The safety and efficacy of palbociclib in older patients with advanced breast cancer in a real-world setting

Aims:Palbociclib has been approved in combination with endocrine therapy(ET)for hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2-)advanced breast cancer(ABC),regardless of age.Even though ABC is one of the most prevalent cancers in older patients,very few patients≥65 years old were included in pivotal trials.Therefore,the current study evaluated the safety and efficacy of palbociclib in“real-world”routine treatment of unselected older patients with HR+/HER2-ABC.Methods:Data were collected on patients>70 years old who were treated with palbociclib plus ET for HR+/HER2-ABC in our institution.We analyzed safety data(CTCAE v4.0 criteria)and outcomes,such as progression-free survival(PFS)and overall survival(OS),as well as any associations between main geriatric characteristics and our results.Furthermore,we assessed safety at a national level by analyzing all palbociclib-related adverse events(AEs)reported in the French Pharmacovigilance Database(FPVD)during the same period.Results:From February 2016 to July 2019,52 patients were identified with a median age of 80.9 years,of whom 88%presented an AE.The most common grade 3-4 AE was neutropenia(64%).Median PFS and OS were nine months and not reached,respectively.The FPVD reports 227 cases of palbociclib-related AEs,with older and younger patients sharing similar characteristics.Conclusion:Palbociclib is well tolerated in older patients with efficacy comparable to that in younger patients.However,the addition of palbociclib to ET should be evaluated individually in this older and frailer subgroup.

Stimulation of in vitro bone formation by canine prostate cancer

Aim:Patients with prostate cancer frequently develop osteoblastic bone metastases.Canine models are important because dogs are the only mammal to develop spontaneous prostate cancer with osteoblastic bone metastases similar to men.The mechanism by which prostate cancer induces bone formation is unclear;however,it depends on the complex interaction between prostate cancer cells and bone microenvironment.This study investigated the effects of three canine prostate cancer cell lines(Ace-1,LuMa,and Probasco)on bone formation and resorption in vitro.Methods:Mouse calvaria were treated with conditioned medium(CM)from cell lines.Calvaria were evaluated by histology,fluorescent calcein uptake at sites of bone mineralization,medium calcium assay,and alkaline phosphatase activity.The expression of bone-related genes was measured using quantitative reverse transcription PCR.Results:A novel calcein uptake assay was developed to measure bone formation and mineralization in vitro.Ace-1 CM induced predominantly bone resorption in calvaria,while Probasco CM induced marked bone formation,mineralization,and healing of calvaria defects.The expression of osteoblast-related genes in calvaria showed that Probasco CM stimulated the maturation and differentiation of osteoblasts and inhibited osteoclastogenesis.Both bone modeling and remodeling were involved in Probasco CM-induced bone formation and mineralization by inhibiting remodeling with zoledronic acid.Inhibition of WNT activity by DKK-1 decreased the osteoblastic activity of Probasco cells.Conclusion:Probasco cells induced bone formation and mineralization in vitro that depended on the WNT signaling pathway.Probasco cells will serve as a valuable model for studying the mechanisms of osteoblastic bone metastasis in prostate cancer.

Negative effects of tumor cell nitric oxide on anti-glioblastoma photodynamic therapy

Glioblastomas are highly aggressive brain tumors that can persist after exposure to conventional chemotherapy or radiotherapy.Nitric oxide(NO)produced by inducible NO synthase(iNOS/NOS2)in these tumors is known to foster malignant cell proliferation,migration,and invasion as well as resistance to chemo-and radiotherapy.Minimally invasive photodynamic therapy(PDT)sensitized by 5-aminolevulinic acid(ALA)-induced protoporphyrin IX(PpIX)is a highly effective anti-glioblastoma modality,but it is also subject to NO-mediated resistance.Studies by the authors have revealed that glioblastoma U87 and U251 cells use endogenous iNOS/NO to not only resist photokilling after an ALA/light challenge,but also to promote proliferation and migration/invasion of surviving cells.Stress-upregulated iNOS/NO was found to play a major role in these negative responses to PDT-like treatment.Our studies have revealed a tight network of upstream signaling events leading to iNOS induction in photostressed cells and transition to a more aggressive phenotype.These events include activation or upregulation of pro-survival/pro-expansion effector proteins such as NF-κB,phosphoinositide-3-kinase(PI3K),protein kinase-B(Akt),p300,Survivin,and Brd4.In addition to this upstream signaling and its regulation,pharmacologic approaches for directly suppressing iNOS at its activity vs.transcriptional level are discussed.One highly effective agent in the latter category is bromodomain and extra-terminal(BET)inhibitor,JQ1,which was found to minimize iNOS upregulation in photostressed U87 cells.By acting similarly at the clinical level,a BET inhibitor such as JQ1 should markedly improve the efficacy of anti-glioblastoma PDT.

