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.

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.

Resilience in Older Adults Diagnosed With Cancer and Receiving Chemotherapy.

BACKGROUND: Resilience is the capacity for physical and emotional recovery from stressful events like cancer diagnosis and treatment. OBJECTIVES: The objectives of this study were to review existing literature to understand and illustrate ways to assess and manage resilience when providing holistic care to older adults with cancer. METHODS: A review of the literature was conducted with a focus on assessment, management, and preservation of resilience in older adults with cancer. FINDINGS: Interventions to support resilience include managing problems that occur in the areas of nutrition, exercise, social support, cognition, functional status, and emotion. Cell cycle arrest using pharmacologic agents may provide a novel proactive approach to protect resilience from deteriorating during chemotherapy to treat cancer. The oncology nurse can assess and manage resilience. which can lead to better treatment outcomes.

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.

A Proactive Approach to Prevent Hematopoietic Exhaustion During Cancer Chemotherapy in Older Patients: Temporary Cell-Cycle Arrest.

Age is associated with the decline of multiple organ systems. In older patients, hematological toxicities associated with chemotherapy are often dose limiting, impairing dose intensity and treatment efficacy. Contrary to the classical path using growth factors to activate tissue regeneration, a novel strategy is emerging to prevent chemotherapy toxicity that involves temporary cell-cycle arrest of normal cells, such as hematopoietic or epithelial precursors. This proactive approach may allow the sparing of the stem cell reserve of these tissues. Two molecules are included in this new category, trilaciclib and ALRN-6924, which induce cell-cycle arrest by two different pathways. Previous approaches, such as the use of myelopoietic growth factors, were reactive and they might even have accelerated the depletion of stem cells by enhancing the commitment of these elements. Trilaciclib causes cell-cycle arrest by CDK 4/6 inhibition and ALRN-6924 by p53 activation. In a pooled analysis of three randomized phase II studies of patients with small cell lung cancer, trilaciclib prevented neutropenia, thrombocytopenia, and anemia. Similar chemoprotective results were observed with ALRN-6924 in an open-label phase Ib study of patients with p53-mutated small cell lung cancer. Trilaciclib is now approved as a myelopreservation agent in patients with extensive-stage small cell lung cancer. ALRN-6924 is currently in phase Ib clinical development in patients with p53-mutated cancer. In addition to preserving the normal hemopoietic pool, these drugs promise to preserve the stem cell reserve of other normal tissues with high turnover, preventing potentially other dose-limiting toxicities, such as mucositis and diarrhea. An "ex vivo" study provided early evidence that ALRN-6924 may prevent chemotherapy-induced alopecia. By affording protection from multiple toxicities with a single drug, trilaciclib and ALRN-6924 have the potential to transform the current standards of supportive care for oncology patients and may prevent the depletion of tissue stem cells already compromised with age.

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.

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.

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.

Landmarks in geriatric oncology.

The knowledge of Geriatric Oncology requires some information on her history.Thanks to the effort of investigators throughout the world, embattled but undeterred by the objection of a cautious establishment, geriatric oncology has provided a blueprint for the treatment of the most common form of cancer: cancer in the older person. The history of Geriatric Oncology may be divided in three periods: Prehistory,Past and Contemporay history.

The prevalence of luminal B subtype is higher in older postmenopausal women with ER+/HER2- breast cancer and is associated with inferior outcomes.

