Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge

Abstract

Treatment of malignant pleural mesothelioma (MPM) represents a highly unmet medical need. Here, we discuss the results and therapeutic potential of first- and second-generation immunomodulatory antibodies targeting distinct immune checkpoints for the treatment of MPM, as well as their prospective therapeutic role in combination strategies. We also discuss the role of appropriate radiological criteria of response for MPM and the potential need of ad hoc criteria of disease evaluation in MPM patients undergoing treatment with immunotherapeutic agents.

https://ift.tt/2Kk4HE9

Cancers, Vol. 10, Pages 215: Role of Minimal (Measurable) Residual Disease Assessment in Older Patients with Acute Myeloid Leukemia

Cancers, Vol. 10, Pages 215: Role of Minimal (Measurable) Residual Disease Assessment in Older Patients with Acute Myeloid Leukemia

Cancers doi: 10.3390/cancers10070215

Authors: Francesco Buccisano Richard Dillon Sylvie D. Freeman Adriano Venditti

Minimal (or measurable) residual (MRD) disease provides a biomarker of response quality for which there is robust validation in the context of modern intensive treatment for younger patients with Acute Myeloid Leukemia (AML). Nevertheless, it remains a relatively unexplored area in older patients with AML. The lack of progress in this field can be attributed to two main reasons. First, physicians have a general reluctance to submitting older adults to intensive chemotherapy due to their frailty and to the unfavourable biological disease profile predicting a poor outcome following conventional chemotherapy. Second, with the increasing use of low-intensity therapies (i.e., hypomethylating agents) differing from conventional drugs in mechanism of action and dynamics of response, there has been concomitant skepticism that these schedules can produce deep hematological responses. Furthermore, age-dependent differences in disease biology also contribute to uncertainty on the prognostic/predictive impact on older adults with certain genetic abnormalities including younger patients validated for MRD monitoring. This review examines the evidence for the role of MRD as a prognosticator in older AML, together with the possible pitfalls of MRD evaluation in older age.

https://ift.tt/2N1dIAf

Relationship between CYP1B1 polymorphisms (c.142C > G, c.355G > T, c.1294C > G) and lung cancer risk in Polish smokers

Future Oncology, Ahead of Print.


https://ift.tt/2Klov6M

The role of clinical and molecular factors in low-grade gliomas: what is their impact on survival?

Future Oncology, Ahead of Print.


https://ift.tt/2K7HWUx

Why are women with obesity more likely to develop breast cancer

Future Oncology, Ahead of Print.


https://ift.tt/2IsXn3Z

Surveillance, Epidemiology, & End Results study of ablation versus partial nephrectomy in cT1A renal cell carcinoma

Future Oncology, Ahead of Print.


https://ift.tt/2Kcvcfl

Novel multidisciplinary approaches in the management of metastatic epidural spinal cord compression

Future Oncology, Ahead of Print.


https://ift.tt/2KnmeIq

Detection of volatile organic compounds in exhaled breath to screen lung cancer: a systematic review

Future Oncology, Ahead of Print.


https://ift.tt/2K8iQ84

Rectal radiation dose-reduction techniques in prostate cancer: a focus on the rectal spacer

Future Oncology, Ahead of Print.


https://ift.tt/2KnsjV9

The role of matricellular proteins and tissue stiffness in breast cancer: a systematic review

Future Oncology, Ahead of Print.


https://ift.tt/2K6O7s1

Phase I and biomarker study of plerixafor and bevacizumab in recurrent high-grade glioma

