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International audience; No data concerning antiretroviral drug's (ARV) primary resistance mutation rates in Chad are available. We retrospectively analysed frozen-stored dried blood spot samples that were collected from 48 Chadian human immunodeficiency virus (HIV)-1 seropositive patients naïve of ARV. HIV-1 protease and reverse transcriptase genes were successfully sequenced for 24 (60.0%) of the 40 patients displaying a viral load > 1000 copies/ml. Seven (29.2%) displayed mutations conferring resistance against one or more classes of ARV. We evidenced high levels of primary ARV resistance mutations in Chad, but lower than those observed in patients with failure to first-line ARV.

Background: The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well elucidated. We evaluated plasma circulating tumor DNA– (ctDNA-) based copy number alterations (CNAs) to determine treatment-related predictive and prognostic biomarkers for metastatic castration-resistant prostate cancer (mCRPC). Methods: Serial plasma specimens were prospectively collected from 88 chemotherapy-naive mCRPC patients before and after 12 weeks of AA/P treatment. Sequencing-based CNA analyses were performed on 174 specimens. We evaluated CNA-associated 12-week responses for primary resistance, time to treatment change (TTTC) for secondary resistance, and overall survival for prognosis (P < .05). Associations with primary resistance were analyzed using the Fisher exact test. Kaplan–Meier survival curves and Cox regression analyses were used to determine the associations of CNAs with acquired resistance and overall survival. Results: ctDNA reduced by 3.89% in responders and increased by 0.94% in nonresponders (P = .0043). Thirty-one prostate cancer–related genes from whole genome CNAs were tested. AR and AR enhancer amplification were associated with primary resistance (P = .0039) and shorter TTTC (P = .0003). ZFHX3 deletion and PIK3CA amplification were associated with primary resistance (P = .026 and P = .017, respectively), shorter TTTC (P = .0008 and P= .0016, respectively), and poor survival (P = .0025 and P = .0022, respectively). CNA-based risk scores combining selected significant associations (AR, NKX3.1, and PIK3CA) at the univariate level with TTTC were predictive of secondary resistance (P = .0002). and established prognoses for survival based on CNAs in ZFHX3, RB1, PIK3CA, and OPHN1 (P = .002). Multigene risk scores were more predictive than individual genes or clinical risk factors (P < .05). Conclusion: Plasma ctDNA CNAs and risk scores can predict mCRPC-state treatment and survival outcomes.

In this study, we evaluated clinical parameters to predict the primary resistance of palbociclib in combination with endocrine therapy as the first-line treatment in patients with hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (MBC). We performed a data analysis of patients diagnosed with HR+, HER2-MBC who received palbociclib plus letrozole as the first-line treatment in the metastatic setting from the clinical data warehouse in Samsung Medical Center. In this study, 305 patients were included in the final data analysis. The median follow-up duration was 31 months, and we observed 123 cases of disease progression. The median progression-free survival (PFS) was 28.7 months, and 38 patients (12.5%) had less than a 6-month PFS. The multivariate analysis suggested that primary resistance to adjuvant endocrine therapy (ET) (hazard ratio: 1.91), presence of liver metastasis (hazard ratio: 2.17), initial elevation of serum CA-15-3 (hazard ratio: 1.99), weak positivity of estrogen receptor (ER) (hazard ratio: 2.28), Ki-67 3+ or 4+ (hazard ratios: 2.58 and 10.28), and presence of mutation (hazard ratio: 9.59) were associated with a short PFS duration. A further prediction model was developed with data from 256 patients and 33 cases of disease progression in 6 months. This model included five factors—primary resistance to adjuvant ET (odds ratio, OR: 1.14), liver metastasis (OR: 1.56), initial CA-15-3 elevation (OR: 1.51), weak ER expression (OR: 2.22), and BRCA2 mutation (OR: 2.85)—and the area under the receiver operating characteristic curve was 0.842 (95% CI: 0.775, 0.909; p < 0.001). Finally, we divided them into four risk groups according to the prediction model with the five risk factors. These four groups had different PFS (p < 0.001) and primary resistance of palbociclib with letrozole [OR of group 2 vs. group 1 (ref): 2.18 (p = 0.002), OR of group 3: 3.91 (p < 0.001), and OR of group 4: 4.25 (p < 0.001)]. We developed a prediction model of primary resistance to palbociclib with letrozole as the first-line treatment for HR+, HER2-MBC. Our prediction model might be helpful for considering the first-line treatment strategies. Further well-designed clinical trials would be warranted to validate our prediction model.

Background Leprosy has been treated with multidrug therapy, which has been distributed for free across the globe and regarded as highly efficient. However, the impossibility of growing Mycobacterium leprae in axenic media has historically impaired assessments of M. leprae resistance, a parameter only recently detectable through molecular methods. Methods A systematic, population-based search for M. leprae resistance in suspected leprosy relapse cases and contacts was performed in Prata Village, an isolated, hyperendemic, former leprosy colony located in the Brazilian Amazon. Results led to an extended active search involving the entire Prata population. Confirmed leprosy cases were investigated for bacterial resistance using a combination of in vivo testing and direct sequencing of resistance genes folP1, rpoB, and gyrA. A molecular epidemiology analysis was performed using data from 17 variable number tandem repeats (VNTR). Results Mycobacterium leprae was obtained from biopsies of 37 leprosy cases (18 relapses and 19 new cases): 16 (43.24%) displayed drug-resistance variants. Multidrug resistance to rifampicin and dapsone was observed in 8 relapses and 4 new cases. Single resistance to rifampicin was detected in 1 new case. Resistance to dapsone was present in 2 relapses and 1 new case. Combined molecular resistance and VNTR data revealed evidence of intra-familial primary transmission of resistant M. leprae. Conclusions A comprehensive, population-based systematic approach to investigate M. leprae resistance in a unique population revealed an alarming scenario of the emergence and transmission of resistant strains. These findings may be used for the development of new strategies for surveillance of drug resistance in other populations., Our study, in a unique population, revealed the highest proportion of resistant Mycobacterium leprae isolates to single and multiple drugs ever reported and demonstrated intra-familial transmission of resistant M. leprae: immediate, strong attention to drug resistance in leprosy is suggested.

