Systemic Treatment Strategies Research Articles

Modulation of the Autophagy-lysosomal Pathway in Hepatocellular Carcinoma Using Small Molecules.

Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer; it is the third most frequent cause of cancer-related death worldwide. In early-stage disease, surgical resection and liver transplantation are considered curative treatments. However, the majority of HCC patients present with advanced-stage disease that is treated using palliative systemic therapy. Since HCC is heterogeneous owing to its multiple etiologies, various risk factors, and inherent resistance to chemotherapy, the development of an effective systemic treatment strategy for HCC remains a considerable challenge. Autophagy is a lysosome-dependent catabolic degradation pathway that is essential for maintaining cellular energy homeostasis. Autophagy dysfunction is closely linked with the pathogenesis of various cancers; therefore, the discovery of small molecules that can modulate autophagy has attracted considerable interest in the development of a systemic treatment strategy for advanced HCC. Here, we reviewed the roles of autophagy in HCC and the recent advances regarding small molecules that target autophagy regulatory mechanisms.

Initial Clinical Impressions of the Critical Care of COVID-19 Patients in Seattle, New York City, and Chicago.

Since the first recognition of a cluster of novel respiratory viral infections in China in late December 2019, intensivists in the United States have watched with growing concern as infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus―now named Coronavirus Disease of 2019 (COVID-19)―have spread to hospitals in the United States. Because COVID-19 is extremely transmissible and can progress to a severe form of respiratory failure, the potential to overwhelm available critical care resources is high and critical care management of COVID-19 patients has been thrust into the spotlight. COVID-19 arrived in the United States in January and, as anticipated, has dramatically increased the usage of critical care resources. Three of the hardest-hit cities have been Seattle, New York City, and Chicago with a combined total of over 14,000 cases as of March 23, 2020.In this special article, we describe initial clinical impressions of critical care of COVID-19 in these areas, with attention to clinical presentation, laboratory values, organ system effects, treatment strategies, and resource management. We highlight clinical observations that align with or differ from already published reports. These impressions represent only the early empiric experience of the authors and are not intended to serve as recommendations or guidelines for practice, but rather as a starting point for intensivists preparing to address COVID-19 when it arrives in their community.

DCST1-AS1 Promotes TGF-β-Induced Epithelial-Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1.

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype, and the primary systemic treatment strategy involves conventional chemotherapy. DC-STAMP domain containing 1-antisense 1 (DCST1-AS1) is a long non-coding RNA that promotes TNBC migration and invasion. Studying the role of DCST1-AS1 in promoting epithelial–mesenchymal transition (EMT) and chemoresistance will provide a new strategy for TNBC therapy. In the present study, we found that DCST1-AS1 regulates the expression or secretion of EMT-related proteins E-cadherin, snail family zinc finger 1 (SNAI1), vimentin, matrix metallopeptidase 2 (MMP2), and matrix metallopeptidase 9 (MMP9). Interference with DCST1-AS1 impaired TGF-β-induced TNBC cell invasion and migration. DCST1-AS1 directly binds to ANXA1 in BT-549 cells and affects the expression of ANXA1. DCST1-AS1 enhances TGF-β/Smad signaling in BT-549 cells through ANXA1 to promote EMT. The combination of DCST1-AS1 and ANXA1 also contributes to enhancement of the resistance of BT-549 cells to doxorubicin and paclitaxel. In conclusion, DCST1-AS1 promotes TGF-β-induced EMT and enhances chemoresistance in TNBC cells through ANXA1, and therefore represents a potentially promising target for metastatic breast cancer therapy.

Ретинобластома. Часть 2. Принципы терапии интраокулярной ретинобластомы

Retinoblastoma is one of the most common retinal tumors in young children. Current early diagnostic and treatment strategies focus on the possibility to implement eye-preserving therapies. The 5-year overall survival for children with retinoblastoma is now 100%. First-line eye removal is recommended in extensive intraocular seeding and poor visual prognosis. The volume of adjuvant therapy is based on the histological risk factors for disease progression. This paper discusses the algorithms to determine risk factors and further systemic treatment strategy in several large study groups. Eye and even vision preservation is now possible in at least 65–75% of retinoblastoma patients. The paper also describes in detail the methods of locally administering chemotherapy which are considered eye-preserving treatment options, i.e., selective intra-arterial chemotherapy and intravitreal chemotherapy. Various physical methods of eye-preserving treatment which underwent significant development over the past decade are highlighted. In conclusion, the authors emphasize that retinoblastoma survivors, their siblings and offspring should be carefully monitored.Keywords: children, retinoblastoma, enucleation, polychemotherapy, selective intra-arterial chemotherapy, intravitreal chemotherapy, laser photocoagulation, transpupillary thermotherapy, cryotherapy, brachytherapy, monitoring.For citation: Ivanova S.V., Kuleva S.A., Sadovnikova N.N. et al. Retinoblastoma. Part 2. Treatment strategies for intraocular retinoblastoma. Russian Journal of Clinical Ophthalmology. 2020;20(4):197–203. DOI: 10.32364/2311-7729-2020-20-4-197-203.

