Subsequent Chemotherapy Treatment Research Articles

Immune checkpoint inhibitors as subsequent treatment in older adults with non-small cell lung cancer and synchronous brain metastases.

Immune checkpoint inhibitors (ICIs) have become the mainstay treatment for non-small cell lung cancer (NSCLC). However, there is a lack of studies assessing ICIs as subsequent treatment in older adults with NSCLC and brain metastasis (BM). This retrospective cohort study compared the real-world survival of older patients with NSCLC and BM at diagnosis [synchronous BM (SBM)] previously treated with chemotherapy receiving ICI versus chemotherapy as subsequent treatment. Patients with NSCLC and SBM ≥65 years previously treated with chemotherapy were identified using the SEER-Medicare database (2010-2019). Patients receiving new chemotherapy and/or Food and Drug Administration (FDA)-approved ICIs as second/third-line treatment were included, excluding those ever-receiving targeted therapies. Each ICI patient was matched to one chemotherapy patient by time to subsequent treatment (within ±30 days) from diagnosis. Overall survival (OS) time was measured from the start of subsequent treatment to death, censored at disenrollment from Medicare Part A/B, enrollment in Part C, or end of study (December 31, 2019), whichever came first. OS curves were estimated and compared using the Kaplan-Meier (KM) method and log-rank test. Hazard ratio (HR) was estimated using a multivariable-adjusted Cox proportional hazards model. Matched cohorts included 546 patients [273 in each group; median age 71 (range, 65-87) years]. ICI patients were older, more likely non-Hispanic, with squamous cell carcinoma, and liver metastasis compared to chemotherapy. KM estimated better survival in ICI than chemotherapy {median survival: 209 days [95% confidence interval (CI): 160-275] vs. 155 days (95% CI: 135-187); log-rank P<0.001}. ICI was associated with a lower adjusted hazard of death [HR =0.63; 95% CI: 0.52-0.75; P<0.001] compared to subsequent chemotherapy treatment. In this population-based study of older patients with NSCLC and SBM previously treated with chemotherapy, subsequent treatment with ICI was associated with improved survival compared to chemotherapy.

An Unusual Complication In A Patient With Hodgkin Lymphoma: Bilateral Auricular Hematoma

Hodgkin lymphoma is lymphoid neoplasm in which the malignant cells admixed with a heterogeneous population of non-neoplastic inflammatory cells. A combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD) is the most commonly used chemotherapy regime for Hodgkin lymphoma. In this case report, we present a patient with Hodgkin lymphoma who developed bilateral auricular hematoma after a first time administrition of ABVD treatment. A 27-year-old female patient was presented to the hematology outpatient clinic with a swelling in the neck for two weeks. An excisional biopsy performed from the left axillary region. The pathology report demonstrated classical Hodgkin lymphoma was noticed to be consistent with mixed cellular type. First dose ABVD protocol was administered to the patient. One week after chemotherapy, swelling and discoloration were observed in the patient's bilateral auricles without a history of trauma. The patient was consulted to the Department of Otorhinolarngology-Head and Neck Surgery. Bilateral drainage of auricular hematoma was performed immediately. Intravenous ciprofloxacin was also administered. The auricular hematoma did not reoccur after the subsequent chemotherapy treatments.

Combined Molecular and Morphological Imaging of CTCs for HER2-Targeted Chemotherapy Guidance.

Since biomolecules change dynamically with tumor evolution and drug treatment, it is necessary to confirm target molecule expression in real time for effective guidance of subsequent chemotherapy treatment. However, current methods to confirm target proteins require complex processing steps and invasive tissue biopsies, limiting their clinical utility for targeted treatment monitoring. Here, CTCs, as a promising liquid biopsy source, were used to molecularly characterize the target protein HER2. To accurately identify CTCs, we specifically proposed a combined molecular and morphological imaging method, rather than using specific biomarker alone or morphology analysis, we identified CTCs as CK19+/CD45-/HE+. On the basis of the accurate identification of CTCs, we further analyzed the target protein HER2 in clinical patients at the single-CTC level. Comparative analysis of the clinical results of patient pathological tissue and paired blood samples showed that CTCs had a heterogeneous HER2 expression at the single-cell level and showed results inconsistent with the immunohistochemistry results in some cases. CTC-based analysis could help clinicians have a more comprehensive understanding of patient target protein expression. We believe that CTC-based target protein studies are of great significance for the precise management of targeted therapy.