Targeting adenosine receptor 2B in triple negative breast cancer

In the review“Role of adenosine in tumor progression:focus on A2B receptor as potential therapeutic target”,Sorrentino and Morello make a compelling case for considering adenosine 2B receptor(A2BR)as a target in cancer therapy(J Cancer Metastasis Treat 2017;3:127-38).A large body of evidence has accumulated suggesting A2BR to play an active role in tumor immune suppression and metastasis.Thus,this commentary will discuss the intriguing possibility of targeting A2BR in specific breast cancers that express high levels of A2BR and attract infiltrating immune cells.

Metastatic inguinal lymph nodes with two different histological types in a case of carcinoma of unknown primary site

Cancer of unknown primary site is a group of uncommon cancers where patients present with metastatic disease and the primary site is not identifi ed,even after a complete workup to establish the diagnosis.Inguinal metastasis with unknown primary is even more uncommon,and histological type is the most important guiding factor to look for the primary.This report describes the rare situation of inguinal metastasis with an unknown primary site where a combination of squamous and transitional cell carcinoma was found on fi nal histopathology.It highlights the importance of multimodality approach including an aggressive surgical resection combined with adjuvant radiation therapy to achieve an optimal outcome.

Insights into the co-evolution of glioblastoma and associated macrophages

Glioblastoma(GBM)is one of the most immunosuppressive and heterogeneous tumors with limited treatment options.Most studies relied on treatment-experienced patient samples to elucidate the origins of tumor heterogeneity,introducing bias into the analysis.The analysis of samples from multifocal GBM patients,in which independent lesions arise from the same progenitor and undergo parallel evolution,enables the study of the natural evolution of GBM while removing the effect of therapy on the emergence of heterogeneity.This enables the identification of critical events in the evolution of GBM and the unbiased study of subtype progression,diversity,and invasive potential.The tumor microenvironment of GBM undergoes significant changes throughout tumor progression.Recent studies have highlighted the switch from an abundance of resident microglia-derived macrophages in earlier stages to the prevalence of blood-derived macrophages in later stages of GBM.There is conclusive evidence that these alterations cannot be viewed in isolation and that the tumor microenvironment co-evolves with tumor cells during cancer progression.Together with an increasingly hypoxic environment,this culminates in highly immunosuppressive conditions,resulting in a feedback loop further reinforcing evolutionary changes in the tumor.A new study now provides a unique look at the natural evolution of GBM,identifies critical events in its development,and has the potential to help improve the diagnosis and therapy of this deadly disease.

Special issue on“Immunotherapy of cancer:future possible therapy for metastatic cancer”

The global burden of cancer incidence is estimated to be up to 18.1 million people with 9.6 million deaths in 2018.The major cause of death is due to the high toxicity of chemotherapeutic drugs and drug resistance developed by cancer cells.Thus,there is an unmet need for appropriate therapy which can kill cancer cell alone and reduce drug resistance.Immunotherapy is an alternative therapy for cancer which mainly boosts the immune response of these patients and kills cancer cells alone with fewer side effects.Since Professor James Allison from M.D.Anderson Cancer Centre,Texas,USA,received the Noble prize for his outstanding contribution to the field of immunotherapy,there has been great excitement in this field.Immunotherapy has become a powerful branch of cancer therapy for the treatment of various types of cancers due to milder side effects than the presently available chemotherapy or radiotherapy.It mainly works by strengthening the host immune responses against tumor cells by supplementation of modified immune system components.There are four different types of immunotherapies:monoclonal antibodies,cancer vaccines,immune checkpoint inhibitors,and Chimeric Antigen Receptor-T cell therapies.Immunotherapy can be given in combination with mild doses of chemotherapy or radiotherapy obtain effective and non-toxic treatment for most cancer patients.