Renal cell carcinoma lung metastases treated by radiofrequency ablation integrated with systemic treatments: over 10 years of experience

BackgroundTo determine safety and efficacy of radiofrequency ablation (RFA) for local treatment of lung metastases of renal cell carcinoma (RCC), sequenced or combined with systemic treatments.MethodsRetrospectively, we studied 53 patients treated by RFA for a maximum of six lung metastases of RCC. The endpoints were local efficacy, overall (OS), disease-free (DFS), pulmonary progression-free (PPFS) and systemic treatment-free (STFS) survivals, complications graded by the CTCAE classification and factors associated with survivals. Potential factors analysed were: clinical and pathological data, tumoral staging of TNM classification, primary tumor histology, Fuhrman’s grade, age, number and size of lung metastases and extra-pulmonary metastases pre-RFA.ResultsOne hundred metastases were treated by RFA. Median follow-up time was 61 months (interquartile range 90–34). Five-year OS was 62% (95% confidence interval (CI): 44–75). Median DFS was 9.9 months (95% CI: 6–16). PPFS at 1 and 3 years was 58.9% (95%CI: 44.1–70.9) and 35.2% (95%CI: 21.6–49.1), respectively. We observed 3% major complications (grade 3 and 4 of CTCAE classification). Local efficacy was 91%. Median STFS was 28.3 months. Thirteen patients (25%) with lung recurrence could be treated by another RFA. T3/T4 tumors had significantly worse OS, PPFS and STFS. Having two or more lung metastases increased the risk of pulmonary progression more than threefold.ConclusionIntegrated to systemic treatment strategy, RFA is safe and effective for the treatment strategy of lung metastasis from RCC with good OS and long systemic treatment-free survival. RFA offers the possibility of repeat procedures, with low morbidity.

Sexual Preservation With Radiotherapy: Think Target, Not Tool

With the refinement and advancement of diverse radiation, surgical, and systemic treatment strategies, prostate cancer (PCA) patients have significant survivorship after treatment. The goal of modern PCA treatment, therefore, encompasses not just cure, but also optimization of long-term patient quality of life (QOL). To that end, sexual QOL, and particularly erectile function (EF), is a critical metric in patient’s determination of their overall treatment satisfaction.1 Technology has expanded curative radiotherapy techniques to include brachytherapy (BT), external beam/intensity-modulated RT (EBRT/IMRT), stereotactic-body radiotherapy (SBRT), and proton therapy (PT), and various combinations of the above techniques. More advanced disease commonly includes the addition of androgen deprivation therapy (ADT). There is increasing interest by patients about whether a particular type of RT can offer superior erectile preservation. This editorial will, therefore, review the difficulties of comparing EF across RT modalities and summarize the current literature on EF. We will also suggest future directions to maximize EF through further refinements of RT technique.

Sentinel node biopsy and lymph node dissection in the era of new systemic therapies for malignant melanoma

Recently, adjuvant therapies with checkpoint inhibitors and BRAF/MEK inhibitors have become available for patients with malignant melanoma and microscopic nodal disease. Meanwhile the number of complete nodal dissections for amelanoma-positive sentinel node (SN) have decreased significantly. The authors discuss the significance of sentinel node biopsy (SNB) and early lymph node dissection in the era of adjuvant systemic therapy for stageIII melanoma. Current publications and recommendations were evaluated. Complete nodal dissection for apositive SN significantly reduces the risk of regional nodal relapse. However, neither SNB nor complete nodal dissection following apositive SN are associated with abenefit in survival. With the availability of novel adjuvant systemic treatment strategies for stageIII melanoma, SNB has become an even more important part of modern staging diagnostics. Thus, detection of early dissemination of melanoma cells into the SN as well as the quantification of the tumor load are decisive for further therapy planning. Accurate assessment of the regional lymph node status by SNB is becoming even more important in the era of novel effective adjuvant therapies for microscopic nodal disease. Whether complete lymph node dissection is performed in patients with apositive SN needs to be assessed individually. In the case of "active nodal surveillance" instead of surgery, long-term close follow-up in specialized centers, including ultrasonographic controls, is required.

