Adjuvant chemotherapy for gastric cancer:Current evidence and future challenges

Gastric cancer still represents one of the major causes of cancer mortality worldwide.Patients survival is mainly related to stage,with a high proportion of patients with metastatic disease at presentation.Thus,the cure rate largely depend upon surgical resection.Despite the additional,albeit small,benefit of adjuvant chemotherapy has been clearly demonstrated,no general consensus has been reached on the best treatment option.Moreover,the narrow therapeutic index of adjuvant chemotherapy(i.e.,limited survival benefit with considerable toxicity)requires a careful assessment of expected risks and benefits for individual patients.Treatment choices vary widely based on the different geographic areas,with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States.In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses.The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery;the same Authors also showed that disease free survival may be used as a surrogate end-point for overall survival.We finally discuss future research issues such as the need of economic evaluations,development of prognostic or predictive biomarkers,and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment.

Is endoscopic ultrasound examination necessary in the management of esophageal cancer?

Despite substantial efforts at early diagnosis, accurate staging and advanced treatments, esophageal cancer(EC) continues to be an ominous disease worldwide. Risk factors for esophageal carcinomas include obesity, gastroesophageal reflux disease, hard-alcohol use and tobacco smoking. Five-year survival rates have improved from 5% to 20% since the 1970 s, the result of advances in diagnostic staging and treatment. As the most sensitive test for locoregional staging of EC, endoscopic ultrasound(EUS) influences the development of an optimal oncologic treatment plan for a significant minority of patients with early cancers, which appropriately balances the risks and benefits of surgery, chemotherapy and radiation. EUS is costly, and may not be available at all centers. Thus, the yield of EUS needs to be thoughtfully considered for each patient. Localized intramucosal cancers occasionally require endoscopic resection(ER) for histologic staging or treatment; EUS evaluation may detect suspicious lymph nodes prior to exposing the patient to the risks of ER. Although positron emission tomography(PET) has been increasingly utilized in staging EC, it may be unnecessary for clinical staging of early, localized EC and carries the risk of false-positive metastasis(over staging). In EC patients with evidence of advanced disease, EUS or PET may be used to define the radiotherapy field. Multimodality staging with EUS, crosssectional imaging and histopathologic analysis of ER, remains the standard-of-care in the evaluation of early esophageal cancers. Herein, published data regarding use of EUS for intramucosal, local, regional and metastatic esophageal cancers are reviewed. An algorithm to illustrate the current use of EUS at The University of Texas MD Anderson Cancer Center is presented.

Impact of Oxaliplatin-Induced Neuropathy on Subsequent Paclitaxel for Advanced Gastric Cancer

Purpose: Several studies have shown that fluoropyrimidine plus oxaliplatin (SOX) is non-inferior to fluoropyrimidine plus cisplatin as first-line chemotherapy for advanced gastric cancer. We investigated retrospectively the choice of second-line regimen, along with the proportion and feasibility of paclitaxel-containing regimen, in the subsequent treatment of patients with advanced gastric cancer treated with SOX as first-line chemotherapy. Materials and Methods: We retrospectively analyzed the impact of oxaliplatin-induced neuropathy on both the choice of subsequent regimens and feasibility of subsequent chemotherapy with paclitaxel, focusing on patients with advanced gastric cancer who received S-1 plus oxaliplatin as first-line chemotherapy. Results: Twenty-seven from a total of 31 patients enrolled into the phase 2 and phase 3 study assessing S-1 plus oxaliplatin were analyzed (4 patients were deemed ineligible). Among 24 patients that had received second-line treatment, paclitaxel was not selected in 2 patients due to oxaliplatin-induced neuropathy. Paclitaxel was selected as second-line chemotherapy in 16 patients, as third-line chemotherapy in 6 patients and fourth-line chemotherapy in one patient. Severity of sensory neuropathy was grade 0/1/2/3 in 11/10/2/0 patients, respectively, immediately before treatment with paclitaxel, while the worst toxicity profile during paclitaxel treatment was grade 0/1/2/3 in 7/13/1/2 patients, respectively. Although there were no patients requiring dose reductions of paclitaxel due to neuropathy, 2 patients discontinued paclitaxel use due to grade 3 sensory neuropathy after 4 or 8 administrations of paclitaxel. Conclusion: Oxaliplatin-induced neuropathy during first-line chemotherapy may affect the choice and feasibility of subsequent chemotherapy with paclitaxel in advanced gastric cancer patients.

Squamous cell carcinoma of the scrotum: A look beyond the chimneystacks

Despite the low incidence, squamous cell carcinoma(SCC) remains the most common scrotal malignancy featuring a propensity for recurrence and metastasis. In recent years there has been a significant change in the epidemiology of scrotal SCC. Surgery is the mainstay of treatment for resectable disease. Sentinel lymph node dissection similar to algorithm for patients with penile SCC can reduce the morbidity of routine lymph node dissection. Emerging treatments for advanced and metastatic SCC are at the cusp of significantly changing management of this disease. We have performed a comprehensive review of scrotal SCC with a focus on these topics.