Purpose: Although anti-angiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. Correlative clinical studies suggest that the SDF-1α/CXCR4 axis may mediate resistance to VEGFR inhibition. Preclinical data have demonstrated that plerixafor (a reversible CXCR4 inhibitor) could inhibit glioma progression after anti-VEGF pathway inhibition. We conducted a Phase I study to determine the safety of plerixafor and bevacizumab in recurrent HGG. Experimental Design: Part 1 enrolled 23 patients with a 3x3 dose escalation design to a MTD of plerixafor 320µg/kg subcutaneously on days 1-21 and bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle. CSF and plasma samples were obtained for pharmacokinetic analyses. Plasma and cellular biomarkers were evaluated before and after treatment. Part 2 enrolled 3 patients and was a surgical study to determine plerixafor's penetration in tumor tissue. Results: In Part 1, no DLTs were seen at the MTD of plerixafor+bevacizumab. Treatment was well tolerated. After plerixafor 320µg/kg treatment, the average CSF drug concentration was 26.8±19.6ng/mL. Plerixafor concentration in resected tumor tissue from patients pre-treated with plerixafor was 10-12µg/g. Circulating biomarker data indicated that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF1α and PlGF. PFS correlated with pre-treatment plasma sMET and sVEGFR1, and OS with the change during treatment in CD34+ progenitor/stem cells and CD8-T cells. Conclusions: Plerixafor + bevacizumab was well tolerated in HGG patients. Plerixafor distributed to both the CSF and brain tumor tissue, and treatment was associated with biomarker changes consistent with VEGF and CXCR4 inhibition.

https://ift.tt/2MpGzgy

Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R/InsR inhibitors

Purpose: Insulin-like growth factor 1 (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R/insulin receptor (InsR) therapies in breast cancer. Experimental Design: Breast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R/InsR therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data was used to compare IGF1R/InsR activation in estrogen receptor positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy. Results: Diminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R/InsR therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R/InsR phosphorylation were observed in E-cadherin deficient ER+ILC compared to IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R/InsR inhibition reduced proliferation in ILC tumor explant culture. Conclusions: We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R/InsR targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin deficient breast cancers.

https://ift.tt/2KlCjkY

TERT promoter mutation detection in cell-free tumor-derived DNA in patients with IDH wild-type glioblastomas - a pilot prospective study

Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)-mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients. Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp-mutation in the CSF-tDNA was correlated with patients' outcome. Results: Thirty-eight patients had TERTp-mutant, IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity and 92.1% sensitivity (n=35/38). In contrast, the sensitivity in the plasma-tDNA was far lower (7.9%). We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared to patients with high VAF, irrespective of using the lower quartile VAF (11.45%) [14.0 mo. (95%CI 10.3-17.6) vs. 8.6 mo. (95%CI 4.1-13.2), p=0.035], the lower third VAF (13%) [15.4 mo. (95%CI 11.6-19.2) vs. 8.3 mo. (95%CI 2.3-14.4), p=0.008] or the median VAF (20.3%) [14.0 mo. (95%CI 9.2-18.7) vs. 8.6 mo. (95%CI 7.5-9.8), p=0.062] to dichotomize the patients. Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp-mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients.

https://ift.tt/2Itb96D

Inhibition of BET bromodomain proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a biologically aggressive variant of Endometrial Cancer