Heterogeneity of first-line palliative systemic treatment in synchronous metastatic esophagogastric cancer patients: A real-world evidence study.

The optimal first‐line palliative systemic treatment strategy for metastatic esophagogastric cancer is not well defined. The aim of our study was to explore real‐world use of first‐line systemic treatment in esophagogastric cancer and assess the effect of treatment strategy on overall survival (OS), time to failure (TTF) of first‐line treatment and toxicity. We selected synchronous metastatic esophagogastric cancer patients treated with systemic therapy (2010–2016) from the nationwide Netherlands Cancer Registry (n = 2,204). Systemic treatment strategies were divided into monotherapy, doublet and triplet chemotherapy, and trastuzumab‐containing regimens. Data on OS were available for all patients, on TTF for patients diagnosed from 2010 to 2015 (n = 1,700), and on toxicity for patients diagnosed from 2010 to 2014 (n = 1,221). OS and TTF were analyzed using multivariable Cox regression, with adjustment for relevant tumor and patient characteristics. Up to 45 different systemic treatment regimens were found to be administered, with a median TTF of 4.6 and OS of 7.5 months. Most patients (45%) were treated with doublet chemotherapy; 34% received triplets, 10% monotherapy and 10% a trastuzumab‐containing regimen. The highest median OS was found in patients receiving a trastuzumab‐containing regimen (11.9 months). Triplet chemotherapy showed equal survival rates compared to doublets (OS: HR 0.92, 95%CI 0.83–1.02; TTF: HR 0.92, 95%CI 0.82–1.04) but significantly more grade 3–5 toxicity than doublets (33% vs. 21%, respectively). In conclusion, heterogeneity of first‐line palliative systemic treatment in metastatic esophagogastric cancer patients is striking. Based on our data, doublet chemotherapy is the preferred treatment strategy because of similar survival and less toxicity compared to triplets.

Cutaneous candidiasis - an evidence-based review of topical and systemic treatments to inform clinical practice.

Cutaneous candidiasis is a common skin disease, and several treatments have been investigated within the last fifty years. Yet, systematic reviews are lacking, and evidence-based topical and systemic treatment strategies remain unclear. Thus, the aim of this review was to summarize efficacy and adverse effects of topical and oral therapies for cutaneous candidiasis in all age groups. Two individual researchers searched PubMed and EMBASE for 'cutaneous candidiasis' and 'cutaneous candidiasis treatment', 'intertrigo', 'diaper dermatitis' and 'cheilitis'. Searches were limited to 'English language', 'clinical trials' and 'human subjects', and prospective clinical trials published in abstracts or articles were included. In total, 149 studies were identified, of which 44 were eligible, comprising 41 studies of 19 topical therapies and four studies of three systemic therapies for cutaneous candidiasis. Topical therapies were investigated in infants, children, adolescents, adults and elderly, while studies of systemic therapies were limited to adolescents and adults. Clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated similar efficacy with complete cure rates of 73%-100%. Single-drug therapy was as effective as combinations of antifungal, antibacterial and topical corticosteroid. Four studies investigated systemic therapy, and oral fluconazole demonstrated similar efficacy to oral ketoconazole and topical clotrimazole. Limitations to this review were mainly that heterogeneity of studies hindered meta-analyses. In conclusions, clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated equal good efficacy and mild adverse effects similar to combinations of antifungal, antibacterial and topical corticosteroids. Oral fluconazole was as effective as topical clotrimazole and is the only commercially available evidence-based option for systemic treatment of cutaneous candidiasis.

Updates on the Systemic Treatment of Advanced Non-melanoma Skin Cancer.

