Rapid Clinical Response Research Articles

PARVOVIRUS B19 AS A CAUSE OF CARDITIS IN COMBINATION WITH MYOZITIS

In the article the case of parvovirus B19 infection in a child, which occurred in the form of carditis and myositis, was presented for the first time. There was the rapid progression of the symptoms of acute rhabdomyolysis with a sharp increase in blood levels of creatine phosphokinase, lactate dehydrogenase, myoglobin, ferritin and troponin 1. Ultrasound examination revealed diffuse inflammatory changes in the muscles of the upper and lower extremities with multiple foci of disorganization of the muscular tissue. A high level of PVB19 DNA was determined by the quantitative PCR method, which allowed verifying the parvoviral B19 infection. Rapid clinical and laboratory response in the observed patient was the result of adequate complex therapy, including due to the early use of drugs with antiviral and immunomodulating action.

Osimertinib for the treatment of patients with EGFR mutation-positive non-small cell lung cancer

Epidermal growth factor receptor (EGFR) mutations, mostly seen in exon 19 or exon 21, are present in roughly 50% of patients with advanced non-small cell lung cancer (NSCLC) of Asian ethnicity compared with 12% in Caucasians. EGFR-mutated NSCLC patients have an increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib or afatinib, showing superior response, progression-free survival and overall survival rates with EGFR-TKIs than with platinum doublet chemotherapy, which makes EGFR-TKIs the standard of care in this subgroup of NSCLC patients. This has been the most important step toward molecular-guided precision therapy for NSCLC. Despite the initial rapid and durable clinical responses, acquired resistance to EGFR-TKIs has been found to eventually develop in most cases, with disease progression observed mostly within 9-12 months after treatment. One of the most important mechanisms for resistance to EGFR-TKI therapy is the substitution of threonine to methionine (T790M) on exon 20 of the EGFR gene, which occurs in 49% to 60% of patients. Osimertinib mesylate (formerly AZD-9291) is a potent third-generation TKI which irreversibly inhibits mutated EGFR alleles, including T790M. This review summarizes osimertinib's pharmacology, pharmacokinetics, safety, side effects and clinical utility in the treatment of EGFR-mutated advanced NSCLC.

Rapid Clinical and Radiographic Response With Combined Dabrafenib and Trametinib in Adults With BRAF-Mutated High-Grade Glioma.

BRAF V600E mutations have been successfully treated with targeted therapy in melanoma, non-small cell lung cancer, and thyroid cancer. Interestingly, these mutations have also been identified in a subset of pediatric and adult brain tumors, with several cases reportedly responding to targeted therapy. However, these reports have been limited to single-agent BRAF inhibitor therapy and recurrent disease. Herein, we report dramatic clinical and radiographic responses to combination dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in 2 adults with high-grade gliomas (HGGs), with 1 patient treated in the first-line setting. These observations, together with prior case reports, advocate for routine screening of BRAF point mutations in adult HGGs, and suggest that treatment with dual-targeted therapy, even in newly diagnosed cases, is safe and effective.

Recovery from childhood community-acquired pneumonia in a developing country: Prognostic value of serum procalcitonin

BackgroundChildhood community-acquired pneumonia is a common and potentially life-threatening illness in developing countries. We assessed the prognostic value of serum procalcitonin level upon admission on clinical response to antibiotic treatment. MethodsOut of 89 patients, the median (IQR) age was 19(12–29) months and 60% were boys. Viral (49.5%), typical bacterial (38%) and atypical bacterial (12.5%) infections as well as probable pneumococcal infections (26%) were diagnosed. ResultsSeventy-five (84%) children became afebrile ≤48h after treatment. In 14 children who remained febrile after 48h of treatment, median[IQR] serum procalcitonin (ng/ml) level on admission was higher than in those with rapid recovery (2.1[0.8–3.7] vs 0.6[0.1–2.2]; P=0.025). In the slow-responding children, pneumococcal infections were more common (71% vs 17%; P<0.001). Procalcitonin concentrations on admission were higher in children with pneumococcal pneumonia compared to children with non-pneumococcal pneumonia (2[0.7–4.2] vs 0.5[0.08–2.1]; P=0.002). The ROC curve found that <0.25ng/ml of serum procalcitonin had a high negative predictive value (93%[95%CI:80%–99%]) for pneumococcal infection. All children that remained febrile after 48h of treatment had procalcitonin >0.25ng/ml on admission. The majority of children with pneumonia in a developing country become afebrile within 48h after onset of antibiotic treatment. ConclusionsSerum procalcitonin <0.25ng/ml predicted rapid clinical response and non-pneumococcal etiology.