Purpose: Uterine-serous-carcinoma (USC) is a rare and aggressive variant of endometrial cancer. Whole-exome-sequencing (WES) studies have recently reported c-Myc gene amplification in large number of USC suggesting c-Myc as a potential therapeutic target. We investigated the activity of novel BET bromodomain inhibitors (GS-5829 and GS-626510, Gilead-Science-Inc.) and JQ1 against primary USC-cultures and USC-xenografts. Experimental Design: We evaluated c-Myc expression by qRT-PCR in a total of 45 USC including fresh-frozen-tumor-tissues and primary USC-cell-lines. We also performed immunohistochemistry (IHC) and Western-Blot experiments in 8 USC tumors. USC cultures were evaluated for sensitivity to GS-5829, GS-626510 and JQ1 in-vitro using proliferation, viability and apoptosis-assays. Finally, the in-vivo activity of GS-5829, GS-626510 and JQ1 was studied in USC-ARK1 and USC-ARK2 mouse-xenografts. Results: Fresh-frozen USC and primary USC cell-lines overexpressed c-Myc when compared to normal tissues (p =0.0009 and =0.0083, respectively). High c-Myc expression was found in 7 of 8 of primary USC cell lines tested by qRT-PCR and 5 of 8 tested by IHC. In-vitro experiments demonstrated high sensitivity of USC cell-lines to the exposure to GS-5829, GS-626510 and JQ1 with BET-inhibitors causing a dose-dependent decrease in the phosphorylated levels of c-Myc and a dose-dependent increase in caspase activation (apoptosis). In comparative in-vivo experiments GS-5829 and/or GS-626510 were found more effective than JQ1 at the concentrations/doses used in decreasing tumor-growth in both USC-ARK1 and USC-ARK2 mouse-xenograft-models. Conclusions: GS-5829 and GS-626510 may represent novel, highly effective therapeutics agents against recurrent/chemotherapy resistant USC overexpressing c-Myc. Clinical studies with GS-5829 in USC-patients harboring chemotherapy-resistant disease are warranted.

https://ift.tt/2Kly2Oo

Two weeks' notice from allogeneic sources

A novel pipeline for neoantigen-specific T cell receptor (TCR) identification has been validated in ovarian cancer, making use of HLA-matched allogeneic healthy donor T cells. This workflow allows for the identification of tumor-specific TCRs two weeks after antigen-specific stimulation and eliminates problematic patient-to-patient variation in the selection of neoantigen-specific TCRs.

https://ift.tt/2MlMu6A

The combination of the PARP inhibitor olaparib and the Wee1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer

Purpose:Introduced in 1987, platinum-based chemotherapy remains standard of care for small cell lung cancer, a most aggressive, recalcitrant tumor. Prominent barriers to progress are paucity of tumor tissue to identify drug targets and patient relevant models to interrogate novel therapies. Following our development of circulating tumour cell patient-derived explants (CDX) as models that faithfully mirror patient disease, here we exploit CDX to examine new therapeutic options for small cell lung cancer. Experimental Design: We investigated the efficacy of the PARP inhibitor olaparib alone or in combination with the Wee1 kinase inhibitor AZD1775 in ten phenotypically distinct SCLC CDX in vivo and/or ex vivo. These CDX represent chemosensitive and chemorefractory disease including the first reported paired CDX generated longitudinally before treatment and upon disease progression. Results:There was a heterogeneous depth and duration of response to olaparib/AZD1775 which diminished when tested at disease progression. However, efficacy of this combination consistently exceeded that of cisplatin/etoposide with cures in one CDX model. Genomic and protein analyses revealed defects in homologous recombination repair and oncogenes that induce replication stress (such as MYC family members), predisposed CDX to combined olaparib/AZD1775 sensitivity though universal predictors of response were not noted. Conclusions:These preclinical data provide a strong rationale to trial this combination in the clinic informed by prevalent, readily accessed circulating tumor cell based biomarkers. New therapies will be evaluated in SCLC patients after first line chemotherapy and our data suggest that the combination of olaparib/AZD1775 should be used as early as possible and prior to disease relapse.

https://ift.tt/2K7xbS9

Utility of a minimal skin incision laparotomy technique for removing uterine leiomyomas at a regional core hospital: a retrospective study

We present a minimal skin wound abdominal myomectomy performed in our hospital and attempt to identify the optimal range of this technique by considering the characteristics of target leiomyomas. In this proce...

https://ift.tt/2IpU1Pn

Osteolytic lesions (brown tumors) of primary hyperparathyroidism misdiagnosed as multifocal giant cell tumor of the distal ulna and radius: a case report

Brown tumors represent a rare clinical manifestation reported in approximately 3% of patients with primary hyperparathyroidism and correspond to radiologically osteolytic lesions with well-defined borders in d...

https://ift.tt/2lxUplK

Perceptions of future health and cancer risk in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study