Case Report: A PD-L1-Positive Patient With Pleomorphic Rhabdomyosarcoma Achieving an Impressive Response to Immunotherapy

There is currently a lack of effective systemic treatment for patients with advanced pleomorphic rhabdomyosarcoma (PRMS). Although programmed death protein 1 (PD-1) inhibitors have shown efficacy in various solid tumors, their effects on PRMS have not been well established. Here, we present a case of a 12-year-old Chinese male adolescent with metastatic PRMS who benefited from the PD-1 inhibitor nivolumab. The patient initially underwent primary tumor resection but failed to respond to subsequent first-line chemotherapy and second-line pazopanib treatment. Pathological examination showed positive PD-L1 expression and tumor-infiltrating lymphocytes in the tumor tissue, and the patient was administered nivolumab as a posterior-line treatment. After attaining a clinically partial response (PR), surgical resection was performed, which was followed by adjuvant nivolumab. At the time of the submission of this manuscript, the patient achieved recurrence-free survival (RFS) lasting 45 months and counting. This is the first clinical evidence that a patient with refractory PRMS was controlled by anti-PD-1 antibody, with an RFS lasting more than 3 years. This case suggests that PD-L1 expression and T-cell infiltration could be used as potential biomarkers for PRMS immunotherapy.

P28.02 Individualized Nutritional Management in Patients Eligible for Thoracic Surgery Experience of a Chest Tumor Center in Brazil

Lung cancer (LC) has an increased incidence and early diagnosis can be instituted as a curative measure for these patients. Surgery is the treatment of choice for early-stage disease, which can be combined with systemic treatment. The personalized nutritional intervention in these patients can contribute to an adequate pre and postoperative and subsequent chemotherapy treatment. Research in these areas is necessary to establish a diet that will guarantee an adequate caloric and protein intake in these patients in order to preserve nutritional status and quality of life. The objective is to describe an experience report of a nutritional intervention protocol applied pre- and postoperatively in patients undergoing thoracic surgery at a referral center. This is a qualitative, descriptive, experience report type study carried out in an oncology clinic. The protocol used in the unit consists of the application of nutritional risk tracking instruments, the Patient-Generated Subjective Global Assessment (PG-SGA) and subsequent assessment of nutritional status by anthropometric methods (weight, history of weight loss, height, body mass, calf perimeter, food history (24-hour recall for 3 consecutive days), laboratory tests (blood count, blood glucose, glycosylated hemoglobin, albumin, protein C reactive) and comorbidities. with nutritional risk, considered in our center as patients with unintentional weight loss, low force palm pressure by dynamometry according to the European Working Group on Sarcopenia in Older People (EWGSOP), low protein intake according to the guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) and American Society for Parenteral and Enteral Nutrition (ASPEN). Patients at high risk of malnutrition are chosen to receive immunomodulatory nutritional therapy between 7 and 14 days pre- and postoperatively, as shown in figure 1. Adequate nutritional status appears to be achieved when this protocol is completed. The referral of patients with chest tumors eligible for surgery to nutrition, allows an early and more effective nutritional intervention. Having this flow as a service routine allows the patient a better response to treatment and a positive impact on their quality of life.

Hyperprogressive disease and its clinical impact in patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with immune-checkpoint inhibitors: Korean cancer study group HN 18-12.