Biosimilars in Brazil: The Beginning of an Era of Broader Access

Cancer is a major public health issue worldwide, especially in the developing world where 70% of the cancer-related deaths occur. During the last three decades, with the advent of targeted therapies using monoclonal antibodies, patients’ survival and quality of life have dramatically improved. Unfortunately, these great accomplishments came at the expense of high financial costs which most of the population living in low-and middle-income countries cannot afford. Biosimilars (biotherapeutic products that are similar to an already licensed reference biotherapeutic product in terms of quality, safety and efficacy) have been successfully used in Europe and in US with a substantial reduction in price of around 30%. Brazil is about to have trastuzumab as the first biosimilar available to treat cancer patients in the country. Based on strict regulatory legislations, biosimilars are expected to deliver affordable yet effective and safe treatment options all over the world, expanding the access to cancer treatment and reducing inequalities.

Study protocol of the Asian XELIRI ProjecT(AXEPT):a multinational,randomized,non-inferiority,phase Ⅲ trial of second-line chemotherapy for metastatic colorectal cancer, comparing the eicacy and safety of XELIRI with or without bevacizumab versus FOLFIRI w

Background: Capecitabine and irinotecan combination therapy(XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer(m CRC). Recently, in the Association of Medical Oncology of the German Cancer Society(AIO) 0604 trial, tri?weekly XELIRI plus bevacizumab, with reduced doses of irinotecan(200 mg/m^2 on day 1) and capecitabine(1600 mg/m^2 on days 1–14), repeated every 3 weeks, has shown favorable tolerability and eicacy which were comparable to those of capecitabine and oxaliplatin(XELOX) plus bevacizumab. The doses of capecit?abine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab(BIX) as second?line chemotherapy was well tolerated and had promising eicacy in Japanese patients.Methods: The Asian XELIRI Projec T(AXEPT) is an East Asian collaborative, open?labelled, randomized, phase Ⅲ clinical trial which was designed to demonstrate the non?inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI(5?fluorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second?line chemo?therapy for patients with m CRC. Patients with 20 years of age or older, histologically conirmed m CRC, Eastern Coop?erative Oncology Group performance status 0–2, adequate organ function, and disease progression or intolerance of the irst?line regimen will be eligible. Patients will be randomized(1:1) to receive standard FOLFIRI with or with?out bevacizumab(5 mg/kg on day 1), repeated every 2 weeks(FOLIRI arm) or XELIRI with or without bevacizumab(7.5 mg/kg on day 1), repeated every 3 weeks(XELIRI arm). A total of 464 events were estimated as necessary to show non?inferiority with a power of 80% at a one?sided α of 0.025, requiring a target sample size of 600 patients. The 95% conidence interval(CI) upper limit of the hazard ratio was pre?speciied as less than 1.3.Conclusion: The Asian XELIRI Projec T is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second?line treatment option of mCRC.

Non-AIDS-related Kaposi’s sarcoma:A single-institution experience

AIM:To evaluate the outcomes and potential prognostic factors in patients with non-acquired immunodeficiency syndrome(AIDS)-related Kaposi’s sarcoma(KS).METHODS:Patients with histologically proven non-AIDS-related KS treated with systemic chemotherapy were included in this retrospective analysis.In some cases,the human herpes virus 8 status was assessed by immunohistochemistry.The patients were staged according to the Mediterranean KS staging system.A multivariable model was constructed using a forward stepwise selection procedure.A P value<0.05 was considered statistically significant,and all tests were two-sided.RESULTS:Thirty-two cases were included in this analysis.The average age at diagnosis was 70 years,with a male/female ratio of approximately 2:1.Eighty-four percent of the cases had classic KS.All patients received systemic chemotherapy containing one of the following agents:vinca alkaloid,taxane,and pegylated liposomal doxorubicin.Ten patients(31.5%)experienced a partial response,and a complete response was achieved in four patients(12.4%)and stable disease in sixteen cases(50%).Two patients(6.2%)were refractory to the systemic treatment.The median progression-free survival(PFS)was 11.7 mo,whereas the median overall survival was 28.5 mo.At multivariate analysis,the presence of nodular lesions(vs macular lesions only)was significantly related to a lower PFS(hazard ratio:3.09;95%CI:1.18-8.13,P=0.0133).CONCLUSION:Non-AIDS-related KS appears mostly limited to the skin and is well-responsive to systemic therapies.Our data show that nodular lesions may be associated with a shorter PFS in patients receiving chemotherapy.