Cancer, EarlyView.


https://ift.tt/2yJVwZ2

PET imaging for assessing tumor response to therapy

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2lCxqG1

A practical guide for the use of indocyanine green and methylene blue in fluorescence‐guided abdominal surgery

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2yHuiSP

Molecular fluorescence‐guided surgery of peritoneal carcinomatosis of colorectal origin: A narrative review

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2lzNskj

Clinical evaluation of intensity-modulated radiotherapy for locally advanced pancreatic cancer

The purpose was to retrospectively evaluate the effect of intensity-modulated radiotherapy (IMRT) on gastrointestinal (GI) toxicities and outcomes compared to three-dimensional conformal radiotherapy (3DCRT) f...

https://ift.tt/2Mm6zcI

Significance of intra-fractional motion for pancreatic patients treated with charged particles

Uncertainties associated with the delivery of treatment to moving organs might compromise the accuracy of treatment. This study explores the impact of intra-fractional anatomical changes in pancreatic patients...

https://ift.tt/2Ki6CsF

Dose constraints in the rectum and bladder following carbon-ion radiotherapy for uterus carcinoma: a retrospective pooled analysis

Carbon-ion radiotherapy (C-ion RT) provides better dose distribution in cancer treatment compared to photons. Additionally, carbon-ion beams provide a higher biological effectiveness, and thus a higher tumor c...

https://ift.tt/2Iq7BSL

Correction to: Retrospective dosimetry study of intensity-modulated radiation therapy for nasopharyngeal carcinoma: measurement-guided dose reconstruction and analysis

The original version of this article [1] unfortunately contained a mistake.

https://ift.tt/2K7Utrc

New on NCI Websites for June 2018

NCI periodically provides updates on new websites and other online content of interest to the cancer community. See selected content that has been added as of June 2018.

https://ift.tt/2K81WGM

The right chance for temozolomide in metastatic colorectal cancer?

https://ift.tt/2KgqCbY

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma

Abstract

Background

Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment.

Methods

The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8^th Edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant targeted or immune therapy. Patterns of pathologic response provided context to inform these guidelines.

Results

Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant targeted and immune checkpoint therapy is described and illustrated.

Conclusions

Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

https://ift.tt/2K6bSAC

The value of radical radiotherapy in the primary tumor of newly diagnosed oligo-metastatic nasopharyngeal carcinoma patients

Abstract

Background

To explore the efficacy and patterns of treatment failure of radical radiotherapy in newly diagnosed oligo-metastatic nasopharyngeal carcinoma patients.

Methods

We included 39 newly diagnosed oligo-metastatic nasopharyngeal carcinoma patients who received radical radiotherapy and chemotherapy in Zhejiang Cancer Hospital. Treatment and prognosis information were collected. The Kaplan–Meier methods and Cox proportional hazards models were used to calculate survival rates and analyze prognostic factors.

Results

After a median follow-up time of 38 months, the 1-, 3-, and 5-year overall survival rates were 97, 70, and 57.9%, while the 1-, 3-, and 5-year progression-free survival rates were 87, 59, and 50.9%, respectively. Age, numbers of metastases lesions, cycles, and schemes of chemotherapy were independent prognostic factors of the overall survival. Patients with no more than three metastasis lesions had a higher survival rate than those with ≥ 3 metastatic lesions (P = 0.023). More than four cycles chemotherapy provide a higher survival rate than less than four cycles. Chemotherapy including docetaxel had a significantly survival advantages (P = 0.041).

Conclusion

Radical radiotherapy is important for newly diagnosed oligo-metastatic nasopharyngeal carcinoma patients, which can still achieve long-term survival after chemo-radiotherapy.

https://ift.tt/2tsAWqW

A semi-automatic technique to quantify complex tuberculous lung lesions on 18 F-fluorodeoxyglucose positron emission tomography/computerised tomography images

Abstract

Background

There is a growing interest in the use of ¹⁸F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner.