Although immune-checkpoint inhibitors (ICIs) have emerged as therapeutic options for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC), concerns have been raised on exceptional acceleration of tumor growth during treatment with ICIs, a condition described as hyperprogressive disease (HPD). This study examined the incidence, potential predictors, and clinical impact of HPD in R/M-HNSCC. We retrospectively collected data of patients with R/M-HNSCC treated with ICIs between January 2013 and June 2018 from 11 medical centers in Korea. HPD was defined as tumor growth kinetics ratio (TGKr) > 2, which was calculated by comparing TGK on ICIs with that before treatment with ICIs. Of 125 patients, 68 (54.4%) obtained progressive disease as their best responses (progressors). HPD was identified in 18 (26.5% of progressors, 14.4% of total) patients. Relatively younger age, primary tumor of oral cavity, and previous locoregional irradiation were significant predictors of HPD according to multivariable analysis (p = 0.040, 0.027, and 0.015, respectively). Compared to patients without HPD, patients with HPD had significantly shorter median progression-free survival (PFS) (1.2 vs. 3.4months, p < 0.001) and overall survival (OS) (3.4 vs. 10.7months, p = 0.047). However, interestingly, HPD did not significantly affect the therapeutic benefit of post-ICIs chemotherapy. Younger patients with oral cavity cancer or prior treatment with locoregional radiotherapy could be regarded potential risk groups for HPD in patients with R/M-HNSCC treated with ICIs. Although HPD could consistently predict poorer survival outcomes, patients who experienced HPD with ICIs should not be excluded from the subsequent salvage chemotherapy treatments.

Abstract A066: Role of the NRF2 signaling pathway in sustaining chemoresistance in medulloblastoma

Abstract Nrf2, a key orchestrator of cell defense mechanisms against oxidative stress and xenobiotic insults, has been linked to chemotherapy resistance and recurrence in many human cancers. Through the establishment of an in vitro model of chemoresistance, we investigated the role of Nrf2 in sustaining resistance to chemotherapy in medulloblastoma (MB), a highly aggressive pediatric brain tumor intrinsically characterized by fast growth, high invasiveness and resistance to treatments. MB DAOY cells were weekly exposed to a cocktail of drugs commonly used in MB treatment, vincristine, etoposide, cisplatin and cyclophosphamide (VECC) inducing the emergence of a resistant phenotype. After 5 cycles of VECC treatment we obtained a culture of cells resistant to subsequent chemotherapy treatments. We observed increased Nrf2 levels and activity in therapy-exposed cells already from the first received dose of VECC. Nrf2 levels remained high throughout all the rest of chemotherapy cycles and interestingly, its transcriptional activity spiked up when resistance to chemotherapy emerged, as demonstrated by the increase of antioxidant response element (ARE)-driven luciferase activity and the expression of target genes. The knock down of Nrf2 in resistant cells, by the use of specific siRNA, was able to restore chemosensitivity, suggesting a role of Nrf2 signaling pathway in the onset of chemotherapy resistance in MB cells. Resistant cells showed a higher ROS (reactive oxygen species) scavenging capacity after stimulation with hydrogen peroxide. Nrf2 silencing partially reverts the ability of resistant cells to manage oxidative stress, supporting the hypothesis of Nrf2 involvement in the ROS scavenging potential of VECC resistant MB cells. In addition to directly regulate ROS-scavenging enzymes, Nrf2 has been described to control cell metabolism that maintain redox homeostasis in cancer stem cells. Among the Nrf2 target genes upregulated in DAOY resistant cells we found the upregulation of PFKFB-3, G6PD and TKT. The increased expression of this enzymes suggests a metabolic reprogramming in resistant cells. Our data support the involvement of Nrf2 pathway in MB response to VECC treatment and show that the upregulation of this detoxifying system sustains MB resistance to chemotherapy. Citation Format: Fatlum Rruga, Elena Mariotto, Luca Persano, Elena Rampazzo, Alessandra Luchini, Lance A Liotta, Giampietro Viola, Roberta Bortolozzi. Role of the NRF2 signaling pathway in sustaining chemoresistance in medulloblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A066. doi:10.1158/1535-7163.TARG-19-A066

Comparison between stereotactic radiosurgery and whole-brain radiotherapy for 10-20 brain metastases from non-small cell lung cancer.

