrent chemoradiation (CCRT). Cisplatin and cisplatin-based combination chemotherapy were the most common concurrent chemotherapy in previous studies. However, there are still few randomized controlled studies comparing which is better for survival. We conduct this prospective study to compare triweekly combination chemotherapy with weekly cisplatin chemoradiation in adjuvant radiation for cervical cancer patients with high-risk factors after radical surgery.Patients aged 18-70 years early-stage cervical cancer with high-risk pathological factors (adenocarcinoma/adenosquamous carcinoma, parametrial invasion, positive surgical margins, and lymph node metastasis) after radical hysterectomy were included and randomized 1:2 to the DDP group and DP group. The DDP group received chemotherapy with weekly cisplatin (40 mg/m2) of 5 cycles concurrent with radiation. The DP group received a triweekly regimen of cisplatin (75 mg/m2) plus docetaxel (75 mg/m2) of 4 cycles and the first cycle was initiated within 1-2weeks after surgery. Radiotherapy was started concurrently at the second cycle of chemotherapy in DP group. The primary end point was the rate of disease-free survival (DFS) at 5 years.A total of 268 patients were included in the analysis (91 in the DDP group, 177 in the DP group). The median follow-up period is 54 months (2-90m), and 2 cases were lost to follow-up. Baseline demographic and disease characteristics were balanced among the treatment groups. In the intention-to-treat population, 5-year DFS showed a better trend in DP group than DDP group, although there was no statistically significant difference (85.9% vs 78.0%; HR 1.64; 95% CI, 0.91-2.95, P = 0.096). There was no difference in 5-year OS, DMFS and LRFS between the groups (87.0%, 87.6% and 97.2% for DP group; 79.1%, 82.4% and 94.5% for DDP group, P = 0.127, 0.249 and 0.253, respectively). Distant metastasis was the major pattern of treatment failure and occurred in 37 patients (23 in DP group and 14 in DDP group). Lymph nodes (15/37), lung (9/37), liver (5/37), and bone (7/37) were the most common sites of metastasis. Forty-two patients died, of which 3 died from other causes (1 for cardiac, 1 for renal, and 1 for a second primary tumor). 142(80.2%) patients in DP group and 84(92.3%) patients in DDP group completed the treatment according to protocol. Toxic reactions are most common in hematology and intestinal tract. The incidence of severe acute hematological was significantly higher in the DP group than in the DDP group (47.6% vs 21.8%, P = 0.000), but there was no significant difference in severe intestinal reactions.Compared with weekly cisplatin, tri-weekly combined cisplatin plus docetaxel showed a tendency to improve survival in cervical cancer with pathological high-risk factors, but the difference was not statistically significant. Clinical trials.gov identifier NCT01999933.

Safety of same-day administration of gemcitabine plus cisplatin chemotherapy for urothelial carcinoma.

The present study aimed to examine the safety of a gemcitabine and cisplatin (GC) combination chemotherapy regimen with short hydration for the treatment of urothelial cancer administered on the same day (same day regimen). Patients with locally advanced or metastatic urothelial cancer received the same-day GC regimen with short hydration every 4 weeks, and their serum creatinine (Cr) level was measured to assess renal function using linear mixed model analysis. A total of 20 patients receiving the same-day regimen exhibited no significant change in their serum Cr level; nor was there any significant change in the serum Cr level between patients who received the same day regimen and those who received the drugs on different days. The present study demonstrated that the same-day regimen was safe for patients with urothelial cancer.

New combination chemotherapy of cisplatin with an electron-donating compound for treatment of multiple cancers

Cisplatin is the first and most widely used platinum-based chemotherapy drug and is the cornerstone agent in treating a broad spectrum of cancers. However, its clinical application is often limited by severe toxic side effects and drug resistance. Based on the discovered dissociative electron transfer mechanism of cisplatin, a novel combination of cisplatin with [9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene]-diethylammonium chloride (basic violet 10, BV10) is proposed to potentiate the chemotherapeutic effect of cisplatin. Here, we show that this combination enhances the anti-cancer effect of cisplatin in both in vitro cell lines and in vivo xenograft mouse models of cisplatin-sensitive and -resistant lung, ovarian and cervical cancers while introducing minimal additional toxic side effects. Furthermore, femtosecond time-resolved laser spectroscopic measurements demonstrate that cisplatin reacts with BV10 via an electron transfer mechanism. These results indicate that the combination of cisplatin with BV10 is promising for improving the chemotherapy of cancers with various extents of cisplatin resistance.

First person profile: George J. Bosl, MD: Former long-term chair of Memorial Sloan Kettering Cancer Center's Department of Medicine reflects on his multifaceted career.