Non-melanoma skin cancers (NMSCs), which represent a diverse group of cutaneous malignancies, are the most common forms of human neoplasia. The incidence of these diseases is increasing due to a number of factors, including that of increasing human lifespans. The majority of NMSCs are basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC), with the remainder being various rare skin cancers, including extramammary Paget's disease (EMPD), Merkel cell carcinoma (MCC), and several skin adnexal carcinomas. Of these, MCC usually shows aggressive behavior with a high mortality rate. On the other hand, BCC, cSCC, EMPD, and skin adnexal tumors usually show an indolent clinical course and metastasize only rarely. Nevertheless, the metastatic forms of these tumors commonly lead to poor patient outcome. A definitive management strategy for the treatment of advanced NMSC has not been established, mainly due to their rarity and lack of reliable information based on well-controlled randomized trials. Chemotherapeutic regimens for treatment of these diseases have been mainly based on the observations of isolated, small case series or clinical trials with a limited numbers of patients. However, accumulating evidence regarding their pathobiological backgrounds as well as recent advances in molecular biotechnology have facilitated the development of novel drugs for treatment of these diseases. Over the past decade, the U.S. Food and Drug Administration has approved several molecular targeting therapies, including Hedgehog inhibitors for BCC, monoclonal antibodies targeting anti-programmed death ligand-1 and anti- programmed cell death 1 (PD-1) for MCC, and anti-PD-1 for cSCC. Here, we review their clinical utility and discuss updated systemic treatment strategies for advanced NMSC.

Abstract 1307: Inhibition of ERK by LY3214996 augments nab-paclitaxel and gemcitabine combination chemotherapy efficacy in preclinical models of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is currently the third most frequent cause of cancer deaths in the US and is expected to be the second deadliest cancer by 2030. The 5-year survival rate in PDAC patients is only 6% and the poor prognosis is attributed to several factors including late-stage diagnosis, aggressive disease progression and high resistance to conventional therapies. Therefore, there is an urgent need for more effective systemic treatment strategies in PDAC patients. Nab-paclitaxel (Nab-pac) combined with gemcitabine (Gem) or FOLFIRINOX combination chemotherapy regimen are approved as standard of care treatment for frontline metastatic PDAC. Due to limited clinical efficacy of current cytotoxic chemotherapy regimens for PDAC patients, novel approaches are needed to further improve patient survival outcomes. In PDAC, activating mutations in KRAS occur at a frequency of ~90% rendering this a potential therapeutic target of interest. Developing drugs that directly target mutant KRAS protein remains challenging and alternative strategies focus on inhibition of downstream targets of the RAS-MAPK cascade. The addition of ERK inhibitor LY3214996 to the chemotherapy regimen (Nab-pac+Gem) was tested in MIA PaCa-2 (KRAS G12C), Capan-2 (KRAS G12V) and SW1990 (KRAS G12D) pancreatic cancer xenograft models. In the Capan-2 model, combination of LY3214996 with Gem alone was statistically additive (p<0.001) and resulted in 14% tumor regressions (%dT/C =-14). In the MIA PaCa-2 model, LY3214996 has shown dose-dependent single agent activity resulting in 7 out of 7 partial responses at 100 mpk QD. In the combination study, LY3214996 enhanced the efficacy of Nab-pac+Gem and demonstrated 42% tumor regression (%dT/C =-42), and combination effect was additive (p=0.008). Combination of LY3214996+Gem+Nab-pac resulted in 1 complete response (CR) out of 6 whereas Nab-pac+Gem resulted in only 1 partial response (PR) out of 6. In SW1990 model, combination efficacy of LY3214996 and Nab-pac+Gem was additive (p=0.011) and resulted in ~88% tumor growth inhibition (%dT/C=12). Our data suggest that the efficacy of Nab-pac+Gem based chemotherapy can be enhanced through specific inhibition of ERK1/2 kinase activity in KRAS mutant PDAC, and supports the clinical testing of this combination in the current Phase I JUAB (LY3214996) study in metastatic PDAC (NCT02857270). Citation Format: Shripad V. Bhagwat, Wenjuan Wu, Baohui Zhao, Weihua Shen, Lisa Kindler, Jennifer Stephens, Jason Manro, William McMillen, Sajan Joseph, Sheng-Bin Peng, Ramon V. Tiu. Inhibition of ERK by LY3214996 augments nab-paclitaxel and gemcitabine combination chemotherapy efficacy in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1307.