The efficacy and safety of stereotactic radiosurgery (SRS) in comparison with whole brain radiotherapy (WBRT) for brain metastases (BMs) remains unclear. The present study retrospectively reviewed 44 patients who received SRS or WBRT as an initial treatment for 10-20 BMs from non-small cell lung cancer between 2009 and 2016. Of the patients, 24 (54.5%) were treated with SRS and 20 (45.5%) were treated with WBRT. Overall survival (OS), time to intracranial progression (TTIP), neurological survival (NS), and prognostic factors were examined. OS did not significantly differ between the two groups: 7.3 months in the SRS group vs. 7.2 months in the WBRT group (P=0.502). Median TTIP was significantly shorter in the SRS group than in the WBRT group (7.1 vs. 19.1 months, P=0.009). In contrast, there were no significant differences in NS between the two groups (14.5 months in the SRS group vs. 12.9 months in the WBRT group, P=0.346). Univariate and multivariate analysis revealed that the type of initial treatment for BMs (WBRT or SRS) was not a significant prognostic factor (hazard ratio=0.80, 95% confidence interval: 0.42-1.52, P=0.502). However, histology, performance status, subsequent molecular targeted drugs, subsequent chemotherapy and salvage treatment were independent prognostic factors. There were no significant differences in OS and NS between treatment with SRS and treatment with WBRT in patients with 10-20 BMs, although TTIP was improved with WBRT. As an upfront treatment for 10-20 BMs, SRS may delay WBRT and the adverse events associated with WBRT.

31. Neoadjuvant Endocrine Therapy in Breast Cancer Up-Regulates the Cytotoxic Drug Pump ABCG2/BCRP, and May Lead to Resistance to Subsequent Chemotherapy

Background: Neoadjuvant endocrine therapy (NAET) for breast cancer is utilised to down-stage tumours, thereby increasing rates of breast conserving surgery. However, little is known about how NAET impacts on response to subsequent adjuvant therapies. Here, we investigate the relevance of expression of the xenobiotic transporter ABCG2/BCRP, a gene/protein associated with chemoresistance, in the context of NAET and particularly with reference to subsequent chemotherapy treatment after NAET.

Neoadjuvant Endocrine Therapy in Breast Cancer Upregulates the Cytotoxic Drug Pump ABCG2/BCRP, and May Lead to Resistance to Subsequent Chemotherapy

IntroductionNeoadjuvant treatments for primary breast cancer are becoming more common; however, little is known about how these impact on response to subsequent adjuvant therapies. Conveniently, neoadjuvant therapy provides opportunities to consider this question, by studying therapy-induced expression changes using comparisons between pre- and posttreatment samples. These data are relatively lacking in the context of neoadjuvant endocrine therapy, as opposed to the more common neoadjuvant chemotherapy. Here, we investigate the relevance of expression of the xenobiotic transporter ABCG2/BCRP, a gene/protein associated with chemoresistance, in the context of neoadjuvant endocrine therapy and particularly with reference to subsequent chemotherapy treatment. Materials and MethodsABCG2/BCRP expression was assessed by immunohistochemistry or by expression arrays in matched patient samples pre- and post-neoadjuvant endocrine therapy. Cell culture was used to model the impact of endocrine therapy-induced changes in ABCG2/BCRP on subsequent chemotherapy response, using Western blots, quantitative polymerase chain reaction, survival assays, and cell cycle analyses. ResultsABCG2/BCRP was commonly and significantly upregulated in breast cancers after treatment with neoadjuvant endocrine therapy in 3 separate cohorts encompassing a total of 200 patients. Treatment with the endocrine therapeutic tamoxifen similarly induced ABCG2/BCRP upregulation in a relevant model cell line, the estrogen receptor-positive line T47D. Critically, this upregulation was associated with significantly increased chemoresistance to subsequent treatment with epirubicin, an anthracycline commonly used in breast cancer adjuvant chemotherapy. ConclusionOur data suggest that neoadjuvant endocrine therapy may induce poor responses to adjuvant chemotherapy, and therefore, that clinical outcomes following this treatment sequence warrant further study.

