Interplays of electron and nuclear motions along CO dissociation trajectory in myoglobin revealed by ultrafast X-rays and quantum dynamics calculations.

Ultrafast structural dynamics with different spatial and temporal scales were investigated during photodissociation of carbon monoxide (CO) from iron(II)-heme in bovine myoglobin during the first 3 ps following laser excitation. We used simultaneous X-ray transient absorption (XTA) spectroscopy and X-ray transient solution scattering (XSS) at an X-ray free electron laser source with a time resolution of 80 fs. Kinetic traces at different characteristic X-ray energies were collected to give a global picture of the multistep pathway in the photodissociation of CO from heme. In order to extract the reaction coordinates along different directions of the CO departure, XTA data were collected with parallel and perpendicular relative polarizations of the laser pump and X-ray probe pulse to isolate the contributions of electronic spin state transition, bond breaking, and heme macrocycle nuclear relaxation. The time evolution of the iron K-edge X-ray absorption near edge structure (XANES) features along the two major photochemical reaction coordinates, i.e., the iron(II)-CO bond elongation and the heme macrocycle doming relaxation were modeled by time-dependent density functional theory calculations. Combined results from the experiments and computations reveal insight into interplays between the nuclear and electronic structural dynamics along the CO photodissociation trajectory. Time-resolved small-angle X-ray scattering data during the same process are also simultaneously collected, which show that the local CO dissociation causes a protein quake propagating on different spatial and temporal scales. These studies are important for understanding gas transport and protein deligation processes and shed light on the interplay of active site conformational changes and large-scale protein reorganization.

A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer.

OBJECTIVES: To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. METHODS: A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. RESULTS: Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). CONCLUSIONS: Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01836432.

New Advances in Supportive Care: Chemoprotective Agents as Novel Opportunities in Geriatric Oncology.

PURPOSE OF REVIEW: To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. New chemoprotective agents are necessary because age is the main risk factor for chemotherapy complications that account largely for the poorer outcome of cancer in the elderly. Trilaciclib and ALRN-6924 cause a reversible block of the proliferation of normal cells through cell cycle arrest (CCA). With this mechanism, they may prevent the toxicity of cycle-active cancer treatment including neutropenia, anemia, thrombocytopenia, lymphopenia, mucositis, and alopecia. RECENT FINDINGS: Myelopoietic growth factors may prevent neutropenia in the aged, but they may cause severe bone pain, may aggravate thrombocytopenia and anemia, and may cause myelodysplasia and acute leukemia as a late complication. The prevention of thrombocytopenia, anemia, mucositis, and alopecia is unsatisfactory at present. These complications may jeopardize the treatment outcome as they require a reduction of treatment dose/intensity and because many patients find the resulting symptoms intolerable. In three studies of patients with extensive disease small cell lung cancer (ES-SCLC), trilaciclib reduced the severity and duration of neutropenia and thrombocytopenia as well as the need for blood transfusions. In addition, it produced a significant expansion of T-cell clones. Trilaciclib received FDA approval for the prevention of chemotherapy-induced myelosuppression in patients with ES-SCLC. ALRN-6924 is currently studied in phase II study of ES-SCLC. In a phase IB of 38 patients, ALRN-6924 prevented myelosuppression to an extent comparable with trilaciclib. Both drugs proved as effective in patients 65 and older as they were in the younger ones. In an "ex vivo" study, ALRN-6924 protected the epithelial stem cells of hair follicles from taxanes and promised to prevent alopecia. The possibility that CCA of tumor cells may reduce the effectiveness of cycle-active chemotherapy is a major concern. For this reason, the use of trilaciclib, an inhibitor of CDK 4/6, should be limited to tumors with inactivated RB1, and the use of ALRN-6924, an inhibitor of P53, should be limited to tumors with inactivated P53. Chemotherapy-related toxicities limit dose intensity and contribute to significant morbidity and mortality in elderly cancer patients. Trilaciclib and ALRN-6924 are of particular interest to geriatric oncologists because of their novel mechanism of action. Ameliorating chemotherapy-induced toxicities holds the promise of transforming the practice of geriatric oncology by enabling chemotherapeutic regimens that are currently not feasible for this patient population. Specifically, these agents may prevent chemotherapy-induced neutropenia and thrombocytopenia, perhaps the most life-threatening complications of cytotoxic chemotherapy, thereby obviating the need for the use of rescue strategies such as hematopoietic growth factors. In addition, these agents offer the potential for broad tissue protection from other chemotherapy-related toxicities, including mucositis, diarrhea, and alopecia, which historically have been poorly managed. Importantly, by preventing a spectrum of chemotherapy-related toxicities, these agents may permit the administration of chemotherapy at full-dose intensity, prevent functional decline, and grant maintenance of resilience to older cancer patients. As a result, the successful prevention of chemotherapy-induced side effects may not only mitigate the costs of care but also improve patient outcomes and quality of life. Finally, chemoprotective strategies offer the opportunity to apply geriatric principles to clinical trials of cancer treatment. In particular, they may allow the testing of prolongation of "active life expectancy" as a major goal of clinical trials in elderly patients. They may also enable novel and more practical forms of clinical trials. By assessing the risk of chemotherapy-related toxicity with the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) or the Cancer and Aging Research Group (CARG) instruments, these agents may permit researchers to utilize patients as their own controls and endorse the approval of supportive care drugs based upon the risk profile of individual patients.