To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs.

Results

We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case.

Conclusions

Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.

https://ift.tt/2KaJ4GX

Cancers, Vol. 10, Pages 214: A Novel Acquired t(2;4)(q36.1;q24) with a Concurrent Submicroscopic del(4)(q23q24) in An Adult with Polycythemia Vera

Cancers, Vol. 10, Pages 214: A Novel Acquired t(2;4)(q36.1;q24) with a Concurrent Submicroscopic del(4)(q23q24) in An Adult with Polycythemia Vera

Cancers doi: 10.3390/cancers10070214

Authors: Eigil Kjeldsen

Background: Polycythemia vera (PV) is a clonal myeloid stem cell disease characterized by a growth-factor independent erythroid proliferation with an inherent tendency to transform into overt acute myeloid malignancy. Approximately 95% of the PV patients harbor the JAK2V617F mutation while less than 35% of the patients harbor cytogenetic abnormalities at the time of diagnosis. Methods and Results: Here we present a JAK2V617F positive PV patient where G-banding revealed an apparently balanced t(2;4)(q35;q21), which was confirmed by 24-color karyotyping. Oligonucleotide array-based Comparative Genomic Hybridization (aCGH) analysis revealed an interstitial 5.4 Mb large deletion at 4q23q24. Locus-specific fluorescent in situ hybridization (FISH) analyses confirmed the mono-allelic 4q deletion and that it was located on der(4)t(2;4). Additional locus-specific bacterial artificial chromosome (BAC) probes and mBanding refined the breakpoint on chromosome 2. With these methods the karyotype was revised to 46,XX,t(2;4)(q36.1;q24)[18]/46,XX[7]. Conclusions: This is the first report on a PV patient associated with an acquired novel t(2;4)(q36.1;q24) and a concurrent submicroscopic deletion del(4)(q23q24). The study also underscores the benefit of combined usage of FISH and oligo-based aCGH analysis in characterizing chromosomal abnormalities. The present findings provide additional clues to unravel important molecular pathways in PV to obtain the full spectrum of acquired chromosomal and genomic aberrations, which eventually may improve treatment options.

https://ift.tt/2KaBxrF

A rare case of giant cell lung carcinoma with intracardiac extension via the pulmonary vein and thrombus formation

Abstract

A 61-year-old man presented with dyspnea, left thoracic pain and productive cough. Chest computed tomography demonstrated a solid mass of the left upper lobe, 2.9 × 1.8 cm² in size, which had irregular borders and appeared to infiltrate and totally occlude the upper left pulmonary vein extending up to the left atrium (LA) with thrombus formation. The patient underwent median sternotomy and left pneumonectomy, combined with LA thrombus resection under cardiopulmonary bypass (CPB) with bicaval cannulation. The LA was partially resected and the intracavitary thrombus was completely removed. The surgical margins were free of tumor cells. Episodes of embolism were not observed during surgery. The patient was successfully weaned from CPB. The postoperative course was uncomplicated. Pathological examination of the resected specimen revealed giant cell carcinoma.

https://ift.tt/2tBU591

lincROR influences the stemness and crizotinib resistance in EML–ALK+ non-small-cell lung cancer cells

https://ift.tt/2MjLD6i

LASH in Severely Enlarged Uterine Leiomyoma: Removal of a Uterus of 4065 g

Today, even though minimally invasive approaches have become standard worldwide, large uteri are still mainly removed by means of open abdominal approaches. The present case describes the successful removal of the largest uterus ever reported (4065 g) by means of laparoscopy-assisted supracervical hysterectomy (LASH). We combined LASH with the changeover technique which allows a better access and view. We further explain how this approach allows for the safe minimally invasive removal of uteri of any size.

https://ift.tt/2K4Yw7q

Expression of CD3, PD-L1 and CTLA-4 in mammary and extra-mammary Paget disease

Abstract

Background

Mammary and extra-mammary Paget disease is a rare form of intra-epithelial glandular neoplasm which is characteristically recurrent and necessitates multiple excisions that have an important impact on morbidity. Local immuno-modulating treatments have been applied with promising results, but the local immune markers of Paget disease have not been studied.