Background Crizotinib is associated with a favorable survival benefit in patients with ALK‐positive non‐small cell lung cancer (NSCLC); however, a subset of patients harboring ALK rearrangement shows a poor response. Methods We collected the clinical features and survival outcomes of 28 primary‐resistant responders (PRR) with progression‐free survival (PFS) of < 3 months on crizotinib and compared these with 78 long‐term responders (LTR) that achieved > 24 months PFS (control). Results Primary resistance was observed in 6.5% of the patients. The median PFS of the PRR and LTR groups was 1.2 months (95% confidence interval [CI] 0.70–1.73) and 47.0 months (95% CI 34.39–59.64), respectively. A better Eastern Cooperative Oncology Group performance status score was significantly associated with longer PFS (odds ratio 0.06, 95% CI 0.01–0.33; P = 0.001). The median overall survival (OS) of the PRR group was 8.4 months (95% CI 3.47–13.42) and crizotinib as first‐line treatment was an independent predictive factor for survival outcome (P = 0.005). Patients administered ALK‐tyrosine kinase inhibitors after crizotinib progression had significantly longer survival than the PRR group treated with best supportive care (P = 0.007), but no significant difference was found between ALK‐tyrosine kinase inhibitor treatment and single chemotherapy (P = 0.944). Conclusion Patients with primary resistance to crizotinib displayed unfavorable survival outcomes and the underlying mechanism cannot be identified in clinical features. Nevertheless, next‐generation ALK inhibitors and chemotherapy after crizotinib progression could confer a therapeutic and survival benefit in this population.

EGFR-activating mutations have been recognized as the most important predictor of response to EGFR-tyrosine kinase inhibitors (TKIs); however, 20-30% of patients harboring EGFR-activating mutations show poor responses. The mechanisms of such EGFR-TKI primary resistance are still poorly understood. In our case, a non-small cell lung cancer patient developed intrinsic EGFR-TKI resistance and was then confirmed to simultaneously harbor an L858R mutation and ROS1 rearrangement. Salvage chemotherapy plus Endostar showed enduring therapeutic effects, achieving a disease-free survival period of 24 months and overall survival of 30 months. This suggests that co-activation of different oncogenic signal pathways might be a potential mechanism of EGFR-TKI primary resistance. Chemotherapy combined with anti-angiogenesis should be considered an important salvage strategy. Further studies are warranted to verify these findings and explore the underlying mechanisms involved.

Novel treatment strategies incorporating PD-1/PD-L1 inhibitors in the first-line setting of advanced non-small-cell lung cancer (NSCLC) provided relevant improvements in survival outcomes. Among NSCLC patients with PD-L1 tumor proportion score ≥50%, identifying the ones to be addressed to pembrolizumab monotherapy or chemo-immunotherapy combinations is a matter of debate, taking into account the risks of overtreatment and toxicity. Here we report the clinical stories of four NSCLC patients with PD-L1 tumor proportion score ≥50% and good performance status, sharing high tumor burden including serosal involvement. After having rapidly progressed on first-line PD-1/PD-L1 inhibitors, they achieved major clinical and radiological response to pembrolizumab-chemotherapy combination. These cases prove the feasibility and effectiveness of salvage chemo-immunotherapy in pembrolizumab-refractory NSCLC patients.

BackgroundCD19 chimeric antigen receptor T cell (CD19CAR-T) has shown great potential to treat acute B cell lymphoblastic leukemia (B-ALL) and B cell lymphoma, and most of anti-CD19 scFv are derived from murine antibody sequences. However, about 10–20% of B-ALL patients exhibit primary resistance to murine-based CD19CAR-T (CD19mCAR-T). Herein, we report that a humanized selective CD19CAR-T (CD19hsCAR-T) may offer a solution to this problem.Case DescriptionA 10-year old boy was diagnosed with high-risk B-ALL in Mar., 2013, and relapsed in Oct., 2018, after he underwent haplo-identical hematopoietic stem cell transplantation (HSCT) in 2017. The patient then received haplo-identical CD19mCAR-T infusions twice following induction chemotherapy with Vincristine, Dexamethasone and Asparaginase (VDL), but no response was observed. We further treated this patient with CD19hsCAR-T following chemotherapy with Vindesine, Idarubicin, Dexamethasone, and Pegylated Asparaginase (VDLD) plus bortezomib. The patient achieved minimal residual disease-negative (MRDneg) complete remission with incomplete hematopoietic recovery (CRi), and remained in CRi for more than 8 months with manageable side effect. The patient, unfortunately, died of unidentified pulmonary infection on Jan. 25 2020.ConclusionCD19hsCAR-T may have the potential to induce remission in patients who are primarily refractory to CD19mCAR-T.

International audience; Background and objectives: Surveillance of Helicobacter pylori resistance to antibiotics was carried out in France in 2014, 2016, and 2018. We report here the results of the 2018 survey as well as the evolution over the 5-year period.Materials and methods: In this observational study, gastric biopsies were obtained by 62 gastroenterologists randomly selected in 5 regions of France and sent to a central laboratory where culture, antimicrobial susceptibility testing, and a real-time PCR were performed in order to detect H pylori and its mutations associated with clarithromycin resistance.Results and conclusion: During the year 2018, 951 patients were included: 55.3% women, mean age: 52.4 years ± 15.7, 71.6% born in France. Among them, 359 patients were H pylori positive by both culture and real-time PCR, and 7 more by PCR only. There were 244 naive patients, 110 previously treated patients, and unknown for 5. Primary resistance to clarithromycin was 20.9% [16.3-26.4], to levofloxacin 17.6% [13.4-22.9], and to metronidazole 58.6% [52.3%-64.6%]. Secondary resistance for these antibiotics was 56.4%, 22.7%, and 87.3%, respectively. There was no resistance to amoxicillin and tetracycline and very low resistance to rifampicin (1.2%) in both naive and treated patients. Primary resistance to clarithromycin decreased from 22.2% to 20.3% between 2014 and 2016, and appears to be stable since then. This can be linked to a stable consumption of macrolides over the 3-year time period. Primary levofloxacin resistance was relatively stable while metronidazole resistance increased. Interestingly, in both naive and treated patients, amoxicillin and rifampicin resistance were rare.