Abstract B28: Overcoming drug resistance to Trk inhibition by rational combination of entrectinib and trametinib: from bench to bedside

Abstract Abnormal expression and constitutive activation of TrkA, TrkB and TrkC due to gene fusions are oncogenic drivers in many cancer types. Entrectinib, a potent, brain-penetrant Trk inhibitor, has demonstrated rapid, deep, and sustained clinical responses in patients with advanced or metastatic Trk-fusion-positive solid tumors across multiple histologies. For tyrosine kinase inhibitors, point mutations that disrupt the binding between the inhibitor and kinase domain of the target are a common mechanism of resistance. By design, entrectinib retains its potency against gatekeeper mutations in Trk, ROS1 and ALK. On the other hand, solvent front mutations, G595R in TrkA or G623R in TrkC (analogous to ROS1 G2032R and ALK G1202R), have been identified as resistance mutations in a clinical setting. Preclinically, upregulation of the MAPK pathway was observed following the introduction of such mutation in Trk-fusion-positive cancer cell lines. In vitro combination screening and in vivo efficacy study further demonstrated the potential for entrectinib-trametinib (a MEK inhibitor) combination to overcome the drug resistance mediated by solvent front mutations. In the clinic, a 34-year-old female patient with ETV6-NTRK3 positive mammary analog secretory carcinoma (MASC) who progressed despite multiple courses of prior multi-modal therapy, including crizotinib, experienced a rapid confirmed partial response (PR: 89% reduction at nadir) with entrectinib treatment. Seven months later, asymptomatic progressive disease (PD) was detected at a solitary tumor site, a biopsy of which showed a G623R solvent front mutation. After three more months on entrectinib, the patient experienced generalized progression and was in need of additional therapy. She was then treated with another Trk inhibitor with no clinical benefit. She then received palliative radiation therapy to symptomatic pleural/chest wall metastases. Supported by the preclinical data on combination therapy, a single patient protocol was subsequently developed to allow co-administration of entrectinib and trametinib. Significant tumor regression was achieved within the first eight weeks, including sustained resolution of tumor-associated pain and hypertrophic osteoarthropathy. In conclusion, we have identified a mitigation strategy, utilizing an approved agent combined with a well-characterized clinical stage agent, to overcome acquired Trk-inhibitor resistance, presumably by overcoming solvent front mutation-driven MAPK activation. The successful translation of a preclinical observation made at the bench to clinical practice at the bedside has greatly extended the duration of tumor regression and provided continued care to a Trk-fusion positive patient even after the emergence of resistance. This clinical observation will be further explored in a dedicated Phase 1/1b combination study. Citation Format: Ge Wei, Edna Chow Maneval, Vanessa Esquibel, Michael F. Berger, Sofia Haque, Roopal Patel, Colin Walsh, Zachary Hornby, Pratik Multani, Gary Li. Overcoming drug resistance to Trk inhibition by rational combination of entrectinib and trametinib: from bench to bedside [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B28.

Case report of hyperglycemic nonketotic chorea with rapid radiological resolution