Abstract 2588: Restoring downregulated microRNAs miR-195-5p and miR-497-5p increases sensitivity to chemotherapy in colorectal cancer cells

Abstract Background: Patients with advanced colorectal cancer (CRC) are commonly treated with systemic combination therapy, however the success of treatment is hampered by drug resistance. MicroRNAs (miRNAs) have recently emerged as important players in therapy resistance in CRC. The aim of this study was to improve therapy efficacy by sensitizing CRC cells to the chemotherapeutics currently used in clinical practice for patients with advanced CRC by restoring downregulated miR-195-5p and miR-497-5p. Methods: Sensitivity to 5FU, oxaliplatin (OHP) and irinotecan before and after transfection with miR-195-5p and miR-497-5p mimics was analyzed using tetrazolium reduction and clonogenic assays in CRC cell lines HCT116, RKO, DLD1 and SW480. Transfection with cel-miR-39-3p and untransfected cells were used as controls. Proteomic analyses of transfected and untransfected cells were implemented to identify possible targets involved in sensitivity to chemotherapy. Group comparisons by beta-binomial statistics were performed to analyze significantly altered peptides after restoring miRNA expression. Results: After transfection with miR-195-5p and miR-497-5p mimics, RKO showed an increased sensitivity to OHP (IC50 decreased from 1100 nM to 900 nM and 800 nM, respectively) and HCT116 showed increased sensitivity to OHP (IC50 decreased from 600 nM to 200 nM and 180 nM, respectively) and 5FU (IC50 decreased from 3500 nM to 2900 nM and 2800 nM, respectively). No increased sensitivity to irinotecan was observed. Clonogenic assay revealed that HCT116 formed 20% and 50% less colonies when treated with 5FU after transfection with miR-195-5p and miR-497-5p mimics, respectively, and 60% less colonies when treated with OHP after transfection with either mimic. RKO showed a 20% decrease in colonies when treated with OHP after transfection with miR-497-5p mimic. No differences in sensitivity to OHP, 5FU or irinotecan were found in transfected SW480 and DLD1. Unsupervised clustering of the proteome showed that HCT116 and RKO cells transfected with miR-195-5p and miR-497-5p mimics could be distinguished from the cells transfected with a control mimic and the untransfected cells. Transfected and control SW480 and DLD1 could not be distinguished based on the proteome profiles. In the combined analyses of HCT116 and RKO 12 peptides showed significantly altered expression (FDR<0.1) after transfection. No significantly altered peptides were detected in transfected SW480 and DLD1 cell lines. Conclusion: Restoring miR-195-5p and miR-497-5p expression enhanced sensitivity to OHP in HCT116 and RKO cells and to 5FU in HCT116 cells. Proteomics revealed 12 peptides with significantly altered expression after restoring expression of these miRNAs. Treatment with miRNA mimics to sensitize tumor cells to chemotherapy could be an alternative systemic treatment strategy for patients with advanced CRC. Citation Format: Lenka N. Boyd, Dennis Poel, Tim Schelfhorst, Thang V. Pham, Sander R. Piersma, Jaco C. Knol, Connie R. Jimenez, Henk M. Verheul, Tineke E. Buffart. Restoring downregulated microRNAs miR-195-5p and miR-497-5p increases sensitivity to chemotherapy in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2588.

The Treatment Strategies for Failed Fixation of Intertrochanteric Fractures

IntroductionDespite the generally successful outcome of intertrochanteric fracture fixation, the treatment is challenging when fixation failure occurs. Some studies have reported a systemic treatment strategy for salvaging failed intertrochanteric fracture fixation. This prospective study with a retrospective review of data aimed to evaluate and validate the efficacy of an evidence-based protocol developed for the treatment of failed intertrochanteric fractures. Patients and methods: Between 1997 and 2016, 83 patients who could be followed up for more than 1 year after treatment were enrolled at an academic medical centre. An evidence-based protocol was established in July 2008 and was implemented prospectively. The treatment protocol was determined keeping in mind the condition of the femoral head, the deformation of the fracture site and the bone defect. Clinical results were evaluated, and fracture union and femoral neck-shaft angle were evaluated radiographically for patients in valgus osteotomy and re-fixation subgroups. ResultsThe Pain score, leg length discrepancy, Koval score for ambulatory levels and modified Harris Hip Score showed statistically significant improvement after the implementation of the new protocol. The radiographic success rate was 73% (27 of 37 patients) in the pre-protocol group and 91% (42 of 46 patients) in the post-protocol group, which shows statistically significantly improvement. ConclusionThe new treatment strategy for failed intertrochanteric fracture fixation based on the condition of the femoral head, deformation of the fracture site and bone defect is successful based on clinical and radiographic results. Restoration of NSA of failed intertrochanteric fractures is a key factor for obtaining successful results.