Angiogenesis in acute myeloid leukemia

Angiogenesis is a word that refers to new blood vessel formation,and this process is of fundamental importance for physiological development and tissue homeostasis,as well as the genesis of several diseases,including tumors.Thus,studies carried out in the last years have shown that angiogenesis is essential for the growth of many solid tumors.Angiogenesis is also important for the growth of many hematological malignancies,including acute myeloid leukemia(AML).Endothelial cells are essential constituents of the bone marrow vascular niches,structures essential for the survival and maintenance of normal hematopoietic stem/progenitor cells.Bone marrow endothelial cells play an essential role in leukemia development and there is growing evidence that a targeting of both leukemic and endothelial cells of the leukemic vascular niche may improve the efficacy of antileukemic therapies.Bone marrow angiogenesis is frequently increased in AML,is morphologically evidenced as increased microvascular density,and is typically associated with some AML subtypes.The molecular mechanisms underlying the increased angiogenesis in some AML subtypes have been defined.In conclusion,a better understanding of angiogenesis as well as the fundamental interactions between bone marrow endothelial cells and leukemic stem cells may contribute to improve antileukemia treatments.

Sequential treatment with doxorubicin and zoledronic acid has no additive effects in an aggressive model of established bone metastases

Aim: Bisphosphonates are used as an adjuvant treatment in breast cancer bone metastasis patients, often simultaneously with chemotherapeutic agents. Interestingly, their sequential combination has been reported to have synergistic anti-tumor effects on bone metastases in preclinical models. We studied the effects of doxorubicin (DOX) and zoledronic acid (ZOL) and their combination on established bone metastases in the MDA-MB-231(SA) GFP bone metastasis model. Methods: Tumor burden and osteolytic bone lesions were quantitated by fluorescence imaging and radiography, respectively. The mice were randomized in four groups receiving vehicle, DOX, ZOL or both DOX and ZOL in a sequential combination on day 14. Serum marker of osteoclast number was followed weekly, and blood ionized calcium was measured at sacrifice. Bone and tumor area, apoptosis and proliferation of tumor cells were analyzed from histological sections. Results: ZOL prevented hypercalcemia and osteolytic lesion progression, whereas DOX induced apoptosis in the MDA-MB-231(SA)GFP cells. However, neither of the treatments alone nor in sequential combination were able to reduce tumor burden in bone. Furthermore, no additive effects on tumor cell apoptosis were observed in the ;combination group. Conclusion: No additive effects in combination of DOX and ZOL were observed in this aggressive model of breast cancer bone metastasis.

Controversies in the treatment of digestive neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors(NETs)have an incidence of 2.39 per 100,000 inhabitants per year,and a prevalence of 35 cases per 100,000 inhabitants;the gap between these rates is due to the relatively long survival time of these tumors,which can be thus considered as chronic oncological diseases.Recently,more therapeutic options have become available,but criteria for defining timing,priority and sequence of different therapeutic options are still debated.This review offers an overview of pancreatic and small bowel NETs,critically underlining the issues that still need to be clarified and some controversial issues on the therapeutic approach for NET patients.

Surgical route and pathological risk factors in early cervical cancer-Node Zero(SURPEC-N0)

Aim:The aim of this study is to compare disease-free survival(DFS)and overall survival(OS)in patients with stage I cervical cancer(≤4cms,lymph node-negative)undergoing open radical hysterectomy(ORH)vs.minimally invasive radical hysterectomy(MIRH).Methods:All patients undergoing radical hysterectomy between January 2012-December 2018 from the largest tertiary referral cancer centre were included.A 1:1 propensity matching was done based on four independent prognostic factors to compare DFS and OS with the route of surgery.Results:One hundred and ninety-nine patients were included during the study period.The median age of the cohort was 50 years.The median follow-up of patients was 47 months.Following 1:1 propensity matching,a total of 174 patients were analysed for DFS and OS in ORH(n=87)and MIRH(n=87)groups.Protective measure was used in two-thirds of the patients during MIRH.Twenty-nine patients(16.7%)had recurrences.For the matched cohort(n=174),the DFS at 36 and 60 months was 84.8%(78.1%-89.6%)and 81%(73.4%-86.6%)respectively and the OS was 96.5%(91.7%-98.5%)and 95.6%(90.3%-98%)respectively.There was no statistically significant difference in DFS or OS between ORH and MIRH.Conclusion:The present study showed no difference in oncological outcomes in MIRH compared to ORH.Retrospective audits on patient characteristics such as screening/vaccination history along with surgical technique/load and matching for crucial risk factors should be factored in future studies to eliminate the possible methodological errors.