First person profile: George J. Bosl, MD: Former long-term chair of Memorial Sloan Kettering Cancer Center's Department of Medicine reflects on his multifaceted career.

Lophira lanceolata protects testicular and spermatological damages induced by cisplatin in male Wistar rats

sBackgroundChemotherapy is associated with male infertility. Cisplatin (CP), an antineoplastic agent has been successfully used for the treatment of diverse kinds of malignancies, however, the use of this effective agent could induce oxidative stress injury, nephrotoxicity, hepatotoxicity, and testicular damage. Combined CP chemotherapy with plant extracts can diminish the toxicity and enhance the antitumor efficacy of the drug. The objective of the study was to determine the protective effect Lophira lanceolata leaf extract (LLLE) on CP-induced toxicity on male reproductive organs.MethodsThe study was carried out with 30 (n = 30) male Wistar rats (Rattus norvegicus). The rats were randomly assigned into 6 groups of 5 rats each. Rats in group 1 (Control) were administered distilled water per os. Rats in group 2 were administered 5 mg/kg of CP intraperitoneally (i.p). Rats in groups 3 and 4 were administered per os LLLE at the doses of 200 and 400 mg/kg body weight and rats in groups 5 and 6 were administered 5 mg/kg body weight of CP + LLLE at the doses of 200 and 400 mg/kg body weight respectively.ResultsThe results showed a significant decrease in the sperm parameters in the group treated with CP alone when compared with the control and there in the sperm parameters in the groups administered CP + LLLE. The body and organ weights of the rats were significantly (p < 0.05) decreased in the CP treated group relative to the control. However, there was an increase in the weight of the organs in the LLLE pretreated groups. The photomicrographs showed degenerative changes in the testicular tissues of the rats administered CP alone whereas the group pretreated with the LLLE showed amelioration induced by the CP. Our study revealed that CP treatment has deleterious effects on sperm parameters and testicular tissues and the accessory sex organs (Epididymis, prostate, seminal vesicles) of the rats. Oral administration of LLLE at 200 and 400 mg/kg bodyweight for 26 days conferred protective effects against testicular damage induced by CP.ConclusionThis study revealed that pretreatment with LLLE protected against CP-induced testicular toxicity.

422P Response rate and time to progression after first line chemotherapy with cisplatin and adriamycin in patients with metastatic osteosarcoma at presentation

Metastatic osteosarcoma at presentation forms 10 to 20% of total osteosarcomas diagnosed. They have a very poor prognosis compared to non-metastatic subset. Patients with resectable metastasis have a better DFS and OS compared to unresectable metastatic disease at presentation. This study was done to find the response rate to first line cisplatin and adriamycin combination chemotherapy to upfront metastatic osteosarcoma patients and time to progression after first line chemotherapy. Secondary objective was to find the overall survival. Patients diagnosed with osteosarcoma at madras medical college were identified from the database for a period of 5.5 years from January 2013 to June 2018. From that patients who had metastasis at presentation were further sorted out and taken for analysis. 77 patients were diagnosed to have osteosarcoma during the 5.5year period. Among them 36 patients had metastatic disease at presentation. 28 patients were male (77.8%) and 8 patients were female (22.2%). Median age of the patients was 19.5 years. 23 patients had ECOG PS 2 (63.9%) and 12 had ECOG PS 1 (33.3%) and 1 had ECOG PS 3 (2.8%). Tibia and femur were the most common primary site (75%). 5 patients had resectable lung metastasis and underwent pulmonary metastasectomy and were excluded from analysis and 1 patient was on palliative care only. Among remaining 30 patients, 27 patients had multiple lung metastasis (90%) and 3 patients had bone metastasis (10%). 30 patients received 6 cycles of chemotherapy with adriamycin 25mg/m2 on d1-d3 and cisplatin 100mg/m2 on d1 repeated every 21 days except 3 who progressed during chemotherapy. 17 patients (56.7%) had grade 1-2 vomiting. No one developed any acute cardiotoxicity. No treatment related death occurred. At the end of 6 cycles, 22 patients (73.3%) had partial response and 5 patients (16.7%) had stable disease and 3 patients (10%) had progressive disease. Median time to progression was 11.5 months. 2year OS was 73.3%. This platinum doublet is a reasonable option for these patients as most of them are young.