Association of Ustekinumab vs TNF Inhibitor Therapy With Risk of Atrial Fibrillation and Cardiovascular Events in Patients With Psoriasis or Psoriatic Arthritis

Accumulating evidence indicates that there is an increased risk of cardiovascular disease among patients with psoriatic disease. Although an emerging concern that the risk of atrial fibrillation (AF) may also be higher in this patient population adds to the growing support of initiating early interventions to control systemic inflammation, evidence on the comparative cardiovascular safety of current biologic treatments remains limited. To evaluate the risk of AF and major adverse cardiovascular events (MACE) associated with use of ustekinumab vs tumor necrosis factor inhibitors (TNFi) in patients with psoriasis or psoriatic arthritis. This cohort study included data from a nationwide sample of 78 162 commercially insured patients in 2 US commercial insurance databases (Optum and MarketScan) from September 25, 2009, through September 30, 2015. Patients were included if they were 18 years or older, had psoriasis or psoriatic arthritis, and initiated ustekinumab or a TNFi therapy. Exclusion criteria included history of AF or receipt of antiarrhythmic or anticoagulant therapy during the baseline period. Initiation of ustekinumab vs TNFi therapy. Incident AF and MACE, including myocardial infarction, stroke, or coronary revascularization. A total of 60 028 patients with psoriasis or psoriatic arthritis (9071 ustekinumab initiators and 50 957 TNFi initiators) were included in the analyses. The mean (SD) age was 46 (13) years in Optum and 47 (13) in MarketScan, and 29 495 (49.1%) were male. Overall crude incidence rates (reported per 1000 person-years) for AF were 5.0 (95% CI, 3.8-6.5) for ustekinumab initiators and 4.7 (95% CI, 4.2-5.2) for TNFi initiators, and for MACE were 6.2 (95% CI, 4.9-7.8) for ustekinumab initiators and 6.1 (95% CI, 5.5-6.7) for TNFi initiators. The combined adjusted hazard ratio for incident AF among ustekinumab initiators was 1.08 (95% CI, 0.76-1.54) and for MACE among ustekinumab initiators was 1.10 (95% CI, 0.80-1.52) compared with TNFi initiators. No substantially different risk of incident AF or MACE after initiation of ustekinumab vs TNFi was observed in this study. This information may be helpful when weighing the risks and benefits of various systemic treatment strategies for psoriatic disease.

Long-term control with chemoradiation of initially metastatic mixed adenoneuroendocrine carcinoma of the rectum: a case report

BackgroundMixed adenoneuroendocrine carcinomas are highly malignant tumors with both adenocarcinomatous and neuroendocrine components. They can originate in any organ but are more common in the rectum. Due to their rarity, current treatment recommendations for mixed adenoneuroendocrine carcinoma are based on limited data and follow general guidelines for the management of adenocarcinomas and neuroendocrine neoplasms. Uncertainty regarding the efficacy of the available local and systemic treatment strategies is a compounding issue. Even those patients with locally limited disease have a relatively short life expectancy. In this report, we describe a case of deep rectal mixed adenoneuroendocrine carcinoma with long survival after chemoradiation.Case presentationA 48-year-old Caucasian woman was diagnosed with a grade 3 rectal adenocarcinoma combined with a poorly differentiated large cell neuroendocrine carcinoma component and synchronous metastases (cT3cN1cM1) in both lobes of the liver in 2012. She received concomitant chemoradiotherapy followed by four additional cycles of cisplatin plus irinotecan. Initial treatment induced complete remission of the rectal tumor and liver metastases. Consequently, it was not necessary to surgically resect the primary tumor or any of the metastases. Three months after the end of treatment, one metastasis in the first segment of the liver showed regrowth, and stereotactic body radiotherapy of the metastasis and chemotherapy resulted in a clinical complete response. The patient has been recurrence-free for more than 5 years.ConclusionsExtended long-term control of a poorly differentiated metastatic (stage IV) mixed adenoneuroendocrine carcinoma is rare. The multimodal first- and second-line regimens of radiotherapy and chemotherapy described in this case report represent a new therapeutic approach. Encouraged by the results in this case, we compiled a review of the literature on mixed adenoneuroendocrine carcinoma.