Taxane acute pain syndrome (TAPS) in patients receiving chemotherapy for breast or prostate cancer: a prospective multi-center study.

Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 2-3days after taxane-based chemotherapy and lasting up to 7days. In the absence of validated tools, many studies use the presence of both the myalgia and arthralgia components of the Common Terminology Criteria for Adverse Events (CTCAE) to define TAPS. The present study prospectively evaluated the frequency, severity, and impact of TAPS in patients with breast or prostate cancer. In this prospective, non-randomized study, patients with breast or prostate cancer commencing taxane-based chemotherapy completed the CTCAE (version 4.03), the Functional Assessment of Cancer Therapy-Taxane (FACT-T), and Brief Pain Inventory (BPI) questionnaires at baseline and once between days 5 and 7 of each chemotherapy cycle. From March 2015 to April 1, 2016, 75 patients (breast n = 66, prostate n = 9) were enrolled; 83% received docetaxel and 16% paclitaxel and 1% withdrew. After the first cycle of taxane, TAPS was reported by 25/69 (36.2%) patients; a further 8/69 (18.2%) reporting TAPS after a subsequent chemotherapy treatment. Overall incidence of TAPS was 33/75 (44%). While associated with detrimental scores on FACT-T and BPI as well as increased use of analgesics in 63% (21/33) of patients with TAPS, TAPS did not lead to alterations in chemotherapy dosing. TAPS is common after taxane-based chemotherapy, and its presence is associated with reduced quality of life and increased analgesic requirements. Prospective patient-reported outcome assessments are crucial to help individualize treatment strategies and improve management of TAPS.

Particular cause of obstructive dyspnea in children

Dyspnea in infants and small children is a common symptom of addressability to a medical service. For a doctor, setting a diagnosis is challenging, because dyspnea can be a symptom in multiple conditions. The first step in establishing the diagnosis of dyspnea in children is explaining the mechanism (obstructive dyspnea, nonobstructive or “sine materia”). In the presence of an obstructive dyspnea, besides common causes (laryngitis, bronchiolitis, bronchial asthma, aspiration of foreign bodies), some mediastinal disorders should be evoked. We present the case of a one year and two month old male patient, presented for cough, expiratory dyspnea and wheezing, the presumed clinical diagnosis being acute bronchitis. Given that dyspnea was enhanced under treatment, a chest radiograph was performed, which revealed a homogeneous oval opacity occupying almost the entire right thorax. Thoracic CT revealed in the right lateromediastinal part a tumor with an apparently cystic form, with inner calcifications, with left displacement of the mediastinal structures. Thoracotomy with tumor excretion was performed, macroscopically seemed to be teratoma, microscopically confirmed. The child has undergone subsequent chemotherapy treatment with favorable evolution.

SURG-07A MULTI-INSTITUTIONAL EXPERIENCE ON LASER THERMAL ABLATION AS TREATMENT FOR CORPUS CALLOSAL GLIOBLASOTMAS

INTRODUCTION: Surgical management of glioblastomas involving the corpus callosum is of particular challenge. Accordingly, patients afflicted with this disease entity exhibit poor survival relative to other forms of glioblastomas. The development of minimally invasive, stereotactic laser thermal ablation now offers a new surgical option against this disease. METHODS: We present a multi-institutional experience (Cleveland Clinic, University of California San Diego, University Hospital-Case Medical Center) in the treatment of glioblastoma that involve the corpus callosum. Radiographic control, peri-operative morbidities, time of hospitalization, and overall survival were examined. RESULTS: All 16 patients harbored histologically confirmed diagnosis of glioblastoma. Five patients were newly diagnosed and underwent ablation before TMZ/RT while the remaining 10 patients were treated after TMZ/RT failure. The median age of the cohort is 52 (range: 29-68), with a median KPS of 80 (range 60-100). Three patients suffered transient post-operative hemiparesis. The average length of hospital stay was 3.3 days (range: 1-11 days). 13 of the 16 patients underwent subsequent chemotherapy treatment. No tumor growth was observed within the region of thermal ablation in any of the treated patient. The median survival of the cohort has not been reached. Eleven of the treated patients (69%) survived > 3 months – the reported median survival for corpus callosal glioblastoma patients without surgical resection. The overall survival for these 11 patients ranged 5 to 35 months. CONCLUSIONS: Glioblastoma involving the corpus callosum can be safely treated through laser thermal ablation. Our multi-institutional experience provides evidence in support of safety and suggest potential efficacy in select patients.