Introduction Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20–30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study. Methods Targeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC. Results Four patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research. Conclusion MDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.

Background: Mucosal melanomas including melanomas of the urogenital tract represent a rare type of melanoma characterized by low mutational burden and poor prognosis. Immune checkpoint inhibition has so far only been assessed in a limited number of mucosal melanoma patients and, in contrast to response in cutaneous melanoma, was associated with disappointing response rates. The oncolytic viral immunotherapy Talimogene laherparepvec (T-VEC) has recently been approved for treatment of locally advanced or unresectable melanoma. T-VEC combines direct oncolytic effects with local and systemic immune-mediated anti-tumor response. Our rationale to use T-VEC in this case was an expected augmentation of immunogenicity by tumor lysis to overcome primary resistance of a mucosal melanoma to immune checkpoint blockade. Objective: To report the first case of an advanced mucosal melanoma of the urethra treated with intralesional application of Talimogene laherparepvec. Case Report: A 78-years old female patient was diagnosed with an advanced mucosal melanoma of the urethra with inguinal lymph node metastases and intravaginal mucosal metastases. Shortly after surgical resection of the tumor mass, intravaginal mucosal metastases, and new nodal metastases in proximity of the left iliac vessels were diagnosed. The patient was treated with the anti-PD1 antibody pembrolizumab and obtained a stable disease lasting for 30 weeks. However, upon checkpoint inhibition the patient developed a loco-regional progressive disease featuring bleeding intravaginal metastases, while nodal metastases remained stable. We stopped treatment with pembrolizumab and administered T-VEC directly into the intravaginal mucosal metastases. After five injections T-VEC yielded a partial response with clinical regression of the injected mucosal metastases. Disease remained stable for 16 weeks under biweekly T-VEC treatment. Thereafter the patient showed disease progression in nodal metastases. T-VEC was discontinued. Immunotherapy with pembrolizumab was restarted but failed to achieve a response. Finally, targeted therapy with imatinib was induced in presence of a druggable c-KIT mutation, leading to a considerable response of all tumor sites that is still ongoing. Conclusion: T-VEC represents an effective and well-tolerated treatment option for patients with loco-regionally advanced mucosal melanoma. In combination with immunotherapy, T-VEC bears the potential of synergistic effects to overcome the specific primary resistance of mucosal melanoma to immune checkpoint blockade.

Background: Primary resistance to immunotherapy can be observed in approximately 40&ndash, 65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan&ndash, Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p &lt, 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.

Current National Comprehensive Cancer Network (NCCN) guidelines suggest plasma‐based testing (liquid biopsy) for T790M in epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung carcinoma (NSCLC) with acquired resistance to first‐/second‐generation EGFR tyrosine kinase inhibitors (TKIs). Positivity for resistant mutation on liquid biopsy may obviate the need for invasive tissue biopsy. We report a rare case of primary resistance to osimertinib, although liquid biopsy revealed EGFR T790M positivity. A 63‐year‐old male, never smoker, was diagnosed with stage IV lung adenocarcinoma with EGFR exon 19 deletion. Treatment started with erlotinib and was continued for 15 months until disease progression. Osimertinib was initiated when liquid biopsy showed EGFR T790M positivity. However, primary resistance to osimertinib was noted on follow‐up imaging. Re‐biopsy revealed small cell lung cancer. Detection of T790M via liquid biopsy among NSCLC patients with acquired resistance to EGFR‐TKI might miss other possible resistant mechanisms. Tissue biopsy should be considered to exclude small cell lung carcinoma (SCLC) transformation., Liquid biopsy to diagnose T790M presence in non‐small cell lung carcinoma (NSCLC) patients resistant to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) might miss other possible resistance mechanisms. Tissue biopsy should be considered to exclude the presence of small cell lung carcinoma (SCLC) transformation.

Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first‐line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients’ survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short‐term treatment, defined as primary resistance. The present study is aimed to explore the role of stress‐inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up‐regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib‐induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor‐AKT and phosphor‐AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.

Yong-hong Pan, Lin Jiao, Cai-yu Lin, Cong-hua Lu, Li Li, Heng-yi Chen, Yu-bo Wang, Yong He Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China Aim: Although EGFR tyrosine kinase inhibitors (TKIs) have shown dramatic effects against sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), ~20%–30% of NSCLC patients with EGFR-sensitive mutation exhibit intrinsic resistance to EGFR-TKIs. The purpose of the current study was to investigate the enhanced antitumor effect of metformin (Met), a biguanide drug, in combination with gefitinib (Gef) in primary resistant human lung cancer cells and the associated molecular mechanism.Experimental design: H1975 cell line was treated with Met and/or Gef to examine the inhibition of cell growth and potential mechanism of action by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Ki67 incorporation assay, flow cytometry analysis, small interfering RNA technology, Western blot analysis and xenograft implantation.Results: Insulin-like growth factor-1 receptor (IGF-1R) signaling pathway was markedly activated in EGFR-TKI primary resistant H1975 cells as compared to EGFR-TKI acquired resistance cells (PC-9GR, H1650-M3) and EGFR-TKI sensitivity cells (PC-9, HCC827). Inhibition of IGF-1R activity by AG-1024 (a small molecule of IGF-1R inhibitor), as well as downregulation of IGF-1R by siRNA, significantly enhanced the ability of Gef to suppress proliferation and induce apoptosis in H1975 cells via the inhibition of AKT activation and subsequent upregulation of Bcl-2-interacting mediator of cell death (BIM). Interestingly, the observation showed that Met combined with Gef treatment had similar tumor growth suppression effects in comparison with the addition of AG-1024 to therapy with Gef. A clear synergistic antiproliferative interaction between Met and Gef was observed with a combination index (CI) value of 0.65. Notably, IGF-1R silencing mediated by RNA interference (RNAi) attenuated anticancer effects of Met without obviously resensitizing H1975 cells to Gef. Finally, Met-based combinatorial therapy effectively blocked tumor growth in the xenograft with TKI primary resistant lung cancer cells.Conclusion: Our findings demonstrated that Met combined with Gef would be a promising strategy to overcome EGFR-TKI primary resistance via suppressing IGF-1R signaling pathway in NSCLC. Keywords: metformin, gefitinib, IGF-1R, primary resistance, lung cancer