Synergistic inhibition of SCR1- and ERBB2-driven brain metastatic breast cancer cells

Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzumab, and pertuzumab, no effective therapy for brain metastases is currently available. This study seeks to identify novel gene targets and pharmaceutical Intervention against breast cancer brain metastasis. Methods: The detailed methods applied to this study, including comparative RNA sequencing and bioinformatics analysis of sequence data, ingenuity pathway analysis, protein-protein interaction analysis, high throughput screening of clinical and pre-clinical drugs, cell viability and proliferation assay, toxicity and apoptosis assay using fluorescence-activated cell sorting, real-time PCR, western blotting, statistical analysis of data. Results: The study reveals critical roles for SRC, ERBB2, PIK3CA, and GABA in the proliferation and survival of breast cancer brain metastatic (BBM) cells and showed that SRC- and ERBB2-mediated activation of PIK3-AKT/mTOR signaling regulates BBM cell survival. Selective inhibition of these candidate genes alone or in combination induces robust apoptosis in BBM cells Conclusion: The findings of this study provide a rationale for further preclinical evaluation of SRC-targeting regimens in combination with ERBB2 inhibitors and/or GABA agonists to target breast cancer brain metastasis.

Training and evaluation of a knowledge-based model for automated treatment planning of multiple brain metastases

Aim: Volumetric modulated arc therapy (VMAT) has been utilized to plan and treat multiple cranial metastases using a single isocenter due to its ability to provide steep dose gradients around targets as well as low doses to critical structures. VMAT treatment is delivered in a much shorter time compared to using a single isocenter for the treatment of each lesion. However, there is a need to develop methods to reduce the treatment planning time for these cases while also standardizing the plan quality. In this work we demonstrate the use of RapidPlan, which is knowledge-based treatment (KBP) planning software to plan multiple cranial SRS cases. Methods: The 66 patient plans with 125 lesions (range 1-4, median 1) were used to train a model. In addition, the model was validated using 10 cases that were previously treated and chosen randomly. The clinical plans were compared to plans generated by RapidPlan for target coverage and critical organ dose. Results: Coverage to the target volume, gradient index, conformity index and minimum dose to the target showed no significant difference between the original clinical plan vs. the plan generated by KBP. A comparison of doses to the critical organs namely the brainstem, brain, chiasm, eyes, optic nerves and lenses showed no significant difference. Target dose homogeneity was slightly better with the clinical plan, however this difference was also statistically insignificant. ;Conclusion: This work demonstrates that KBP can be trained and efficiently utilized to help not only speed up the planning process but also help standardize the treatment plan quality.

Pharmacogenetics and cancer management

The science of one’s genetic background and its impact on disease susceptibility and drug response has come of age and firmly established its proper place in the clinic.Its impact is felt more in the treatment of cancer than any other disease area several reasons:critical time,narrow therapeutic index and overlapping toxicity window.We realize that the true potential of pharmacogenetics will be realized when we have been able to integrate other variants like insertion-deletion,copy number variation,etc.,in addition to single nucleotide polymorphism for their collective influence on drug response and toxicity.Technology has rapidly evolved and has become affordable to be used in the clinic once it gets standardized and validated not only in one population but in several major world population-particularly those which are under-represented in human variant database.

Squamous cell carcinoma of tongue 18 years after renal transplantation:a case report

Solid organ transplant recipients are at increased risk of developing malignancies,even decades after transplant,due to the prolonged use of immunosuppressant drugs.A 35-year-old male underwent renal transplant for end stage renal disease 18 years previously and was on immunosuppressive drugs since that time and was on regular follow up.In 2016,he developed a squamous cell carcinoma of tongue,which was operated and adjuvant radiation therapy was given.The patient is currently on follow up and asymptomatic.Though squamous cell carcinoma of tongue is a relatively common malignancy in the general population,it is very rare in transplant recipients.Hence,such patients require longer follow-up,active surveillance,and screening for early diagnosis and prompt treatment of premalignant and malignant conditions.

Changing paradigm in treatment of lung cancer

Lung cancer is one of the most common and deadliest forms of cancer.It accounts for 13%of all new cancer cases and 19%of cancer-related deaths.In India,lung cancer constitutes 6.9%of all new cancer cases and 9.3%of all cancer cases.There has also been a dramatic rise worldwide in both the absolute and relative frequencies of lung cancer occurrence.In 1953 it became the most common cause of cancer mortality in men.By 1985,it became the leading cause of cancer deaths in women,causing almost twice as many deaths as breast cancer.The demographic profile of lung cancer has changed greatly over the years;however,methods for diagnosing,screening,and managing lung cancer patients have improved.This is due to our growing understanding of the biology of lung cancer.It is now possible to further define lung cancer types beyond small cell lung carcinoma and non-small cell lung carcinoma.Moreover,new histology-based therapeutic modalities have been developed,and more new lung cancer biomarkers have been uncovered.Therefore,more detailed histological characterization of lung cancer samples is warranted in order to determine the best course of treatment for specific patients.This review article describes how these new molecular technologies are shaping the way lung cancer can be treated in future.