OBJECTIVES: To establish whether clinicopathologic and genomic characteristics may explain the poor prognosis associated with advanced age in ER+/HER2- breast cancer. MATERIALS AND METHODS: The cohort included 271 consecutive post-menopausal patients with ER+/HER2- invasive breast cancer ages 55 years and older. Patients were categorized as "younger" (ages 55- < 75) and "older" (ages ≥75). The Kaplan-Meier method was used to estimate locoregional recurrence (LRR), recurrence-free interval (RFi), and overall survival (OS). Gene expression of tumor samples was assessed with Affymetrix Rosetta/Merck Human RSTA microarray platform. Differential gene expression analysis of tumor samples was performed using R package Limma. RESULTS: 271 breast cancer patients were identified, including 186 younger and 85 older patients. Older patients had higher rates of Luminal B subtype (53% vs 34%) and lower rates of Luminal A subtype (42% vs 58%, p = 0.02). Older patients were less likely to receive chemotherapy (9% vs 40%, p < 0.001) and hormone therapy (71% vs 89%, p < 0.001). For cases of grade 1-2 disease, older patients had a higher proportion of the luminal B subtype (49% vs. 30%, p = 0.014). Age ≥ 75 predicted for inferior OS (HR = 3.06, p < 0.001). The luminal B subtype predicted for inferior OS (HR = 2.12, p = 0.014), RFi (HR 5.02, p < 0.001), and LRR (HR = 3.12, p = 0.045). There were no significant differences in individual gene expression between the two groups. CONCLUSION: Women with ER+/HER2- breast cancer ≥75 years old had higher rates of the more aggressive luminal B subtype and inferior outcomes. Genomic testing of these patients should be strongly considered, and treatment should be intensified when appropriate.

Charge transfer driven by ultrafast spin transition in a CoFe Prussian blue analogue.

Photoinduced charge-transfer is an important process in nature and technology and is responsible for the emergence of exotic functionalities, such as magnetic order for cyanide-bridged bimetallic coordination networks. Despite its broad interest and intensive developments in chemistry and material sciences, the atomic-scale description of the initial photoinduced process, which couples intermetallic charge-transfer and spin transition, has been debated for decades; it has been beyond reach due to its extreme speed. Here we study this process in a prototype cyanide-bridged CoFe system by femtosecond X-ray and optical absorption spectroscopies, enabling the disentanglement of ultrafast electronic and structural dynamics. Our results demonstrate that it is the spin transition that occurs first on the Co site within ~50 fs, and it is this that drives the subsequent Fe-to-Co charge-transfer within ~200 fs. This study represents a step towards understanding and controlling charge-transfer-based functions using light.

Older cancer patients and COVID-19 outbreak: Practical considerations and recommendations.

Since the COVID-19 outbreak started, it has been affecting mainly older individuals. Among the most vulnerable older individuals are those with cancer. Many published guidelines and consensus papers deal with prioritizing cancer care. Given the lack of high-quality evidence for management of cancer in older patients also in normal times, it is even more stringent to provide some resources on how to avoid both undertreatment and overtreatment in this population, who as of now is twice challenged to death, due to both a greater risk of getting infected with COVID-19 as well as from cancer not adequately addressed and treated. We hereby discuss some general recommendations (implement triage procedures; perform geriatric assessment; carefully assess comorbidity; promote early integration of palliative care in oncology; acknowledge the role of caregivers; maintain active take in charge to avoid feeling of abandonment; mandate seasonal flu vaccination) and discuss practical suggestions for specific disease settings (early-stage and advanced-stage disease for solid tumors, and hematological malignancies). The manuscript provides resources on how to avoid both undertreatment and overtreatment in older patients with cancer, who as of now is twice challenged to death, due to both a greater risk of getting infected with COVID-19 as well as from cancer not adequately addressed and treated.

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 The Elderly Cancer Patients Complexity: The Radiation Oncology Potential.

Radiation oncology has the potential to be an excellent option for the frail elderly cancer patients because of its limited systemic toxicities. It can be effective for curative, prophylactic, disease control or palliative purposes. Currently about 60% of all cancer patients undergoing active treatment at some point receive radiation treatment. However, though widely used, there are limited clinical trials strictly designed for the elderly. This paper will review the key points in the assessment and treatment of elderly cancer patient including quality of life, active life expectancy, cognitive performance, frailty, sarcopenia and how the new technologies can help to reach the key goal of maintaining autonomy and independence for the elderly cancer patient.