The European Society for Medical Oncology (ESMO) consensus conference onmalignant lymphoma was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the questions devised by their group. These recommendations were then presented to the entire multidisciplinary panel and a consensus was reached. This manuscript presents recommendations regarding the management of the following 'ultra-high-risk' situations: (1) early central nervous system relapse of diffuse large B-cell lymphoma, (2) primary refractory Hodgkin lymphoma and (3) plasmablastic lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. All expert panel members approved this final article.

Background Trastuzumab emtansine (T-DM1) is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), and has high efficacy. However, some patients exhibit primary resistance to T-DM1, and thus methods that can predict resistance in clinical practice are needed. Genomic analysis of circulating tumor DNA (ctDNA) in plasma is a non-invasive and reproducible method. This study aimed to predict primary resistance to T-DM1 by combining genomic analysis of ctDNA and other clinicopathological features of patients with HER2-positive ABC. Methods The study population comprised 34 patients with HER2-positive ABC who had been treated with T-DM1. Correlations between clinicopathological characteristics of patients and primary resistance to T-DM1 were examined, and HER2 gene copy number and PIK3CA gene mutations were analyzed using plasma ctDNA samples obtained from 16 patients before T-DM1 administration. Results Among the 34 patients, nine (26.5%) had progressive disease at the first efficacy analysis; these patients were considered to have primary resistance to T-DM1. No significant difference was found in the rate of primary resistance to T-DM1 between groups. Among 16 patients whose ctDNA was analyzed, four showed primary resistance to T-DM1. These four patients showed negative HER2 gene amplification in ctDNA and were ER-positive and/or PR-positive by immunohistochemistry. Conclusions HER2 gene amplification in ctDNA and ER and PR status may predict primary resistance to T-DM1. A liquid biopsy before the initiation of T-DM1 treatment could be a non-invasive way to predict whether a patient would exhibit primary resistance to T-DM1.

// Yihan Ma 1 , Xiaoyan Pan 1, 2 , Peiqi Xu 3 , Yanjun Mi 1 , Wenyi Wang 1 , Xiaoting Wu 1 , Qi He 1 , Xinli Liu 1 , Weiwei Tang 1 and Han-Xiang An 1 1 Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China 2 Department of Medical Oncology, Linyi Cancer Hospital, 276000 Shandong, China 3 Reproduction Center, The Second Affiliated Hospital of Kunming Medical University, 650101 Yunnan, China Correspondence to: Han-Xiang An, email: anhanxiang@xmu.edu.cn Keywords: EGFR, EGFR-TKI, NSCLC, circulating miRNA, primary resistance Received: November 02, 2016 Accepted: July 18, 2017 Published: August 03, 2017 ABSTRACT Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have obtained excellent therapeutic effects against non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, some patients have exhibited primary resistance which becomes a major obstacle in effective treatment of NSCLC. The mechanisms of EGFR-TKIs resistance involved are still poorly understood. Many studies suggest that miRNAs play an important role in regulating drug sensitivity of EGFR-TKIs. The aim of the present study was to examine differentially expressed miRNAs in plasma between EGFR-TKIs sensitive and EGFR-TKIs primary resistance patients. MiRNA microarray of plasma from patients’ blood identified 16 differentially expressed miRNAs of which 15 (hsv2-miR-H19, hsa-miR-744-5p, hsa-miR-3196, hsa-miR-3153, hsa-miR-4791, hsa-miR-4803, hsa-miR-4796-3p, hsa-miR-372-5p, hsa-miR-138-2-3p, hsa-miR-16-1-3p, hsa-miR-1469, hsa-miR-585-3p, ebv-miR-BART14-5p, hsa-miR-769-3p, hsa-miR-548aq-5p) were down regulated while only hsa-miR-503-3p was up regulated in primary resistant patients’ plasma. Volcano plot and hierarchical clustering were performed to examine the accuracy of the miRNAs. Then validation with quantitative real-time PCR was performed and the result was in accordance with the array data. Functional analysis of these differentially expressed miRNAs with Ingenuity Pathway Analysis (IPA) revealed a common signaling network including MYC, CCND1, IGF1 and RELA. In conclusion, our finding may play important role in understanding the mechanisms underlying the problem and should be further evaluated as potential biomarkers in primary resistance of NSCLC.