BackgroundHemichorea is a rare manifestation of nonketotic hyperglycemia that usually affects elderly Asian women with poor glycemic control. Non-contrast computerized Tomography and T1- weighted Magnetic Resonance Imaging shows characteristic hyperintense basal ganglia lesions.Case presentationA Fifty-seven year old Sri Lankan female presented with a two-day history of right upper limb chorea. She had been diagnosed with diabetes mellitus one year ago, but was not on any treatment and did not have any micro vascular or macro vascular complications. Random blood sugar was 420 mg/dl and full blood count, liver function tests, renal function tests, inflammatory markers, thyroid function tests, Urine protein / creatinine ratio, electrocardiogram and 2D Echo were normal. Arterial blood gas did not show acidosis and ketone bodies were not detected in urine. Non-contrast computerized Tomography brain on day 1 showed left side hyperdense lentiform and caudate nuclei and MRI on day 3 showed slightly high signal intensity of left side basal ganglia on T1- weighted images and low signal intensity on T2-weighted and Fluid-attenuated inversion recovery images. She was started on insulin and a low dose of clonazepam and glycemic control was achieved on day 3. Two days later, the chorea completely disappeared. CT brain was repeated 4 days and 10 days following glycemic control, which showed rapid resolution of CT changes. Clonazepam was stopped in 2 weeks and chorea did not recur.ConclusionThis is a rare manifestation of diabetes in Sri lanka and diagnosing this rare entity will direct clinicians to achieve optimum glycemic control as the treatment which will lead to rapid clinical response without any other medications. In this case report we high light that with the clinical improvement, repeating a CT scan even after a very short period like 2 weeks will show rapid radiological resolution. This repeat imaging can also be useful to confirm the diagnosis, which will minimize unnecessary investigations and treatments. Further cases of hyperglycemic nonketotic chorea with brain imaging performed within short intervals is needed to evaluate the nature of rapid radiological changes, which will be useful to understand the pathology of this condition.

Recombinant humanised anti-PD-1 monoclonal antibody (JS001) treatment for patients with refractory or metastatic nasopharyngeal carcinoma: preliminary results of an open-label, phase 1b/2, clinical study

BackgroundPatients with unresectable or recurrent nasopharyngeal cancer who have disease progression after standard therapy have few treatment options and represent an important, unmet medical need. Nasopharyngeal cancer is closely associated with Epstein-Barr virus (EBV) infection and has been reported to have high concentrations of PD-L1 expression and tumour-infiltrating lymphocytes, which indicate a potential implication of PD-1 blockade in the treatment of nasopharyngeal cancer. JS001, a humanised recombinant IgG4 antibody against PD-1, selectively blocks the interactions of PD-1, with its ligands PD-L1 and PD-L2, and promotes antigen-specific T-cell activation. Results of a phase 1 study of JS001 treatment in Chinese patients with heavily pretreated solid tumours have shown an acceptable safety profile in doses up to 10 mg/kg once every 2 weeks until progressive disease, intolerance, withdrawal of consent, or investigator decision. Here we report the safety and efficacy of JS001 in a phase 1b/2 clinical study. MethodsWe did this open-label, phase 1b/2, clinical study in Chinese patients with refractory or metastatic nasopharyngeal cancer received JS001 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity. All patients with measurable disease were assessed for clinical response every 8 weeks according to the immune-related Response Evaluation Criteria In Solid Tumors (iRECIST) criteria. Tumour PD-L1 expression, plasma EBV DNA concentration, and additional potential predictive biomarkers were monitored for correlation with clinical response. This study is registered with ClinicalTrials, number NCT02915432. FindingsBetween Dec 29, 2016, and June 19, 2017, we enrolled 48 patients with nasopharyngeal cancer. Of 23 evaluable patients, the median age was 46 years (range 33–70), 81% were male, and EBV serology tested positive in 92%. Adverse events occurred in 46 (96%) of 48 patients, which were mostly grade 1 or 2. Grade 3 and worse adverse events occurred in 17 patients (35%), including abnormal liver function (n=6, 13%), dysphagia (n=2, 4%), and pulmonary infection (n=2, 4%). Rapid and deep clinical responses were observed. Seven patients (15%) had partial responses while ten patients (21%) achieved stable disease, with the proportion of patients who achieved an objective response of 30% and a disease control of 73%. The responses seemed unrelated to PD-L1 expression status on tumour biopsy. InterpretationJS001 treatment has shown good clinical activity in heavily pretreated patients with nasopharyngeal cancer and a manageable safety profile. We plan to enrol 54 patients with nasopharyngeal cancer to further monitor the safety and efficacy of JS001 treatment. FundingShanghai Science and Technology Innovation Fund.