Aim of the study

To investigate the local immune micro-environment of Paget disease.

Materials and methods

Sixty-four specimens from 41 patients, including cases with multiple recurrences and underlying primary neoplasm, have been studied for their expression of CD3, PD-L1 and CTLA-4.

Results

Nineteen cases were mammary; 22 were extra-mammary and involved the vulva, the anus, the inguinal region and the lower extremity. PD-L1 was not expressed by any neoplastic lesion or the associated lymphocytes. CTLA-4 expression was found in nine cases. Higher stromal CD3 expression and moderate levels of intra-epithelial CD3 expression were present in most cases. Biopsies, subsequent excision specimens and recurrences showed the same immunohistochemical profile of CD3 and PD-L1, although there were different levels of CTLA-4 in a few cases. The underlying lesions in mammary Paget disease showed the same immunohistochemical profile as the intra-epithelial neoplastic cells. The expression of the markers did not correlate with age, sex, localization or recurrence.

Conclusion

Paget disease is characterized by an intense lymphocytic response, devoid of the immune-suppressive impact of the PD-L1 pathway, but with occasional CTLA-4 expression.

https://ift.tt/2MlC7jb

Dendritic cell trafficking in tumor-bearing mice

Abstract

Prostate cancer is one of the leading causes of cancer deaths, with no curative treatments once it spreads. Alternative therapies, including immunotherapy, have shown limited efficacy. Dendritic cells (DC) have been widely used in the treatment of various malignancies. DC capture antigens and move to the lymphoid organs where they prime naive T cells. Interaction between DC and T cells are most active in lymph nodes and suppression of DC trafficking to lymph nodes impairs the immune response. In this work, we aimed to study trafficking of DC in vivo via various routes of delivery, to optimize the effectiveness of DC-based therapy. A DC labeling system was developed using 1,1′-dioctadecyltetramethyl indotricarbocyanine Iodine for in vivo fluorescent imaging. DC harvested from C57B/6 mice were matured, labeled, and injected intravenously, subcutaneously, or intratumorally, with or without antigen loading with whole tumor lysate, into C57B/6 mice inoculated with RM-1 murine prostate tumor cells. Signal intensity was measured in vivo and ex vivo. Signal intensity at the tumor site increased over time, suggesting trafficking of DC to the tumor with all modes of injection. Subcutaneous injection showed preferential trafficking to lymph nodes and tumor. Intravenous injection showed trafficking to lungs, intestines, and spleen. Subcutaneous injection of DC pulsed with whole tumor lysate resulted in the highest increase in signal intensity at the tumor site and lymph nodes, suggesting subcutaneous injection of primed DC leads to highest preferential trafficking of DC to the immunocompetent organs.

https://ift.tt/2KjTR0N

The effect of time from diagnosis to surgery on oncological outcomes in patients undergoing surgery for colon cancer: a systematic review

Publication date: Available online 25 June 2018
Source:European Journal of Surgical Oncology
Author(s): C. Hangaard Hansen, M. Gögenur, M. Tvilling Madsen, I. Gögenur
Many countries have implemented cancer pathways with strict time limits dictating the pace of diagnostic testing and treatment. There are concerns that prehabilitation may worsen long-term oncological outcomes if surgery is delayed. We aimed to systematically review the literature investigating the association between increased time between diagnosis of colon cancer and surgical treatment, with special focus on survival outcomes.MethodsThrough a systematic search and analysis of the databases PubMed (1966-2017), EMBASE (1974-2017), CINHAL (1981-2017), and The Cochrane Library performed on June 7^th, 2017, the effect of treatment delays on overall survival in colon cancer patients was reviewed. Treatment delay was defined as time from diagnosis to initiation of surgical treatment. All patients included were diagnosed with colon cancer and treated with elective curative surgery without neoadjuvant chemotherapy. This review was prospectively registered on the PROSPERO database of systematic review protocols with registration number CRD42017059774.ResultsFive observational studies including 13,514 patients were included. The treatment delay intervals ranged from 1- ≥56 days. Four of the five studies found no association between time elapsed from diagnosis to surgery and reduced overall survival. One study found a clinically insignificant association between longer treatment delays and overall survival. Three studies investigated the effect on disease specific survival and found no negative associations.ConclusionThe available data showed no association between treatment delay and reduced overall survival in colon cancer patients.