Biological and Functional Biomarkers of Aging: Definition, Characteristics, and How They Can Impact Everyday Cancer Treatment.

PURPOSE OF REVIEW: Recognize which are the elements that predict why a person is aging faster or slower and which intervention we can arrange to slow down the process, which permits to prevent or delay the progression of multimorbidity and disability. RECENT FINDINGS: Aging is a complex process that leads to changes in all the systems of the body and all the functions of the person; however, aging develops at different rates in different people, and chronological age is not always consistent with biological age. Gerontologists are focused not only on finding the best theory able to explain aging but also on identifying one or more markers, which are able to describe aging processes. These biomarkers are necessary to better define the aging-related pathologies, manage multimorbidity, and improve the quality of life. The aim of this paper is to review the most recent evidence on aging biomarkers and the clusters related to them for personalization of treatments.

Management of Cancer in the Older Age Person: An Approach to Complex Medical Decisions.

The management of cancer in older aged people is becoming a common problem due to the aging of the population. There are many variables determining the complex situation that are interconnected. Some of them can be assessed, such as risk of mortality and risk of treatment complications, but many others are still unknown, such as the course of disease, the host-related factors that influence cancer aggressiveness, and the phenotype heralding risk of permanent treatment-related damage.This article presents a dynamic and personalized approach to older people with cancer based on our experience on aging, cancer, and their biological interactions. Also, novel treatments and management approaches to older individuals, based on their functional age and their social and emotional needs, are thoughtfully explored here. The Oncologist 2017;22:335-342 IMPLICATIONS FOR PRACTICE: The goal of this article is to suggest a practical approach to complexity, a clinical situation becoming increasingly common with the aging of the population. Beginning with the analysis of two clinical cases, the authors offer an algorithm for approaching cancer in the older person that involves the assessment of life expectancy without cancer, the risk that cancer might compromise a patient's survival, function, or quality of life, and the potential benefits and risks of the treatments based on a clinical evaluation. The authors then review possible laboratory assessment of functional age and the importance of rapid-learning databases in the study of cancer and age.

Palliative Care of Cancer in the Older Patient.

The scope of palliative care includes goal setting, symptom management, and care of the care giver. Palliative care is essential for patient-centered care of the older cancer patients. The diversity of this population in terms of life expectancy, treatment tolerance, function, disability, and social support mandates personalized treatment plans. The assessment of physiologic age is currently based on a comprehensive geriatric assessment (CGA). A number of biologic markers of aging including the inflammatory index, the genomic clock, the expression of p16INKa4, and the circulating levels of vitamin D may complement the CGA and fine-tune the determination of physiologic age. Goal setting in older patients may be complicated by communication difficulties related to hearing, cognition, expectation, and culture. Cancer-related pain is a major hindrance to the maintenance of functional independence and fatigue is harbinger of disability and death. The article explores the assessment and the management of the most common and debilitating symptoms in older cancer patients.