Abstract 3018: RET rearrangements as promising therapeutic targets in breast cancer

Abstract Background: Receptor tyrosine kinase alterations have played a significant role in therapeutic decisions for cancer due to their oncogenic nature and response to targeted small molecule kinase inhibitors. Increased genomic profiling of tumors using hybrid-capture based next-generation sequencing approaches now reveal the presence of previously unknown fusions and alterations involving kinases in a diverse set of cancers. Here we report the presence and therapeutic significance of recurrent and novel fusions involving RET, a known oncogenic tyrosine kinase receptor, in breast cancer. Methods: Comprehensive genomic profiling on formalin-fixed, paraffin embedded patient tumor tissues was performed using FoundationOne platform that covers the entire coding region for 315 cancer-related genes and introns of 28 genes involved in rearrangements at a depth of 500-1000X (Foundation Medicine, MA). Out of 23 rearrangements, two representative RET fusion expression vectors were synthesized and expressed in non-tumorigenic cell lines (breast MCF10A and mouse 3T3 fibroblasts) and were evaluated for RET kinase signaling, drug response, and tumorigenicity. Results: RET gene fusions, the canonical NCOA4-RET and a novel, noncanonical RASGEF1A-RET fusion, were identified in two separate breast cancers and both include exons required to retain the intact kinase domain of Ret. The novel RASGEF1A-RET fusion includes the non-coding region of RASGEF1A potentially resulting in a truncated RET protein using an alternate internal start site in exon 11 of RET. In vitro characterization of both fusions expressed in mouse 3T3 and human MCF10a cell lines revealed constitutive kinase activation and subsequent downstream signaling as evidenced by phosphorylation of Ret, Erk and Akt. This is the first reported noncanonical RET rearrangement resulting in a 5’ truncated but functional RET kinase. Non-tumorigenic cell lines with stable expression of either rearrangement showed transformed phenotypes assessed by changes in morphology, enhanced growth rate, colony forming ability, and tumor formation in mice. RET fusion-transformed cells were exquisitely sensitive to treatment with RET inhibitors when evaluated in both short-term and long-term functional assays. NCOA4-RET was found by CGP in an index case of metastatic ER+/HER2+ breast cancer that had radiographic evidence of disease progression while on trastuzumab, pertuzumab, and anastrazole. Subsequent treatment with cabozantinib plus anastrazole led to a rapid clinical and radiographic response. Conclusion: CGP techniques involving hybrid-capture based approaches can identify previously unreported but recurrent RET gene fusions in breast cancer. Here, we show that RET fusions including both canonical and non-canonical complex rearrangements are functional and may represent promising therapeutic targets in selected breast cancer patients. Citation Format: Bhavna S. Paratala, Jeffrey S. Ross, Casey B. Williams, Whitney Petrosky, Kirstin A. Williams, Jon Chung, Sonia C. Dolfi, Shridar Ganesan, Siraj Ali, Brian Leyland-Jones, Kim M. Hirshfield. RET rearrangements as promising therapeutic targets in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3018. doi:10.1158/1538-7445.AM2017-3018

Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant unresectable or metastatic melanoma (MM).

9505 Background: D (BRAF inhibitor) + T (MEK inhibitor) combination therapy is associated with rapid clinical responses and has improved clinical outcomes in pts with BRAFV600–mutant MM, but long-term (˃ 3 y) clinical efficacy and safety data are limited. The longest follow-up to date of a randomized trial evaluating D+T at the approved dose (150 mg BID/2 mg QD [150/2]) was of the phase II study BRF113220 (part C; median, 45.6 mo) in which durable outcomes were achieved in some pts with BRAFV600–mutant MM (3-y OS, 38%). Here, we report updated 5-y landmark analyses to further characterize the impact of D+T in MM. Methods: Pts with BRAFV600–mutant mm enrolled in BRF113220 part C (NCT01072175) were randomized 1:1:1 to receive monotherapy D (150 mg BID), D+T (150 mg BID/1 mg QD), or D+T (150/2). Pts who progressed on D alone could cross over to the D+T 150/2 arm. Pt disposition, pt demographics, and 4- and 5-y efficacy and safety were analyzed for both the D-alone and D+T (approved 150/2 dose) arms. Results: This updated analysis represents an additional ≈ 2 y of follow-up (D and D+T arms; n = 54 each). As of 13 Oct 2016, 45 pts (83%) on D alone had crossed over to D+T. 20 pts were ongoing (D, n = 7 [13%]; D+T, n = 13 [24%]); 80% of D pts and 70% of D+T pts had died. D+T OS remained superior to D alone. The 4- and 5-y OS rates with D+T were 30% and 28%, respectively, demonstrating a stabilization of the OS curve. The PFS curve for D+T also remained stable (4- and 5-y: both 13%). Consistent with earlier results, the best OS for pts who received D+T was seen in pts with normal LDH (5-y, 45%) and normal LDH with disease in &lt; 3 organ sites (5-y, 51%). At the 5-y landmark, 1 additional pt who received D+T improved from a partial to a complete response. Additional follow-up revealed no new safety signals with D+T. Detailed analyses of D crossover pts, responders, and post-progression therapy will be presented. Conclusions: This longest follow-up to date of BRAF + MEK inhibitor combination therapy in pts with BRAFV600–mutant mm revealed stable OS and PFS lasting ≥ 5 y with consistent tolerability. These results demonstrate that some pts with mm can achieve durable benefit with D+T therapy. Clinical trial information: NCT01072175.