Preoperative Dural Contact and Recurrence Risk After Surgical Cavity Stereotactic Radiosurgery for Brain Metastases: New Evidence in Support of Consensus Guidelines

PurposeThe incidence of brain metastases is increasing as a result of more routine diagnostic imaging and improved extracranial systemic treatment strategies. As noted in recent consensus guidelines, postoperative stereotactic radiosurgery (SRS) to the resection cavity has lower rates of local control than whole brain radiation therapy but improved cognitive outcomes. Further analyses are needed to improve local control and minimize toxicity. Methods and materialsPatients receiving SRS to a resection cavity between 2006 and 2016 were retrospectively analyzed. Presurgical variables, including tumor location, diameter, dural/meningeal contact, and histology, were collected, as were SRS treatment parameters. Patients had routine follow-up with magnetic resonance imaging, and those noted to have local failure were further assessed for the recurrence location, distance from the target volume, and dosimetric characteristics. ResultsOverall, 82 patients and 85 resection cavities underwent postoperative SRS during the study period. Of these, 58 patients with 60 resection cavities with available follow-up magnetic resonance imaging scans were included in this analysis. With a median follow-up of 19.8 months, local recurrence occurred in 12 of the resection cavities for a 15% 1-year and 18% 2-year local recurrence rate. Pretreatment tumor volume contacted the dura/meninges in 100% of cavities with recurrence versus 67% of controlled cavities (P = .025). A total of 5 infield, 5 marginal, and 4 out-of-field recurrences were found, with a median distance to the centroid from the target volume of 3 mm. The addition of a 10-mm dural margin increased the target volume overlap with the recurrence contours for 10 of the 14 recurrences. ConclusionsDural contact was associated with an increased rate of recurrence for patients who received SRS to a surgical cavity, and the median distance of marginal recurrences from the target volume was 3 mm. These results provide evidence in support of recent consensus guidelines suggesting that additional dural margin on SRS volumes may benefit local control.

Improvement of prognosis by timely treatment : Requirement: initial presentation within 6 weeks

Rheumatoid arthritis (RA) is one of the most frequent chronic inflammatory rheumatic diseases and when untreated leads to chronic tissue destruction and increased mortality. Due to innovative systemic treatment strategies established over the last 20-25years, the prognosis has considerably improved in terms of disease and socioeconomic burdens, symptoms, long-term prognosis, ability to work and mortality; however, as a rule a prerequisite is long-term and continuous treatment. Amedicinal cure of RA is still not in view. For many patients this means the long-term use of very expensive medications. In addition to hemato-oncology, rheumatology has become the second most expensive discipline in Germany in terms of cost per patient. Convincing data from many studies imply that an early start of treatment within the first few weeks after clinical onset of symptoms improves the prognosis, reduces the necessity for expensive drugs and thereby considerably decreases medical costs. This results in the requirement that every patient with symptoms of arthritis must be seen by arheumatologist within the first 6 weeks following initial manifestation of the disease. Such an improvement in treatment can only be achieved in Germany if the numbers of rheumatologists and trained healthcare professionals in practices such as clinics are considerably increased. This is not only in the interests of patients but also in the interests of the health insurance companies because the investment in the healthcare infrastructure with internistic rheumatologists will result in substantial economic benefits for the cost bearer. It must be the common task of all players in healthcare policy, cost bearers and internistic rheumatologists to provide optimal conditions in medical as well as economical terms.

Changing patterns and survival improvements of young breast cancer in China and SEER database, 1999-2017.

ObjectiveBreast cancer in young females was usually considered more aggressive and requires aggressive therapy. We investigated whether early detection and improved treatments changed the patterns of characteristics, management and outcomes of young breast cancer patients over time.MethodsFemales under 40 years of age diagnosed with breast cancer during the periods 1999−2017 and 1999−2015 were identified in the Fudan University Shanghai Cancer Center (FUSCC) and the population-based Surveillance, Epidemiology, and End Results (SEER) registry, respectively. Clinicopathologic characteristics and treatment information were collected. Patients diagnosed before 2013 were followed up.ResultsThe proportions of young breast cancer patients were 15.0% and 5.3% in the FUSCC and SEER cohorts, respectively. In the FUSCC cohort, there was a significant increase in the proportion of ductal carcinoma in situ (DCIS) (from 8.8% to 16.9%; P<0.0001) and it remained stable in SEER cohort. The proportion of T1-stage tumors increased dramatically in the FUSCC cohort (from 35.3% to 41.9%; P=0.008), whereas it decreased in SEER cohort (from 42.4% to 33.0%; P<0.0001). The percentage of estrogen receptor (ER)-positive cancers was consistently increased in both the invasive ductal carcinoma (IDC) and DCIS patients in the two cohorts. Breast-conserving surgery and immediate implant reconstruction after mastectomy both exhibited increased use over time in the FUSCC cohort. Both the FUSCC and SEER cohorts showed a significantly better prognosis in the recent time period. ConclusionsWith the increased early-stage and ER-positive diseases in young patients as well as better systemic treatment strategies, improved survival has been observed in recent years. There has been a substantial de-escalation in surgical therapies in young breast cancer patients.