An interesting presentation of a sacrococcygel teratoma with an associated neuroendocrine tumor: A case report

Abstract Teratomas are the most frequently occurring germ cell tumors, with 45–65 percent occurring in the sacrococcygeal region [1]. The case presented below involves a newborn male with a malignant sacrococcygeal teratoma and a number of congenital deformities including a left lower extremity amputation, an absent left kidney, hypoplastic and absent left hemipelvis musculature. After excision of the teratoma and subsequent chemotherapy treatment, the patient returned with a persistent abnormal soft tissue, containing persistent malignant elements around the left femur, suspicious for a neuroendocrine tumor. This case shows a rare association between two exceedingly uncommon malignancies.

1548PD - Absolute Neutrophil Counts in a Study of Lipegfilgrastim Compared with Pegfilgrastim in Patients with Breast Cancer Who are Receiving Chemotherapy

ABSTRACT Background Cancer chemotherapy frequently causes neutropenia, leading to an increased risk of infections and delays in subsequent chemotherapy treatments. In a randomized, double-blind, phase 3, active-controlled, noninferiority trial, the efficacy and safety of lipegfilgrastim, a glycosylated and pegylated recombinant granulocyte colony stimulating factor (G-CSF), was compared with pegfilgrastim, a pegylated recombinant G-CSF. Here we report the results of the absolute neutrophil counts (ANC) from this study. Methods Patients with high-risk stage II, III, or IV breast cancer and an absolute neutrophil count ≥1.5x109 cells/L were randomly assigned to lipegfilgrastim 6 mg (n = 101) or pegfilgrastim 6 mg (n = 101). Study medication was injected subcutaneously on day 2 of the chemotherapy cycle (4 cycles maximum). The primary efficacy endpoint, the duration of severe neutropenia, was reported previously. Secondary endpoints included ANC nadir and time to ANC recovery and were analyzed using a Poisson regression. The intent-to-treat (ITT) analysis population included all randomized patients. Results ANC nadir and time to ANC recovery for cycle 1 (ITT population) are summarized in the table. Measurement Lipegfilgrastim (n = 101) Pegfilgrastim (n = 101) LS Mean Difference (95% CI), p value Depth of ANC nadir (109/L) Mean (SD) 1.2 (1.3) 1.0 (1.2) 0.146 (-0.169 to 0.461) Median (range) 0.6 (0.0 to 5.5) 0.4 (0.0 to 5.2) p = 0.3610 Time to ANC recovery (days) Mean (SD) 5.8 (3.3) 7.4 (3.6) -1.570 (-2.547 to -0.592) Median (range) 7.0 (0.0 to 12.0) 8.0 (0.0 to 21.0) p = 0.0018 Conclusions Patients who received lipegfilgrastim had significantly faster time to ANC recovery than those who received pegfilgrastim. Disclosure O.A. Gladkov: Investigator in Teva-sponsored studies, I.M. Bondarenko: Investigator in Teva-sponsored studies R. Elsaesser: Employee of Teva Pharmaceuticals and own Teva Pharmaceuticals stock, A. Buchner: Employee of Teva Pharmaceuticals and own Teva Pharmaceuticals stock, P. Bias: Employee of Teva Pharmaceuticals and own Teva Pharmaceuticals stock.