IgG4-related disease presenting as posterior scleritis and vitritis, progressing to multifocal orbital involvement

IgG4-related disease (IgG4-RD) is a rare, chronic inflammatory condition that may involve nearly every organ system. Originally identified as a cause of autoimmune pancreatitis, its characteristic histological and clinical features...

Empagliflozin/linagliptin single-pill combination therapy for patients with type 2 diabetes mellitus

ABSTRACTIntroduction: Type 2 diabetes mellitus (T2DM) is typically progressive, with sequential addition of therapies often needed to address increasing hyperglycemia over the disease course. Using treatments in combination may be preferred to sequential addition, as a means of providing a more rapid clinical response and potentially avoiding clinical inertia. In such cases, a single-pill combination can help to reduce pill burden. Although various single-pill combinations of oral glucose-lowering agents are available, empagliflozin/linagliptin was the first approved combination of a sodium glucose co-transporter 2 (SGLT2) inhibitor with a dipeptidyl peptidase 4 (DPP-4) inhibitor in the United States.Areas covered: Two publications of the clinical trial investigating the efficacy and safety of single-pill combinations of empagliflozin/linagliptin in treatment-naive or metformin-treated patients with T2DM (NCT01422876) are reviewed, and their potential impact on clinical practice is discussed.Expert opinion: The study discussed provides evidence for the efficacy and safety of empagliflozin/linagliptin single pills. Addition of an empagliflozin/linagliptin single pill may be considered in patients with inadequate glycemic control on metformin, or as an alternative to first-line treatment with empagliflozin or linagliptin when metformin is not suitable, particularly in patients with very poor glycemic control, or those who need to achieve target more quickly.

Pro: Prevention of acute kidney injury: time for teamwork and new biomarkers.

Acute kidney injury (AKI) is a common condition in critically ill patients. Multiple studies have identified AKI as a strong independent risk factor for higher morbidity and mortality. AKI is often multifactorial, asymptomatic and difficult to predict. In recent years, the discovery of several AKI biomarkers, including the recent validation and approval of cell cycle arrest biomarkers (NephroCheck, Astute Medical, San Diego, CA, USA), has provided additional tools to detect patients at high risk of AKI and improve their outcomes. We propose a protocol to integrate the use of NephroCheck into a multidisciplinary rapid clinical response team to potentially reduce AKI development, severity and the number of patients who need dialysis. We have designed a stepped alarm system for nephrologists and critical care physicians that starts with the recognition of high-risk patients in the clinical setting. The evaluation of patients' clinical situation together with the NephroCheck value will lead to a list of recommendations to prevent the development of AKI or progression to acute kidney stress or injury. We propose that the routine clinical application of a NephroCheck Rapid Response Team (RRT), where the NephroCheck RRT acts under the principle of improving safety and avoiding deterioration of patients, can impact patients' well-being in a positive way.

“Did I Hear You Correctly? The Organism Identified Was Corynebacterium diphtheriae?”