Clinical characteristics and treatment outcomes in six cases of malignant tenosynovial giant cell tumor: initial experience of molecularly targeted therapy

BackgroundAlthough tenosynovial giant cell tumor (TGCT) is classified as a benign tumor, it may undergo malignant transformation and metastasize in extremely rare occasions. High aberrant expression of CSF1 has been implicated in the development of TGCT and recent studies have shown promising activity of several CSF1R inhibitors against benign diffuse-type TGCT; however, little is known about their effects in malignant TGCT.Case presentationInformation from six consenting patients (3 men, 3 women) with malignant TGCT presenting to Dana-Farber Cancer Institute for initial or subsequent consultation was collected. Median age at initial diagnosis of TGCT was 49.5 years (range 12–55), and median age at diagnosis of malignant TGCT was 50 years (range 34–55). Two patients developed malignant TGCT de novo, while four other cases showed metachronous malignant transformation. All tumors arose in the lower extremities (3 knee, 2 thigh, 1 hip). Five patients underwent surgery for the primary tumors, and four developed local recurrence. All six patients developed lung metastases, and four of five evaluable tumors developed inguinal and pelvic lymph node metastases. All six patients received systemic therapy. Five patients were treated with at least one tyrosine kinase inhibitor with inhibitory activity against CSF1R; however, only one patient showed clinical benefit (SD or PR). Five patients were treated with conventional cytotoxic agents. Doxorubicin-based treatment showed clinical benefit in all four evaluable patients, and gemcitabine/docetaxel showed clinical benefit in two patients. All six patients died of disease after a median of 21.5 months from diagnosis of malignant TGCT.ConclusionsThis study confirms that TGCT may transform into an aggressive malignant tumor. Lymph node and pulmonary metastases are common. Local recurrence rates are exceedingly high. Conventional cytotoxic chemotherapy showed clinical benefit, whereas tyrosine kinase inhibitors against CSF1R showed limited activity. Given its rarity, a prospective registry of malignant TGCT patients is needed to further understand the entity and to develop effective strategies for systemic treatment.

Percutaneous hepatic perfusion (chemosaturation) with melphalan in patients with intrahepatic cholangiocarcinoma: European multicentre study on safety, short-term effects and survival.

Cholangiocarcinoma is the second most common primary liver tumour with a poor overall prognosis. Percutaneous hepatic perfusion (PHP) is a directed therapy for primary and secondary liver malignancies, and its efficacy and safety have been shown in different entities. The purpose of this study was to prove the safety and efficacy of PHP in patients with unresectable intrahepatic cholangiocarcinoma (iCCA). We retrospectively reviewed data from 15 patients with unresectable iCCA treated with PHP in nine different hospitals throughout Europe. Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Adverse events (AEs) and toxicity were evaluated. Fifteen patients were treated with 26 PHPs. ORR was 20%, disease control was achieved in 53% after the first PHP. Median OS was 26.9 months from initial diagnosis and 7.6 months from first PHP. Median PFS and hPFS were 122 and 131 days, respectively. Patients with liver-only disease had a significantly longer median OS compared to patients with locoregional lymph node metastases (12.9 vs. 4.8 months, respectively; p < 0.01). Haematological toxicity was common, but manageable. No AEs of grade 3 or 4 occurred during the procedures. PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with iCCA, especially in non-metastatic disease. • Percutaneous hepatic perfusion (PHP) offers an additional locoregional therapy strategy for the treatment of unresectable primary or secondary intrahepatic malignancies. • PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with intrahepatic cholangiocarcinoma (iCCA), especially in non-metastatic disease. • Side effects seem to be tolerable and comparable to other systemic or local treatment strategies.