First-line pazopanib in patients with advanced non-clear cell renal carcinoma:An Italian case series

BACKGROUND Non-clear cell(ncc)metastatic renal-cell carcinoma(RCC)has dismal results with standard systemic therapies and a generally worse prognosis when compared to its clear-cell counterpart.New systemic combination therapies have emerged for metastatic RCC(mRCC),but the pivotal phase III trials excluded patients with nccRCC,which constitute about 30%of metastatic RCC cases.AIM To provide a piece of real-life evidence on the use of pazopanib in this patient subgroup.METHODS The present study is a multicenter retrospective observational analysis aiming to assess the activity,efficacy,and safety of pazopanib as first-line therapy for advanced nccRCC patients treated in a real-life setting.RESULTS Overall,48 patients were included.At the median follow-up of 40.6 mo,the objective response rate was 27.1%,the disease control rate was 83.3%,and the median progression-free survival and overall survival were 12.3(95%confidence interval[CI]:3.6-20.9)and 27.7(95%CI:18.2-37.1)mo,respectively.Grade 3 adverse events occurred in 20%of patients,and no grade 4 or 5 toxicities were found.CONCLUSION Pazopanib should be considered as a good first-line option for metastatic RCC with variant histology.

Reversible dysphagia due to gabapentin-induced jaw myoclonus

An 89-year-old woman was admitted with a 3-day history of dysphagia and lower jaw twitching. She had a history of hypertension, diabetes mellitus, surgically corrected left proximal humeral fracture, and right C5 dermatome postherpetic neuralgia. The jaw twitching had caused dysphagia with an inability to drink liquids. Physical examination confirmed the persistent lower jaw myoclonus (Supplementary Video;http://links.lww.com/CM9/A48). The patient was fully conscious and had no twitching or nystagmus in any of her other extremities. The results of neurological examination and biochemical analysis (including complete blood profile, electrolyte level, random glucose concentration, renal function test, and liver function test) were all within the normal range. Computed tomography of the brain was unremarkable and an electroencephalogram showed no evidence of seizure. A careful review of her prescribed medications revealed the following: the patient complained of allodynia over the right C5 dermatome around 3 months prior and was prescribed gabapentin. The dosage of gabapentin was increased to 300 mg total dissolved solids (TDS) around 2 months prior. Creatinine levels were normal but her glomerular filtration rate, as estimated by the Cockcroft-Gault equation, was 36 mL/min.[1] Since the patient’s relatives supervised her medication intake, overdosage was not possible. Gabapentin was discontinued and replaced with pregabalin 50 mg BD and the patient was prescribed valium 2 mg TDS transiently. The jaw myoclonus subsided on the second day. After a consultation with a speech therapist, the patient resumed oral intake and remained tolerant of a normal diet. Upon review after 1 month, the patient remained free from jaw myoclonus.

Cold air plasma:A potential strategy for inducing apoptosis of rheumatoid arthritis fibroblast‐like synoviocytes

Rheumatoid arthritis(RA)is an autoimmune disease of the joints characterised by synovial hyperplasia and chronic inflammation.Rheumatoid arthritis fibroblast‐like synoviocytes(RA‐FLS)cells are the dominant cell type in the hyperplastic synovial membrane,which play a key role in the pathogenesis of RA.They can invade cartilage,cause inflammation,destroy joints,and show tumour‐like anti‐apoptosis characteristics.Thus,the purpose of this study is to investigate the effect of cold air plasma(CAP)on RA‐FLS cells.The results showed that CAP treatment for 120 s could significantly reduce the viability of RA‐FLS cells,increase the content of intracellular reactive ox-ygen species(ROS),and significantly down‐regulate the ratio of apoptosis‐related protein Bcl‐2 to Bax.In this study,a novel approach of inducing apoptosis in RA‐FLS cells using CAP was proposed,which may provide a new choice for joint tar-geting therapy of RA.

Understanding sarcoma drug resistance one cell at a time

As true for any cancer,intrinsic and acquired drug resistance represent perhaps the single biggest obstacle limiting our ability to cure patients with metastatic disease.Yet,tackling this challenge has been particularly difficult for sarcoma.First and foremost,sarcomas are rare and diverse,which splits a class of tumors representing less than 1 percent of all malignancies into more than fifty smaller molecularly and histologically distinct entities,each having its own etiology,prognosis,and clinical presentation.Even the most“common”sarcoma subtypes(e.g.,liposarcoma,leiomyosarcoma,or gastrointestinal stromal tumors)have annual incidences in the thousands in the United States,whereas rarer subtypes like desmoplastic small round cell tumors number less than fifty per year.Due to their scarcity,it’s not uncommon for just a few cell lines,organoids,or patient-derived tumor explants to exist for each sarcoma subtype.This shortage limits their usefulness to model the wide variety of innate and adaptive mechanisms that exist in human tumors.Many times,no representative preclinical model exists.The scarcity of FDA-approved drugs aimed at sarcoma-specific targets,often fusion proteins and transcription factors,is also problematic.