Diphtheria is a bacterial infection caused by Corynebacterium diphtheriae and is primarily transmitted from person to person through close physical and respiratory contact; disease can involve almost any mucous membrane and is classified depending on the anatomic site of infection. Diphtheria is an acute, toxin-mediated disease whose occurrence is characterized by periodicity and epidemic waves, with a high incidence and mortality. Once one of the leading causes of childhood death, global diphtheria incidence declined approximately 70% through implementation of widespread vaccination programs. However, a major epidemic of diphtheria occurred during the 1990s in the Russian Federation and the newly independent states of the former Soviet Union. Although the epidemic is under control, toxigenic C. diphtheriae strains are still reported in Europe and globally, including North and South America, the Indian subcontinent, Africa, Southeast Asia, and the eastern Mediterranean. Rapid clinical and public health responses are required to control diphtheria outbreaks, with the clinical microbiology laboratory playing an essential role in providing prompt and rapid identification. In light of experience with a recent case of nontoxigenic C. diphtheriae respiratory infection, aspects of this organism and the diseases it causes are reviewed.

Abstract P3-07-02: Are we missing actionable targets in breast cancer? Novel insights into recurrent Ret alterations

Abstract Background: Recurrent gene fusions in breast cancer have been rarely reported suggesting that they either are not present or are not easily detected by standard sequencing methods. Comprehensive genomic profiling (CGP) by hybrid capture-based, high depth next-generation sequencing approaches, can be used to detect recurrent rearrangements and other genomic alterations involving target genes. We found that CGP can identify recurrent alterations involving RET, a known oncogenic tyrosine receptor kinase, in a subset of breast cancer. Methods: CGP using FoundationOne platform was performed interrogating the entire coding region for up to 315 cancer-related genes and introns of up to 28 genes involved in rearrangements at a depth of 500-1000X in formalin-fixed, paraffin embedded tumor tissue (Foundation Medicine, MA). Engineered representative RET fusion vectors were synthesized and expressed in non-tumorigenic cell lines (breast MCF10A and mouse 3T3 fibroblasts), and cells were evaluated for RET kinase signaling, drug response, and tumorigenicity. Patient-derived xenografts (PDX) generated from two triple negative breast cancers (TNBCs) were used in an ex vivo assay (Response3DXTM, Molecular Response LLC, San Diego, CA). Results: Twenty-two RET rearrangements were identified in 8119 (0.27%) breast cancer cases. Of these, 5 rearrangements were activating RET fusions including CCDC6-RET (n=4) and NCOA4-RET (n=1), that have been described in other cancer types. Five other cases had clear evidence of genomic rearrangement involving RET, but the 5' partners could not be definitively identified. The remaining twelve cases had complex rearrangements of RET including internal duplications. RET amplification was also observed, both in TNBC and in a HER2+ breast cancer at onset of resistance to HER2-targeted therapy. Both NCOA4-RET and a novel RASGEF1A-RET fusion were characterized in vitro. Non-tumorigenic cells engineered to stably overexpress either RET fusions demonstrated transformed phenotypes. The fusions were constitutively active, as shown by endogenous phosphorylation of the kinase domain, and drove activation of downstream signaling as shown by increased phosphorylation of ERK and AKT. Cells transformed by RET-fusions were exquisitely sensitive to treatment with RET inhibitors. Interestingly, a PDX model of RET-amplified TNBC was sensitive to treatment with a PIK3CA inhibitor. An index case of ER+/PR-/HER2+, metastatic breast cancer that had radiographic evidence of disease progression while on trastuzumab, pertuzumab, and anastrazole was found to have a NCOA4-RET fusion by CGP. Subsequent treatment with with cabozantinib plus anastrazole led a rapid clinical and radiographic response. Conclusions: CGP can identify recurrent RET rearrangements in breast cancer that act as primary oncogenic drivers and can be therapeutically targeted. RET alterations may also play a role in acquired resistance to HER2-targeted therapies, suggesting a role for combined RET and HER2-targeted therapy in this setting. Our data demonstrate that RET alterations can be identified by clinical-grade CGP and are promising candidates as therapeutic targets in selected breast cancer patients. Citation Format: Hirshfield KM, Paratala BS, Hindoyan A, Dolfi SC, Yilmazel B, Schrock A, Gay L, Ali SM, Ross JS, Williams CB, Nair P, Ganesan S, Leyland-Jones B. Are we missing actionable targets in breast cancer? Novel insights into recurrent Ret alterations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-02.