Efficacy and safety of lipegfilgrastim compared with pegfilgrastim in patients with breast cancer who are receiving chemotherapy.

e19587 Background: Cancer chemotherapy frequently causes neutropenia, leading to an increased risk of infections and delays in subsequent chemotherapy treatments. Pegfilgrastim is a pegylated recombinant form of granulocyte colony stimulating factor (G-CSF) that extends the half-life and requires less frequent dosing than nonpegylated G-CSF. Lipegfilgrastim is a glycosylated and pegylated G-CSF. The objective of this study was to compare the efficacy and safety of lipegfilgrastim and pegfilgrastim in chemotherapy-naïve patients with breast cancer who are candidates to receive docetaxel/doxorubicin. Methods: In this double-blind, randomized, active-controlled, noninferiority trial, patients with high-risk stage II, III, or IV breast cancer and an absolute neutrophil count ≥1.5x109 cells/L were randomly assigned to lipegfilgrastim 6 mg (n=101) or pegfilgrastim 6 mg (n=101). Study medication was injected subcutaneously on day 2 of the chemotherapy cycle (4 cycles maximum). Primary efficacy endpoint was the duration of severe neutropenia (days with an absolute neutropenia count &lt;0.5x109 cells/L) during cycle 1. Secondary endpoints included the incidence of febrile neutropenia. Efficacy analysis population included patients who were randomized but did not have major protocol violations. Results: Overall, 37%, 46%, and 17% of patients had stage II, III, and IV breast cancer, respectively. The mean duration of severe neutropenia in cycle 1 was 0.7 days in the lipegfilgrastim group and 0.8 days in the pegfilgrastim group (poisson regression least squares mean [95% CI] -0.218 [-0.498 to 0.062]). 56% and 49%, respectively, did not experience severe neutropenia in cycle 1. Three patients experienced febrile neutropenia; all were in the pegfilgrastim group during cycle 1. 28% of patients in the lipegfilgrastim group and 26% in the pegfilgrastim group had adverse events that the investigator considered to be related to study medication. Three and 7 patients, respectively had serious adverse events. Conclusions: The results of this study confirm that the efficacy of lipegfilgrastim is comparable with pegfilgrastim. No unexpected safety events were observed.

Large-Cell Neuroendocrine Cancer of the Colon following Rituximab-Based Lymphoma Treatment

A 58-year-old man was referred in June 1991 with rectal bleeding for a colonoscopy that showed a sigmoid adenocarcinoma. Anterior resection revealed extension into, but not through, the muscularis propria, as well as 18 benign lymph nodes. Annual colonscopies were performed for five years, then every three years. In 2002, he underwent prostatectomy for prostate carcinoma. In 2008, a stage IVA, diffuse large B-cell right testicular lymphoma was treated with right orchidectomy, scrotal radiation and six cycles of CHOP-R (cyclophosphamide-doxorubicin-vincristine-prednisolone-rituximab). In 2008, colonoscopy and computed tomography (CT) scans of the head, abdomen and pelvis were normal, with no evidence of lymphoma. While travelling in southern France and Spain in June 2011, he developed abdominal pain and diarrhea for three days. This resolved for approximately one week and then recurred over a two-week period after his return to Canada. His physical examination was normal and laboratory studies revealed a mild anemia (hemoglobin level 122 g/L), but a normal white blood cell count and no left shift or eosinophilia. Fecal studies for bacteria and parasites were negative. A CT scan showed circumferential thickening of the hepatic flexure along with hepatic hypodense lesions, and colonoscopy showed an obstructing carcinoma. A right hemicolectomy and partial hepatectomy revealed a large cell neuroendocrine carcinoma invading through the colonic wall and involving seven of 14 regional lymph nodes and the liver. Microscopic evaluation showed predominately trebecular and insular architecture; the nests comprised of relatively monomorphous, but large cells, with moderate amounts of cytoplasm, an open nuclear chromatin pattern and a high mitotic apoptotic rate (Figure 1). Immunohistochemical staining for synaptophysin was stongly positive (Figure 2). Chromogranin was also positive. Subsequent chemotherapy treatment included carboplatin and etoposide. Figure 1) Trebecular/insular arrangement of high-grade malignancy of hepatic flexure with monomorphous large epithelioid cells with an open nuclear chromatin pattern and a high mitotic/apoptotic rate. Hematoxylin and eosin stain (original magnification ×200) ... Figure 2) Immunohistochemical stain for synaptophysin showing strong cytoplasmic positivity in the malignant cells. Original magnification ×200