Introduction: The widespread use of antiretroviral therapy increased the transmission of antiretroviral resistant HIV strains. Antiretroviral therapy initiation during acute/recent HIV infection limits HIV reservoirs and improves immune response in HIV infected individuals. Transmitted drug resistance may jeopardize the early goals of early antiretroviral treatment among acute/recent HIV infected patients. Methods: Patients with acute/recent HIV infection who underwent resistance test before antiretroviral treatment initiation were included in this analysis. HIV-1 sequences were obtained using an in house protease/reverse transcriptase genotyping assay. Transmitted drug resistance was identified according to the Stanford HIV Database for Transmitted Drug Resistance Mutations, based on WHO 2009 surveillance list, and HIV-1 subtyping according to Rega HIV-1 subtyping tool. Comparison between patients with and without transmitted drug resistance was made using Kruskal–Wallis and Chi-square tests. Results: Forty-three patients were included, 13 with acute HIV infection and 30 with recent HIV infection. The overall transmitted drug resistance prevalence was 16.3% (95% confidence interval [CI]: 8.1–30.0%). The highest prevalence of resistance (11.6%, 95% CI: 8.1–24.5) was against non-nucleoside reverse transcriptase inhibitors, and K103N was the most frequently identified mutation. Conclusions: The high prevalence of nonnucleoside reverse transcriptase inhibitors resistance indicates that efavirenz-based regimen without prior resistance testing is not ideal for acutely/recently HIV-infected individuals in our setting. In this context, the recent proposal of including integrase inhibitors as a first line regimen in Brazil could be an advantage for the treatment of newly HIV infected individuals. However, it also poses a new challenge, since integrase resistance test is not routinely performed for antiretroviral naive individuals. Further studies on transmitted drug resistance among acutely/recently HIV-infected are needed to inform the predictors of transmitted resistance and the antiretroviral therapy outcomes among these population. Keywords: HIV, Infection, Transmission, Primary resistance, Antiretroviral therapy

Background From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. Objective To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. Design, setting, and participants A total of 150 mRCC patients with rapidly PD on first-line sunitinib (within two cycles, n = 93, or four cycles, n = 57) were identified: median age 59 yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarcomatoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). Outcome measurements and statistical analysis Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Progression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). Results and limitations Median OS from the start of first-line treatment was 7.4 mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 everolimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second-line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9 mo; p = 0.536). Median OS from the start of second-line treatment was 5.0 mo for mTOR inhibitors and 6.6 mo for TKIs (p = 0.15). Conclusions Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. Patient summary The present work collected data about 150 patients affected by metastatic renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases.

// Ben Zhao 1 , Lu Wang 1 , Hong Qiu 1 , Mingsheng Zhang 1 , Li Sun 1 , Ping Peng 1 , Qianqian Yu 1 and Xianglin Yuan 1 1 Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China Correspondence to: Xianglin Yuan, email: // Keywords : colorectal cancer, epidermal growth factor receptor, targeted drug, primary resistance, acquired resistance Received : May 31, 2016 Accepted : December 05, 2016 Published : December 18, 2016 Abstract Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is effective for patients with RAS wild type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients are sensitive to anti-EGFR therapy and even the best cases finally become refractory to this therapy. It has become apparent that the RAS mutations correlate with resistance to anti-EGFR therapy. However, these resistance mechanisms only account for nearly 35% to 50% of nonresponsive patients, suggesting that there might be additional mechanisms. In fact, several novel pathways leading to escape from anti-EGFR therapy have been reported in recent years. In this review, we provide an overview of known and novel mechanisms that contribute to both primary and acquired anti-EGFR therapy resistance, and enlist possible treatment strategies to overcome or reverse this resistance.

// Sun Min Lim 1, 2 * , Hye Ryun Kim 1 * , Eun Kyung Cho 3 , Young Joo Min 4 , Jin Seok Ahn 5 , Myung-Ju Ahn 5 , Keunchil Park 5 , Byoung Chul Cho 1 , Ji-Hyun Lee 6 , Hye Cheol Jeong 6 , Eun Kyung Kim 6 , Joo-Hang Kim 2 1 Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 2 Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea 3 Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea 4 Department of Oncology, Asan Medical Center, University of Ulsan college of Medicine, Seoul, Korea 5 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea * These authors have contributed equally to this work Correspondence to: Joo-Hang Kim, email: kim123@cha.ac.kr Keywords: primary resistance, epidermal growth factor, next-generation sequencing, tyrosine kinase inhibitor Received: March 01, 2016 Accepted: April 05, 2016 Published: April 21, 2016 ABSTRACT Background: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor ( EGFR ) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. Methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients’ tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). Results: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs . 12.8 months, P =0.04, 15.7 vs. not reached, P

Aberrant EGFR signaling is widespread in cancer, making the EGFR an important target for therapy. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition has not been effective in treating this tumor. Here, we propose that primary resistance to EGFR inhibition in glioma cells results from a rapid compensatory response to EGFR inhibition that mediates cell survival. We show that in glioma cells expressing either EGFR wild type or the mutant EGFRvIII, EGFR inhibition triggers a rapid adaptive response driven by increased TNF secretion that leads to activation of a TNF-JNK-Axl-ERK signaling axis. Inhibition of this adaptive axis at multiple nodes renders glioma cells with primary resistance sensitive to EGFR inhibition. Our findings provide a possible explanation for the multiple failures of anti-EGFR therapy in GBM and suggest a new approach to the treatment of EGFR expressing GBM using a combination of EGFR and TNF inhibition.

Objective Patients with non-small-cell lung cancer (NSCLC) and primary or acquired resistance do not respond to targeted drugs. We explored whether cancer cells can be cultured from liquid biopsies from patients with primary resistance to tyrosine kinase inhibitors (TKIs). We aimed to predict patients’ responses to drugs according to in vitro drug testing results. Methods Cancer cell cultures were established from the pleural effusion of a patient with TKI-resistant NSCLC using a conditional reprogramming technique. Phenotypic drug sensitivity tests were performed using the Cell Counting Kit-8 assay. We tested individual drugs and compared the synergistic and inhibitory effects of drug combinations. Results The results of our in vitro sensitivity test using the combination of cisplatin and pemetrexed were correlated with the patient’s response. Conclusion This represents the first successful report of predictive testing for combination therapy in patients with epidermal growth factor receptor-mutant NSCLC and primary TKI resistance. This strategy should be applicable to both chemotherapies and targeted therapies, and it will significantly improve the clinical treatment and management of patients with NSCLC and primary or acquired resistance to targeted therapies, as well as patients lacking targetable mutations.