Identification of Patient Characteristics Associated With Rapid Clinical Response in Hospitalized Patients With Skin and Soft Tissue Infections

Identification of Patient Characteristics Associated With Rapid Clinical Response in Hospitalized Patients With Skin and Soft Tissue Infections

From guidelines to real daily practice: Prolactinoma in pregnancy

Introduction Prolactinoma is a frequent cause of hypogonadisme. Dopamine agonist treatment is usually safe and efficient to restore fertility. During pregnancy, prolactinoma behavior depends on its initial size and its management can be challenging. In consequence, follow-up should be intensified in pregnant women. Observation We report here the case of a 28-year-old women, treated for symptomatic macroprolactinoma (adenoma size: 11mm (figure)-PRL: 429 mg/L). Cabergoline treatment (0,5 mg/week) allows a rapid clinical and radiological response (size: 5mm-PRL: 2,1 mg/L), leading to regular menses. Cabergoline treatment was stopped on July 2015 because of a pregnancy. After 4 months, she reports galactorrhea. At that time, PRL levels raised up to 827 mg/L and MRI revealed a tumor growth (size: 18 mm). Low dose cabergoline treatment (dose: 0,25 mg/week) was then reintroduced but did not control PRL levels (1226 mg/L). Treatment was then intensified (dose: 0,5 mg/week) and led to a better control of PRL levels (247 mg/L) and tumor size (11 mm). Conclusion Estrogen levels can influence lactotroph cells replication and prolactinoma size. Tumor growth of prolactinoma during pregnancy depends on their size (4,8% in treated macroprolactinomas, − 2,7% in treated microprolactinomas, − 22,9% in untreated marcoprolactinomas). On the other hand, dopamine agonists are usually discontinued during pregnancy, although evidences about cabergoline and bromocriptine safety are growing. As PRL levels rise physiologically during pregnancy, management of prolactinoma in this situation can be challenging. In our case, a rapid elevation of PRL levels suggests a tumor growth. We therefore recommend a monthly evaluation in macroprolactinoma, even if initial response to dopamine agonist was positive.

Terminal complement activation is increased and associated with disease severity in CIDP.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic autoimmune neuropathy. While both cell‐mediated and humoral mechanisms contribute to its pathogenesis, the rapid clinical response to plasmapheresis implicates a circulating factor responsible for peripheral nerve injury. We report that treatment‐naïve patients with CIDP show increased serum and CSF levels of the anaphylatoxin C5a and the soluble terminal complement complex (sTCC). Systemic terminal complement activation correlates with clinical disease severity as determined by the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. These data indicate that complement activation contributes to peripheral nerve injury and suggest that complement inhibition should be explored for its potential therapeutic merit in CIDP.

Automation Highlights from the Literature

Automation Highlights from the Literature

The evolution of combined molecular targeted therapies to advance the therapeutic efficacy in melanoma: a highlight of vemurafenib and cobimetinib.

Metastatic melanoma is an aggressive, rapidly progressive disease which historically had very few effective treatment options. However, since 2011, the therapeutic landscape of melanoma has undergone a dramatic transformation with two distinct approaches and has catalyzed the successful advancement in the clinical field of immuno-oncology. In addition, the recognition of a key oncogenic driver mutation in melanoma, BRAF, stimulated the development of multiple potent kinase inhibitors which has also influenced the expansion and use of targeted agents in the practice of oncology. Vemurafenib, the initial BRAF inhibitor approved for the treatment of melanoma, was the first agent to demonstrate rapid clinical responses and significantly improved survival which was a clinical breakthrough in the treatment of melanoma. Although exciting and practice changing, the unparalleled responses with vemurafenib are usually not sustained. Further investigations delineated several mechanisms of acquired resistance which are most often mediated by the upregulation of the MAPK pathway. MEK inhibitors, another class of small-molecule inhibitors, were developed as an alternative agent to suppress the MAPK pathway downstream, independent from BRAF activation. Multiple studies have demonstrated the improvement in antitumor activity when MEK inhibitors are used in combination with BRAF inhibitors in the treatment of metastatic melanoma. This is a review of the investigations that led to the US Food and Drug Administration approval in 2015 of the combination of vemurafenib and cobimetinib, adding to the quickly growing armament for the treatment of advanced or metastatic melanoma with a BRAF V600 mutation.

Rapid Clinical Response to Omalizumab in Severe Atopic Keratoconjunctivitis

Rapid Clinical Response to Omalizumab in Severe Atopic Keratoconjunctivitis