Profiling of differentially expressed proteins in stage IV Colorectal cancers with good and poor outcomes

Screening patients at high risk of recurrence of cancer would allow for more accurate and personalized treatment. In this study, we tried to identify the prognosis-related protein profile by applying two different quantitative proteomic techniques, difference in-gel electrophoresis and cleavable isotope-coded affinity tag method. Six tumor tissues were obtained from stage IV colorectal cancer (CRC) patients, of which three have survived more than five years (good prognostic group, GPG) and the other three died within 25 months (poor prognostic group, PPG) after palliative surgery and subsequent chemotherapy treatment. From the two independent quantitative analyses, we identified 175 proteins with abundance ratios greater than 2-fold. Gene ontology analysis revealed that proteins related to cellular assembly/organization and movement were generally increased in the PPG. Twenty-two proteins, including caveolin-1, were chosen for confirmatory studies by Western blot and immunohistochemistry. The Western blot data for each individual protein were analyzed with Mann-Whitney tests, and a multi-marker panel was generated by logistic regression analysis. Five proteins, fatty acid binding protein 1, intelectin 1, transitional endoplasmic reticulum ATPase, transgelin and tropomyosin 2, were significantly different between the two prognostic groups within 95% confidence. No single protein could completely distinguish the two groups from each other. However, a combination of the five proteins effectively distinguished PPG from GPG patients (AUC=1). Our study suggests a multi-marker panel composed of proteome signatures that provide accurate predictive information and potentially assist personalized therapy. This article is part of a Special Issue entitled: Proteomics: The clinical link.

Subsequent chemotherapy reverses acquired tyrosine kinase inhibitor resistance and restores response to tyrosine kinase inhibitor in advanced non-small-cell lung cancer

BackgroundPatients with advanced or metastatic non-small cell lung cancer (NSCLC) can develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Here, we report the successful treatment with alternating chemotherapy and TKIs of two cases of advanced NSCLC who developed resistance to TKI.Case presentationTwo patients with advanced or metastatic NSCLC were treated with palliative chemotherapy followed by erlotinib/gefitinib. When TKI therapy failed, two cycles of chemotherapy were provided, which were followed by re-challenge with erlotinib or gefitinib.ConclusionNSCLC patients with acquired TKI resistance should be managed aggressively whenever possible. Subsequent chemotherapy and target treatment is one of the reasonable choices for those with an initial dramatic clinical response with erlotinib/gefitinib treatment. Further studies are warranted to substantiate the association of erlotinib /gefitinib treatment with the efficacy of NSCLC patients with acquired TKI failure.

Dynamic data‐driven finite element models for laser treatment of cancer

Elevating the temperature of cancerous cells is known to increase their susceptibility to subsequent radiation or chemotherapy treatments, and in the case in which a tumor exists as a well-defined region, higher intensity heat sources may be used to ablate the tissue. These facts are the basis for hyperthermia based cancer treatments. Of the many available modalities for delivering the heat source, the application of a laser heat source under the guidance of real-time treatment data has the potential to provide unprecedented control over the outcome of the treatment process [7, 18]. The goals of this work are to provide a precise mathematical framework for the real-time finite element solution of the problems of calibration, optimal heat source control, and goal-oriented error estimation applied to the equations of bioheat transfer and demonstrate that current finite element technology, parallel computer architecture, data transfer infrastructure, and thermal imaging modalities are capable of inducing a precise computer controlled temperature field within the biological domain.