The development of new systemic agents has led us into a “golden era” of management of metastatic renal cell carcinoma (RCC). Certainly, the approval of immune-checkpoint inhibitors and the combination of these with targeted compounds has irreversibly changed clinical scenarios. A deeper knowledge of the molecular mechanisms that correlate with tumor development and progression has made this revolution possible. In this amazing era, novel challenges are awaiting us in the clinical management of metastatic RCC. Of these, the development of reliable criteria which are able to predict tumor response to treatment or primary and acquired resistance to systemic treatments still remain an unmet clinical need. Thanks to the availability of data provided by studies evaluating genomic assessments of the disease, this goal may no longer be out of reach. In this review, we summarize current knowledge about genomic alterations related to primary and secondary resistance to target therapy and immune-checkpoint inhibitors in RCC

Immune checkpoint inhibitors (ICPis) have revolutionized cancer therapy with broad activities against a wide range of malignancies. However, in many malignancies their efficacy remains limited due to the primary resistance. Furthermore, a high percentage of patients develop progression due to the secondary resistance even after obtaining a response or achieving a stable disease. In this review, we will discuss the mechanisms that underlie the primary and secondary resistance to ICPis in cancer immunotherapy and provide an overview to impart a broad understanding of the critical issues that are encountered in clinical oncology practice.

Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib—a third-generation EGFR-TKI—targets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial⁻mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs.

In the evolving molecular landscape of metastatic colorectal cancer, optimizing available tools to select patients to receive anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies is a modern challenge of colorectal oncologists. Several molecular biomarkers have been investigated in recent years as potential predictors of resistance to anti-EGFR agents in preclinical and clinical retrospective series. Nevertheless, none of them have been implemented in clinical practice due to the lack of a formal prospective demonstration. Here, we propose a literature review of molecular alterations associated with resistance to anti-EGFRs, underlining the reasons why their roadmap from laboratories to clinics was prematurely halted.

Purpose: Refining the selection of HER2-positive metastatic gastric cancer patient candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. Experimental Design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. Results: AMNESIA panel alterations were significantly more frequent in resistant (11 of 20, 55%) as compared with sensitive (0% of 17) patients (P < 0.001), and in HER2 IHC 2+ (7 of 13, 53.8%) than 3+ (4 of 24, 16.7%) tumors (P = 0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free [5.2 vs. 2.6 months; HR, 0.34; 95% confidence interval (CI), 0.07–0.48; P = 0.001] and overall survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09–0.75; P = 0.015). The predictive accuracy of the AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of the AMNESIA panel and HER2 IHC was 84%. Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in patients with HER2-positive metastatic gastric cancer and should be further validated with the aim of molecularly stratifying HER2-addicted cancers for the development of novel treatment strategies. Clin Cancer Res; 24(5); 1082–9. ©2017 AACR.

Background Primary Helicobacter pylori (H. pylori) infection occurs predominantly in childhood. Antimicrobial resistance is the leading cause for H. pylori eradication failure. The aims of this study were (i) to establish for the first time the antimicrobial resistance of H. pylori strains in infected Slovenian children not previously treated for H. pylori infection and (ii) to evaluate the effectiveness of tailored triple therapy, assuming that eradication rate with tailored triple therapy will be >90%. Methods Data on all treatment-naive children 1-18 years old and treated for H. pylori infection according to susceptibility testing were retrospectively analyzed. All relevant clinical information and demographical information were retrospectively collected from the hospital information systems and/or patients’ medical documentation. Results The inclusion criteria were met by 107 children (64.5% girls) with a median age of 12.0 years (range 2.0-17.6 years). Primary antimicrobial resistance rates of H. pylori were 1.0% to amoxicillin (AMO), 23.4% to clarithromycin (CLA), 20.2% to metronidazole (MET), 2.8% to levofloxacin (LEV), and 0.0% to tetracycline (TET). Dual resistances were detected to CLA and MET in 11.5% (n=12) of strains, to CLA and LEV in 2.8% (n=3), and to MET and LEV in 2.9% (n=3). Results of treatment success were available for 71 patients (66.2% girls). Eradication of H. pylori was evaluated using the 13C-urea breath test, monoclonal stool antigen test or in some cases with repeated upper GI endoscopy with histology and cultivation/molecular tests. Eradication was achieved in 61 of 71 (85.9%) patients. Conclusions The primary resistance rates of H. pylori to CLA and MET in Slovenia are high. Our data strongly support the fact that in countries with high prevalence of resistant H. pylori strains susceptibility testing and tailored therapy is essential.

The treatment landscape for patients with advanced non-small cell lung cancer has evolved greatly with the advent of immune checkpoint inhibitors. However, many patients do not derive benefit from checkpoint blockade, developing either primary or secondary resistance, highlighting a need for alternative approaches to modulate immune function. In this review, we highlight the absence of a common definition of primary and secondary resistance and summarize their frequency and clinical characteristics. Furthermore, we provide an overview of the biomarkers and mechanisms of resistance involving the tumor, the tumor microenvironment and the host, and suggest treatment strategies to overcome these mechanisms and improve clinical outcomes.