https://ift.tt/2lz3ydS

Use of fiberoductoscopy for the management of patients with pathological nipple discharge: experience of a single center in Poland

Abstract

Background

Pathological nipple discharge (PND) is associated with serious clinical and diagnostic issues. Fiberoductoscopy (FDS) is a new diagnostic option in PND patients. This study summarizes our initial experience of FDS for the management of PND patients in a single center in Poland and assesses its safety.

Methods

A total of 256 women with PND were included in this prospective, case-controlled, single-center study between 2006 and 2014. Of the 250 patients who underwent FDS, 154 had mammary duct lesions and 96 had no visible lesions. Subsequently, 129 patients with lesions identified by FDS underwent microductectomy and the lesions were pathologically evaluated.

Results

The mean duration of FDS examination was 17 min. The most frequent intraductal lesion was amputation of a duct (35.1%), followed by circular narrowing or hyperplasia (22.7%). Final histological findings were unremarkable in 11.6% of cases, whereas mammary duct papilloma, duct ectasia, and ductal carcinoma in situ were detected in 71.3, 10.9, and 6.2% of cases, respectively.

Conclusions

FDS is an innovative method for visualizing intraductal mammary lesions and allows accurate selection of mammary ducts with suspicious lesions that require surgical removal in women with PND.

https://ift.tt/2yHm25a

Bridging the Gap in Global Advanced Radiation Oncology Training: Impact of a Web-Based Open-Access Interactive Three-Dimensional Contouring Atlas on Radiation Oncologist Practice in Russia

Abstract

Radiation oncologists in Russia face a number of unique professional difficulties including lack of standardized training and continuing medical education. To combat this, under the auspices of the Russian Society of Clinical Oncology (RUSSCO), our group has developed a series of ongoing in-person interactive contouring workshops that are held during the major Russian oncology conferences in Moscow, Russia. Since November 2016 during each workshop, we utilized a web-based open-access interactive three-dimensional contouring atlas as part of our didactics. We sought to determine the impact of this resource on radiation oncology practice in Russia. We distributed an IRB-approved web-based survey to 172 practicing radiation oncologists in Russia. We inquired about practice demographics, RUSSCO contouring workshop attendance, and the clinical use of open-access English language interactive contouring atlas (eContour). The survey remained open for 2 months until November 2017. Eighty radiation oncologists completed the survey with a 46.5% response rate. Mean number of years in practice was 13.7. Sixty respondents (75%) attended at least one RUSSCO contouring workshop. Of those who were aware of eContour, 76% were introduced during a RUSSCO contouring workshop, and 81% continue to use it in their daily practice. The greatest obstacles to using the program were language barrier (51%) and internet access (38%). Nearly 90% reported their contouring practices changed since they started using the program, particularly for delineation of clinical target volumes (57%) and/or organs at risk (46%). More than 97% found the clinical pearls/links to cooperative group protocols in the software helpful in their daily practice. The majority used the contouring program several times per month (43%) or several times per week (41%). Face-to-face contouring instruction in combination with open-access web-based interactive contouring resource had a meaningful impact on perceived quality of radiation oncology contours among Russian practitioners and has the potential to have applications worldwide.

https://ift.tt/2Kfhzbg