Chronic Lymphocytic Leukemia in the Elderly: Epidemiology and Proposed Patient-Related Approach.

BACKGROUND: Chronic lymphocytic leukemia (CLL) occurs primarily in the elderly, and the majority of deaths attributable to CLL occur in persons 65 years of age or older. The greater number of comorbidities and reduced functionality associated with aging have also made successful treatment of CLL in the elderly more difficult. METHODS: The authors reviewed current epidemiology and guidelines for treatment of CLL, as well as recently approved therapies and studies of physiological aging. RESULTS: Determination of physiological age and performance of a thorough geriatric assessment play critical roles in the selection of optimal therapeutic approaches for older patients diagnosed with CLL. CONCLUSION: Older age, expressed via a frailty index, is a prognostic factor for poorer outcome in patients with CLL. However, several novel treatment options may result in reduced mortality and lessened treatment-related toxicity in older CLL patients.

Palliative Care in Older Patients With Cancer.

BACKGROUND: In general, cancer is a disease of aging, and palliative care is an essential step in the management of cancer in patients who are older. The goal of this article is to review common symptoms of cancer and oncology treatment and their management. METHODS: The pertinent medical literature was reviewed. RESULTS: The scope of palliative care includes personalized cancer treatment. This involves choosing treatment options that best fit the needs of each individual patient. Balancing treatment benefits and risks may be challenging in older patients, many of whom have limited life expectancies and decreased functional reserves. The benefits of treatment may diminish, and the risks of such treatment options increase with age. Thus, the first step toward personalized treatment includes determining physiological age, which is best estimated with a comprehensive geriatric assessment. Prevention of common complications, which include neutropenia and mucositis, allows the administration of treatment in full and effective doses. Fatigue is a chronic symptom related to cancer and its treatment and may lead to functional dependence and an increased risk of death. Fatigue might be prevented by daily exercise even during treatment. Other symptoms include pain and feelings of memory loss. CONCLUSIONS: The scope of palliative care encompasses more issues that symptom management and, for this reason, palliative care should be provided once the diagnosis of cancer is established. Determining treatment goals is essential to improve the treatment experience. Symptom management is similar in older and young patients, but symptoms in the older population may be associated with more frequent and severe complications. Many options exist to prevent and ameliorate the complications of oncology treatment in the aged. However, more studies should be conducted on the long-term care of older patients who have survived cancer.

WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides.

Peptide vaccines are capable of eliciting immune responses targeting tumor-associated antigens such as the Wilms' Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity. Six vaccinations were delivered biweekly, continuing then monthly until patients received 12 vaccinations or showed disease relapse or progression. Therapeutic efficacy was evaluated by progression-free and overall survival. Immune responses were evaluated by delayed-type hypersensitivity testing and T-cell IFNγ ELISPOT at specified intervals. In 16 patients who received at least one vaccination, 10 completed the planned course of six vaccinations and six continued for up to six additional monthly vaccinations. Vaccinations were well tolerated, with no patients discontinuing due to toxicity. One of two patients with high-risk MDS experienced a prolonged decrease in transfusion dependence. Two of 14 AML patients demonstrated relapse-free survival >1 year. Both patients were in CR2 at time of vaccination, with duration of their remission exceeding duration of their first remission, suggesting a potential benefit. Our WT1 vaccine was well-tolerated. The clinical benefit that we observed in several patients suggests engagement of a protective immune response, indicating a need for further trials.

Management of prostate cancer in older patients: updated recommendations of a working group of the International Society of Geriatric Oncology.