Background: Primary resistance is the resistance that occurs in patients who have never received treatment OAT or had ever received treatment OAT is less than 1 month. The incidence of primary MDR in Central Java in 2006 2.07%. Extrapulmonary TB about 15-20% of all cases of TB, and TB lymphadenitis is the highest form (35% of all extrapulmonary TB). Patients with decreased immune systems (SLE) can increase the incidence of TB. Research in Spain get 6x higher TB incidence in patients with SLE. Case: We present the case of 19 year old woman SLE who received treatment for 11 months whose came with shortness of breath and chronic cough since 2 month prior to admission. In physical examination we found right and left submandibula lymphonodi enlargement as solid, slightly mobile nodule with diameter 3 cm. Chest X ray showed lung inflammation which suspicion of specific process and minimal left pleural effusion, and concluded as pulmonary TB. FNAB confirmed lymphadenitis TB with granulomatous inflammation. One of AFB result is positive and Gene Xpert is MTB positive with rifampicin resistant that make this patient categorized as primary MDR TB with lymphadenitis TB. This patient received Pirazinamid 1500 mg, Ethambutol 800 mg, Kanamicin 750 mg, Levofloxacin 750 mg, Ethionamide 500 mg, Cicloserin 500 mg, and B6 100 mg. Conclusion: MDR TB in general occur in patients with a history of OAT previous TB (MDR TB secondary). Primary MDR TB with lymphadenitis tb is a rare case, but can occur on the condition that decreases the immune system, one of SLE. This involves multiple immune disorders caused by the use of long-term immunosuppressive therapy.

Background: Primary resistance is the resistance that occurs in patients who have never received treatment OAT or had ever received treatment OAT is less than 1 month. The incidence of primary MDR in Central Java in 2006 2.07%. Extrapulmonary TB about 15-20% of all cases of TB, and TB lymphadenitis is the highest form (35% of all extrapulmonary TB). Patients with decreased immune systems (SLE) can increase the incidence of TB. Research in Spain get 6x higher TB incidence in patients with SLE. Case: We present the case of 19 year old woman SLE who received treatment for 11 months whose came with shortness of breath and chronic cough since 2 month prior to admission. In physical examination we found right and left submandibula lymphonodi enlargement as solid, slightly mobile nodule with diameter 3 cm. Chest X ray showed lung inflammation which suspicion of specific process and minimal left pleural effusion, and concluded as pulmonary TB. FNAB confirmed lymphadenitis TB with granulomatous inflammation. One of AFB result is positive and Gene Xpert is M.tb positive with rifampicin resistant that make this patient categorized as primary MDR TB with lymphadenitis TB. This patient received Pirazinamid 1500 mg, Ethambutol 800 mg, Kanamicin 750 mg, Levofloxacin 750 mg, Ethionamide 500 mg, Cicloserin 500 mg, and B6 100 mg. Conclusion: MDR TB in general occur in patients with a history of OAT previous TB (MDR TB secondary). Primary MDR TB with lymphadenitis tb is a rare case, but can occur on the condition that decreases the immune system, one of SLE. This involves multiple immune disorders caused by the use of long-term immunosuppressive therapy.

Non-small-cell lung cancer (NSCLC) constitutes about 85% of all lung cancers. Approximately 50% of patients diagnosed with NSCLC present with advanced disease (stage III or IV) that is not amenable to curative treatment. The number of patients with stage IIIB or IV disease who are alive at 1 year after diagnosis has increased from 10% in the untreated population in the early 1980s to 50% in patients with a good performance status receiving treatment today. However, those statistics remain dismal, and the two dominant reasons are the large number of patients diagnosed with advanced-stage disease and the observed primary or secondary resistance to current therapies. The present article addresses the question of drug resistance in lung cancer, focusing on subjects that are currently topical and under intense scrutiny.

We evaluated the clinical and immunopathological features of non-small cell lung cancer with primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors. The rate of smoking was significantly higher in primary resistance. The immune microenvironment characterized by low total tumor infiltrating lymphocytes and negative programmed death ligand 1 correlated significantly with primary resistance. Background: Approximately 20% to 30% of nonesmall-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumorinfiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC. However, few studies have directly focused on the relationship between the tumor immunemicroenvironment and primary resistance to EGFR-TKIs. Materials and Methods: The characteristics of 124 NSCLC patients with EGFR mutations who had received EGFR-TKIs were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFRTKI treatment were assessed for the density of TILs expressing CD4 or CD8 and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically. Results: Primary resistance was observed in 13.7% of the patients (17 of 124). A significant difference in smoking history was observed between patients with primary resistance and those with noneprimary resistance. A lower density of total TILs and negative PD-L1 expression on immunohistochemical analysis correlated significantly with primary resistance, in contrast to that with noneprimary resistance. Moreover, the negative PD-L1 expression with low TIL density, indicating immune ignorant phenotype of tumor microenvironment, was observed in those with primary resistance with a significant difference. Conclusion: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs.

Disseminated tuberculosis is a common mode of presentation of tuberculosis in patients both with and without HIV/AIDS in India. However, primary multidrug resistance in disseminated tuberculosis involving only the extrapulmonary sites in an immunocompetent adult is rare. Here, we report a case of a 19-year-old man who had disseminated tuberculosis involving left pleura, pericardium, peritoneum and intraabdominal lymph nodes. He was initially taking WHO category I antituberculous drugs, but was not responding in spite of 5 months of chemotherapy. Culture of the pleural biopsy specimen grew Mycobacterium tuberculosis which was resistant to isoniazid and rifampicin. He was put on therapy for multidrug resistant tuberculosis,following 24 months of chemotherapyhe had an uneventful recovery.

Our ability to detect and directly target the oncogenic alterations responsible for tumor proliferation has contributed significantly to the management of lung cancer in the last decade. The therapeutic efficacy of molecularly targeted therapy is, however, mainly limited to patients harboring certain genetic mutations and is generally short-lived. Herein, we review primary and secondary drug resistance using the most well-studied of the molecularly targeted agents, the tyrosine kinase inhibitors targeting the epidermal growth factor (EGF) receptor and the anaplastic lymphoma kinase (ALK) rearrangement, the current limitations of targeted therapies and their consequences on the management of patients with lung cancer.