The role of radiation therapy in the management of primary thymic epithelial neoplasms

Therapeutic radiation plays an important role in the management of thymoma and thymic carcinoma.These two tumor types differ substantially in their aggressiveness and prognosis.The most pressing issue in radiotherapy is which thymoma and thymic carcinoma patients need radiation.Given that these are rare cancers,few randomized trials have been published.Controversy remains regarding which patients benefit from adjuvant radiation therapy.Existing literature spans patients treated over nearly 50 years,during which time radiation therapy has evolved from rudimentary 2-dimensional based planning to conformal 3-dimensional planning to yet more conformal dose painting techniques such as intensity-modulated radiation therapy and proton therapy.If the effect of radiation is small and the natural history of a disease long,as is the case for stage I favorable histology thymoma,then differences in techniques and toxicities may have as much of an impact as whether radiation was given or not.

Introduction to this special issue - "Autophagy and Cancer: current biology and drug development"

It is my pleasure,as one of the editorial board members,to introduce the readers of JCMT to this special issue entitled"Autophagy and Cancer:current biology and drug development".Autophagy is a fundamental process for cells to degrade unwanted proteins/damaged organelles and also to recycle cellular components.

Management of choroidal metastasis using external beam radiotherapy: a retrospective study and review of the literature

Aim:Choroidal metastases are rare in the evolution of solid cancers and constitute exceptional metastatic sites involving functional visual prognosis.The authors conducted a retrospective study to determine the interest of external radiotherapy for the treatment of choroidal metastases.Methods:The authors reviewed the records of 28 patients with choroidal metastases who had breast(n=15),lung(n=9),ovarian(n=1),kidney(n=1),prostate(n=1)cancer or carcinoma with unknown primitive at the moment of the diagnosis(n=1).The median age was 58 years(extremes:34-71 years).Tumor stage before the discovery of metastatic choroidal metastasis was 50%of patients.Ocular involvement was unilateral(n=22)or bilateral(n=6).The delivered doses ranged from 20 to 50 Gy fractionated with 3-5 Gy in 2D technique(n=5),conformational(n=21),intensity modulation(n=2).The most widely used prescription scheme delivered 30 Gy in 10 fractions(64%)using two 6 MV photons beams.Results:At the end of irradiation,13 patients(46%)showed an improvement of eye symptoms.For the others,a stabilization in symptoms was noted(n=15).No patient had visual degradation.No acute or late grade 2-3 toxicities were objectified.The histological type did not influence the response(P=0.5).There was no dose relationship-response in our series.Conclusion:External radiation therapy is a useful technique in the palliative treatment of choroidal metastases.Acute and late toxicities are acceptable.

The association of the uterine motion with bladder volume during radiotherapy in gynecological malignancies

Aim:This study was performed to assess the extent of interfraction uterine motion during radiotherapy for cervical cancer and uterine body carcinoma while maintaining a strict bladder filling protocol.Methods:Twenty-four patients with cervical cancer or uterine body carcinoma who were treated on a linear accelerator,were recruited.During the course of external beam radiotherapy,cone beam computed tomographic scans were taken,once at the start of treatment and then weekly until the completion of the radiotherapy course.Patients were instructed to maintain a strict bladder filling protocol.After negating the effect of patient’s setup error by offline cone beam computed tomographic imaging,the position of the uterus was defined in the clinical target volume.Then the position of the uterus was compared in the following weekly scans.The position of the uterus was also correlated with the position and the filling of the bladder.This change in uterus position was measured separately in the anterioposterior(AP),superioinferior(SI),and lateral directions.Results:According to calculations based on weekly imaging,The mean values of shift in AP,SI,and lateral directions were respectively 0.67,0.29,and 0.23 The mean extent of motion in the uterine position on a daily basis for individual patients ranged from-2.28 to+1.3 in AP,-0.56 to+0.71 in SI,and from-0.6 to+0.45 in lateral directions.Conclusion:At least once a week cone beam computed tomography might be necessary to minimize the geometrical miss and deliver the planned doses to the target tissue and normal structure provide best results with minimum toxicity by maintaining a bladder volume of about 100 mL and an empty rectum during the whole course of treatment.The daily anatomical shift and contour of the patients maintaining a bladder volume of approximately 100 mL with an empty rectum may result in asymmetrical conforming to the planning target volume and hence appropriate and adequate planning target volume margins are required.