In 2010, the International Society of Geriatric Oncology (SIOG) developed treatment guidelines for men with prostate cancer who are older than 70 years old. In 2013, a new multidisciplinary SIOG working group was formed to update these recommendations. The consensus of the task force is that older men with prostate cancer should be managed according to their individual health status, not according to age. On the basis of a validated rapid health status screening instrument and simple assessment, the task force recommends that patients are classed into three groups for treatment: healthy or fit patients who should have the same treatment options as younger patients; vulnerable patients with reversible impairment who should receive standard treatment after medical intervention; and frail patients with non-reversible impairment who should receive adapted treatment.

Studying cancer treatment in the elderly patient population.

BACKGROUND: Data relating to cancer treatment in the older patient population are limited because older individuals have been under-represented in clinical trials. The goal of this review was to establish which factors hinder the participation of older individuals to clinical trials and to examine possible solutions. METHODS: The literature relating to cancer treatment in the older patient population was reviewed. RESULTS: The benefit of systemic cancer treatment may decrease with age, and risks may be increased due to reduced life expectancy and reduced tolerance of stress in the older population. Therefore, a multipronged approach is recommended for clinical studies in these patients, including phase 2 studies limited to persons 70 years of age and older, stratification by life expectancy and predicted treatment tolerance in phase 3 studies, and registration studies to establish predictive variables for treatment-related toxicity in older individuals. CONCLUSIONS: A combination of prospective and registration studies may supply adequate information to study cancer treatments in the older patient population.

Cancer and ageing: a nexus at several levels.

Cancer is largely a disease of older people. With the relatively recent expansive growth within the geriatric population, a number of pressing biological and clinical questions that currently remain unanswered need to be addressed. These include what effect age itself has on the development or growth of cancer, and what are the benefits and risks of cancer prevention and treatment for the older person? New insights into the underlying biological processes of ageing provide a frame of reference for addressing these and other related questions.

Love and frailty and an avalanche of missteps.

A retired oncologist describes the unexpected death of his wife, Claudia, who spent 25 years as head of the geriatrics service of a major VA hospital. The couple drew comfort in their orchestration of a "good death"; nevertheless they understood that her death was hastened by a number of missteps. In the 2 months following a hip fracture, a chain of complications that required five surgical interventions led to massive hemorrhage from necrotizing esophagitis. Claudia lacked resilience to recover from a sequence of traumas sustainable by a younger person-but even the most experienced geriatrician might not have identified or even suspected her risk. Despite multiple well-controlled comorbidities Claudia was active and independent. She exercised daily and traveled extensively. She did not fit the profile of a frail or vulnerable person, according to assessing instruments in current use. According to the e-prognosis calculator, her mortality risk was 10% lower than that of women her age. It is not surprising, nor deplorable, that after Claudia developed mild dysphagia, a gastroenterologist put off an EGD, awaiting a cardiac consult. That delay, however, proved fatal. Had the procedure been performed as soon as possible, it would have revealed esophagitis caused by a hiatal hernia, signaling need for different medications and prompt treatment. This might have prevented the terminal hemorrhage. The first important lesson from this case is that for an older patient with multiple comorbidities, even under control, delayed treatment is treatment denied. Current evaluation instruments are unable to spot critical resilience reductions in functional seniors. Inadequate pain management, premature discharge after surgery, and poor communication also contributed to the death. The second important lesson is that older patients, even when they are medical doctors, would benefit from a trained advocate to help them navigate the medical system.

Myeloid growth factors.

Febrile neutropenia, a common side effect of myelosuppressive chemotherapy in patients with cancer, can result in prolonged hospitalization and broad-spectrum antibiotic use, often prompting treatment delays or dose reductions of drug regimens. Prophylactic use of myeloid growth factors (mainly the colony-stimulating factors filgrastim and pegfilgrastim) in patients of heightened risk can reduce the severity and duration of febrile neutropenia. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors provide recommendations on the use of these agents mainly in the oncology setting based on clinical evidence and expert consensus. This version includes revisions surrounding the issue of timing of pegfilgrastim administration. It also includes new sections on tbo-filgrastim, a recently approved agent that is biologically similar to filgrastim, and the role of myeloid growth factors in the hematopoietic cell transplant setting.