Purpose Subclones bearing the epidermal growth factor receptor (EGFR) T790M mutation concomitant with deletional mutation in exon 19 (Del19) or a point mutation in exon 21 (L858R) have been reported in non-small cell lung cancer patients before any EGFR tyrosine-kinase inhibitor (TKI) treatment. The effect of pretreatment T790M mutation on the survival of patients with both mutations treated with EGFR TKI is still being debated. Methods A meta-analysis was undertaken to pool eligible trials to better elucidate whether pretreatment T790M mutation predicts a poorer outcome of EGFR TKI treatment. Hazard ratios and their 95% confidence intervals for progression-free survival (PFS) were extracted and used under the random-effects model. Results A total of 246 patients with activating EGFR mutation such as Del19 or L858R participated in four selected trials from 350 articles. The overall incidence of patients with pretreatment T790M mutation was 43.10% (106/246), ranging from 34.88% to 80.00% in the individual trials. The combined hazard ratio for PFS in all four eligible studies was 2.602 (95% confidence interval 1.011-6.695; P=0.047), indicating a shorter PFS in patients who had the T790M mutation before receiving EGFR TKI treatment. Heterogeneity testing indicated significant heterogeneity but the absence of publication bias. Conclusion The meta-analysis reported here found that pretreatment T790M mutation had a negative impact on the PFS of non-small cell lung cancer patients with a Del19 or L858R EGFR mutation who received EGFR TKI treatment.

The benefit of lamivudine (LAM) in hepatitis B virus (HBV) infection is compromised by the progressively increasing emergence of drug-resistant mutant strains. Although the addition of adefovir dipivoxil (ADV) usually induces complete suppression of viral replication, primary non-response to ADV in LAM resistant patients has been reported in a variable percentage of cases. Here we report a case of a patient with HBV infection and hepatocellular carcinoma who started LAM therapy and subsequently developed virological breakthrough. The patient was given ADV, but HBV-DNA negativisation was not reached. However, HBV clearance was obtained when the patient was switched from ADV to tenofovir. Virological evaluations showed two well-known LAM-related mutations (rtL180M and rtM204I) in addition to reverse-transcriptase rtQ215H. This is the first case suggesting that this mutation may have an impact on viral replication. Finally, we also report that rtQ215H is responsive to tenofovir.

Summary: The emergence of drug-resistant tuberculosis (TB) is an increasing problem which adversely affects patient care and public health. This study aimed to determine the rates and patterns of primary anti-TB drugs resistance in Najran, Southwestern Saudi Arabia. The study included 80 smear-positive new pulmonary TB patients. Sputum samples were cultured on Lowenstein–Jensen and Middle-Brook 7H10 media. Mycobacterium tuberculosis susceptibility testing was done by the conventional agar proportion method for isoniazide (INH), rifampicin (RIF), streptomycin (SPM) and ethambutol (EMB). Out of the 68 M. tuberculosis isolates, 42 (61.8%) were sensitive to all 4 drugs and 26 (38.2%) were resistant to one or more drugs. The most common resistance was found to INH (33.8%), followed by RIF (23.5%), SPM (13.2%) and EMB (2.9%). Eight (11.8%) isolates were resistant to one drug, 14 (20.6%) were resistant to 2 drugs, 3 (4.4%) were resistant to 3 drugs and one (1.5%) was resistant to 4 drugs. Multi-drug resistant (MDR) isolates were found in 14 (20.6%) cases. In conclusion, the primary resistance rate to four first-line anti-tuberculous drugs and MDR-TB rate are worryingly high, representing an alarming situation in Najran. Further studies are necessary for continuous surveillance of M. tuberculosis resistance patterns. Keywords: Primary resistance, Pulmonary tuberculosis, Anti-tuberculosis drugs, Multi-drug resistance

Only approximately 10 % of genetically unselected patients with chemorefractory metastatic colorectal cancer experience tumor regression when treated with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab (“primary” or “de novo” resistance). Moreover, nearly all patients whose tumors initially respond inevitably become refractory (“secondary” or “acquired” resistance). An ever-increasing number of predictors of both primary and acquired resistance to anti-EGFR antibodies have been described, and it is now evident that most of the underlying mechanisms significantly overlap. By trying to extrapolate a unifying perspective out of many idiosyncratic details, here, we discuss the molecular underpinnings of therapeutic resistance, summarize research efforts aimed to improve patient selection, and present alternative therapeutic strategies that are now under development to increase response and combat relapse.

Background The spread of multidrug-resistant tuberculosis (MDR-TB) Mycobacterium tuberculosis (M. tuberculosis) strains has been a big challenge to the TB control and prevention in China. Knowledge about patterns of drug resistance in TB high-burden areas of China is crucial to develop appropriate control strategies. We conducted a comprehensive investigation of the resistance pattern of M. tuberculosis in Heilongjiang Province. Methods 1427 M. tuberculosis clinical strains were isolated from pulmonary TB patients hospitalized between 2007 and 2012. The susceptibility of the isolates to the first-line anti-TB drugs and the resistance of MDR M. tuberculosis to fluoroquinolones were examined. We also performed a statistical analysis to identify the correlated risk factors for high burden of MDR-TB. Results The global resistance rates of 2007–2012 to the first-line drugs and MDR were 57.0 and 22.8 %, respectively. Notably, the primary MDR-TB and pan-resistance rates were as high as 13.6 and 5.0 %, respectively. Of MDR M. tuberculosis isolates (2009), approximately 13 % were not susceptible to any of the fluoroquinolones tested. Being age of 35 to 54, high re-treatment proportion, the presence of cavity lesion, and high proportion of shorter hospitalization are correlated with the development of MDR-TB. Conclusions The high prevalence of drug resistant, MDR-TB, and fluoroquinolone-resistant MDR-TB is a big concern for TB control. More importantly, in order to control the development of MDR-TB effectively, we need to pay more attention to the primary resistance. Targeting reducing the prevalence of the risk factors may lead to better TB control in China.