Long-term outcomes and safety of radical transmediastinal esophagectomy with preoperative docetaxel, cisplatin, and 5-fluorouracil combination chemotherapy for locally advanced squamous cell carcinoma of the thoracic esophagus

BackgroundIt is unknown whether transmediastinal esophagectomy (TME) is an acceptable surgical procedure for locally advanced esophageal squamous cell carcinoma (ESCC). Therefore, we investigated the feasibility of long-term survival after TME with neoadjuvant docetaxel, cisplatin, and 5-fluorouracil combination chemotherapy (DCF therapy).MethodsThis retrospective, observational study included locally advanced resectable ESCC. All patients received two cycles of preoperative DCF therapy (60 mg/m2 of docetaxel and cisplatin on day 1 and 700 mg/m2/day of 5-FU on days 1–5 in each cycle) followed by radical TME. The main outcomes were survival and the rate of adverse events of chemotherapy and surgery.ResultsSixteen patients were included in this study. All patients received two cycles of DCF therapy, followed by surgery. The median follow-up duration of the 16 patients was 35.4 months. The 2-year overall survival (OS) was 93.3% (95% confidence interval [CI], 61.3–99.0), and the 3-year OS was 78.8% (95% CI, 47.3–92.7). The 2-year and 3-year relapse-free survivals were both 73.3% (95% CI, 43.6–89.1). Leukopenia and neutropenia occurred in most patients; however, they were controllable. Fifteen patients completed TME, and one was converted to open transthoracic esophagectomy because of tracheal injury. Three-field dissection was performed for 12 of 16 patients (75%), and R0 resection was achieved in 15 of 16 patients (93.8%). Three cases of grade IIIb chylothorax were observed. There was no mortality in this study.ConclusionCombined neoadjuvant DCF and TME for locally advanced ESCC was safe and less invasive than traditional therapies and had a satisfactory long-term prognosis.

Risk Associated with Severe Hematological Toxicity in Patients with Urothelial Cancer Receiving Combination Chemotherapy of Gemcitabine and Cisplatin

Introduction: Combination chemotherapy of gemcitabine and cisplatin (GC) is the standard treatment for patients with urothelial cancer (UC). However, hematological toxicity is a major side effect of GC therapy in patients with UC. In particular, discontinuation of the GC therapy is associated to adverse events such as hematological toxicity. Some studies have reported general risk factors of hematological toxicity such as age. However, little is known about risk factors for GC therapy-associated hematological toxicity in patients with UC. Objective: We aimed to identify risk factors for hematological toxicity in patients with UC receiving GC therapy. Methods: We performed a retrospective evaluation of the data of 128 patients with UC who received GC therapy. The study end point was defined as the occurrence of grade 4 neutropenia and grade ≥3 thrombocytopenia. Logistic regression analysis was used to determine risk factors that were significantly associated with neutropenia and thrombocytopenia. Results: In total, 62 (48.4%) patients experienced grade 4 neutropenia, and 27 (21.1%) patients experienced grade ≥3 thrombocytopenia. In the multivariate analysis, performance status (PS) ≥1 (odds ratio [OR] 3.764, 95% confidence interval [CI] 1.410–10.047, p = 0.008) and neutrophil count (OR 0.648, 95% CI 0.468–0.898, p = 0.009) were significantly associated with grade 4 neutropenia. Platelet count (PLT) (OR 0.896, 95% CI 0.832–0.966, p = 0.004) and potassium (K) level (OR 6.966, 95% CI 1.313–36.989, p = 0.023) were also significantly associated with grade ≥3 thrombocytopenia. Conclusions: PS ≥ 1, neutrophil count, PLT, and K level were important risk factors for GC therapy-induced hematological toxicity in patients with UC. To continue GC therapy, further management systems by hematological toxicity risk factors for patients with UC will be required.

Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos‐related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin‐1 receptor (IL‐1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro‐inflammatory cytokine IL‐1β and the IL‐1R in MPM cells. Stimulation by IL‐1β promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor‐associated macrophages (TAMs) as the major source of IL‐1β in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos‐activated inflammasome in TAMs induced the production of IL‐1β, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL‐1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL‐1β/IL‐1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).

Evaluation of the Tolerability of Gemcitabine and Cisplatin Combination Chemotherapy with a Small Quantity of Replacement Fluid for Biliary Tract Cancer

Cisplatin therapy induces kidney injury as a side effect. Thus, replacement fluid must be administered to prevent kidney injury. In our hospital, we use a Gemcitabine and Cisplatin combination chemotherapy (GC) at a total volume of approximately 500 mL for biliary tract cancer. We investigated the safety of GC with a small amount of replacement fluid. As a result, no serious adverse events and renal injury occurred that required discontinuation of treatment. The median overall survival time was 260 d (95% confidence interval, 154-367 d). This study suggests that GC with a small amount of replacement fluid could be performed tolerability. But we need to be careful about choosing patients such as patients who can drink 1 L orally and patients who can be treated as outpatients.