Rehabilitation of older cancer patients.

Cancer is a disease of aging. With the aging of the population and the improved survival of cancer patients, rehabilitation of older cancer survival is an increasingly common problem. DEFINITION AND ASSESSMENT OF AGING: Age may be constructed as a progressive reduction in functional reserve of multiple organ systems leading to decreased life expectancy and reduced stress tolerance. Physiologic age may be different from chronologic age and is best assessed with a comprehensive geriatric assessment (CGA). The goals of cancer treatment in the older aged person include prolongation of active life expectancy that is prevention of functional dependence. CANCER CONDITION IN WHICH REHABILITATION OF OLDER INDIVIDUALS MAY BE NEEDED: Cancer and cancer treatment may accelerate physiologic aging. Rehabilitation is especially necessary in the case of curable malignancies or malignancies for which a prolonged survival is likely. REHABILITATION NEEDS IN OLDER CANCER SURVIVORS: Long-term complications of cancer treatment that may compromise life expectancy and functional independence include fatigue cognitive decline and peripheral neuropathy. This paper reviews the risk factors and the management of these complications. CONCLUSIONS: The number of older cancer survivors is expected to increase with the aging of the population. Prevention and management of fatigue, cognitive decline and peripheral neuropathy appear as the most important issue to prolong the active life expectancies of these individuals.

Evaluation of intrapsychic processes, anxiety, and depression in postmenopausal women affected by breast cancer: a case-control study.

BACKGROUND: The study of intrapsychic modalities can help to understand the association between depression and breast cancer patients and what kind of intervention can be planned. There is evidence that breast cancer is associated with the development of depression. The study of intrapsychic modalities may explain this association. Therefore, we aimed at investigating the intrapsychic and interpersonal processes of the structure of personality, anxiety, and depression of postmenopause breast cancer women. METHODS: All participants (n = 63) underwent the following tests: SASB questionnaire (Structural Analysis of Interpersonal Behavior), describing intrapsychic and interpersonal processes, validated on the basis of DSMIV, and the CDQ and ASQ questionnaires describing depression and anxiety. We compared two groups: breast cancer (n = 63) and a healthy control group of women without cancer (n = 83). RESULTS: Patients with breast cancer presented medium to high levels of anxiety and depression and intrapsychic level showed that they had less autonomy in their choices with low acceptance of their own feelings and tendency to be depressed compared to the control group (Cl 1 autonomy F = 10.21, p < 0.05, Cl 2 autonomy and love F = 13.01, p < 0.001, Cl 3 love F = 10.50, p < 0.01, Cl 5 control F = 6.44, p < 0.05, Cl 6 control and hate F = 4.49, p < 0.05, ASQ F = 6.07, p < 0.05, and CDQ F = 6.24, p < 0.05). CONCLUSIONS: Intrapsychic characteristics such as tendency to depression, inability to being in contact with their own feelings, may be linked to difficulties in facing treatment and their condition of illness. Knowledge of these modalities could allow to plan a psychotherapeutic and multidisciplinary intervention aimed at facing the different phases of medical treatment.

Senotherapy, cancer, and aging.

INTRODUCTION: We aimed to highlight the effects of senotherapy on the prevention and treatment of cancer in older individuals. The aim of senotherapy is to eliminate senescent cells. These cells express the senescence-associated secretory phenotype (SASP). With production of inflammatory cytokines, growth factors, and different type of proteases, the SASP is responsible for aging-associated disability and diseases. All mammalian cells experience senescence. The main agents of aging include fibroblasts and adipose cells. Senescent tumor cells may undergo genomic reprogramming and re-enter cell cycle with a stem cell phenotype. MATERIALS AND METHODS: We conducted a Medline search for the following key words: senotherapy, senolysis, senomorphic agents. We provide a narrative review of the finding. RESULTS: Different agents may eliminate senescent cells from cell cultures and murine models. These include metformin, rapamycin, desatinib, quercitin, fisetin, ruloxitinib, and BCL2 inhibitors. A randomized controlled study of metformin in 3,000 patients aged 65-79 without glucose intolerance aiming to establish whether senotherapy may prevent or reverse disability and aging associated diseases, including cancer, is ongoing. Senotherapy prolongs the life span and decreases the incidence of cancer in experimental animal models, as well as delays and reverses disability. Senescent tumor cells are found prior to treatment and after chemotherapy and radiation. These elements may be responsible for tumor recurrence and treatment refractoriness. DISCUSSION: Senotherapy may have substantial effects on cancer management including decreased incidence and aggressiveness of cancer, improved tolerance of antineoplastic treatment, and prevention of relapse after primary treatment. Senotherapy may ameliorate several complications of cancer chemotherapy.

Pitfalls in Oncogeriatrics.

An oncogeriatric interdisciplinary activity exists only in a minority of high-income countries, and it is almost absent in those with lower incomes. Considering topics, sessions, and tracks in the main meetings and conferences of the major Oncological Societies in Europe and worldwide, the USA excluded, little attention has thus far been paid to the problem of cancer in the elderly. Again, with the exception of the USA, the major cooperative groups, for example, the EORTC in Europe, have only dedicated marginal attention to the research of cancer in the elderly. Despite major shortcomings, professionals interested in geriatric oncology have taken a number of important initiatives to highlight the benefits of this particular activity, including the organization of an international society (Société Internationale de Oncogeriatrie, or SIOG). In spite of these efforts, the authors believe that the management of cancer in the older population is still encountering several important and generalized pitfalls. The main obstacle is the grossly inadequate number of geriatricians and clinical oncologists necessary to an integrated care of the ever-expanding aging population, but other hurdles have been reported. Additionally, the prejudice of ageism can lead to missing potential resources for the development of a generalized oncogeriatric approach.

Cell cycle arrest: A breakthrough in the supportive care of older cancer patients.

BACKGROUND: Age is a major risk factor for the acute and chronic complications of cancer chemotherapy. The current approach to the prevention of these complications is reactive and involves the reduction of the doses and the delay of treatment which may compromise the outcome. There is a limited number of antidotes to chemotherapy toxicity and these have complications of their own. Oldest old and frail patients are mostly excluded from life saving cancer treatment due to the risk of severe and even lethal complications. METHODS: molecular biology has revealed that different checkpoints control the proliferative cycle of normal and neoplastic cells. Two new drugs, Trilaciclib and ALRN-6924 may cause a temporary cell cycle arrest (CCA) of normal cells without blocking the proliferation of the neoplastic ones and render the normal cells temporarily invulnerable to the toxicity of chemotherapy. We reviewed the publications related to these drugs on the Medline, the published drug information and the presentations to major medical conferences. RESULTS: In three randomized controlled phase II trials Trilaciclib proved effective in preventing neutropenia, thrombocytopenia and anemia in patients with non small cell lung cancer with non proficient RB1 gene. Forty-five percent of patients were 65 and older and age did not prevent the effectiveness of the drug. Trilaciclib was approved by the FDA for the management of these patients. ALRN-6924 appeared promising in preventing myelotoxicity in patients whose cancer had deleted or mutated TP53, but failed to show any significant activity in a randomized controlled study. The development of this drug is now on hold CONCLUSIONS: CCA is a novel proactive approach to the toxicity of chemotherapy of special interest to older patients. At the very least it may prevent all forms of myelotoxicity with a single agent, obviating the risk and cost of polypharmacy. It allows to avoid the complications of myelopoietic growth factors which include severe pain, stem cell competition, bone marrow exhaustion, and hematological malignancies. It may allow the treatment of frail patients with full chemotherapy doses. It is also reasonable to expect that may complications other common and sometimes lethal complications of chemotherapy such as stomatitis, esophagitis, diarrhea and dehydration.