Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

BACKGROUND: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. METHODS: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. FINDINGS: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. INTERPRETATION: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. FUNDING: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Utility of routine pretreatment evaluation of left ventricular ejection fraction in breast cancer patients receiving anthracyclines.

Anthracycline-based chemotherapy is widely used in the management of breast cancer. Despite the lack of clinical evidence, obtaining prechemotherapy left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition scan is a widely adopted practice throughout the world. We present here the results of a retrospective analysis of breast cancer patients who had LVEF measurements in anticipation of an anthracycline chemotherapy to determine whether predefined cardiac risk factors predicted for poor cardiac function. Retrospective data were analyzed from 482 female breast cancer patients in whom LVEF was measured before starting anthracycline-based chemotherapy. Baseline demographics and multiple risk factors associated with congestive heart failure were collected. Twenty-six possible risk factors for CHF were defined, and the frequency of finding an abnormal LVEF as a function of total risk factors was assessed. Statistical tests include chi-squared and logistic regression analysis. The median age of the study population was 52 years. The original chemotherapy plan was changed in 7 patients (1.45%) based on LVEF findings, all of which had asymptomatic LV dysfunction (LVEF ranging 40%-50%). In 32 patients, despite normal LVEF results, anthracyclines were omitted secondary to prior cardiac issues. In 17 patients where LVEF was reported normal, anthracyclines were skipped based on patient's preference, tumor characteristics, or upstaging of the cancer based on imaging studies. No patient with ≤2 risk factors had an abnormal LVEF (N = 350). The probability of finding an abnormal LVEF in patients without any cardiac risk factors is extremely rare. Skipping baseline LVEF assessment may be an option in some patients with no cardiac risk factors undergoing anthracycline-based chemotherapy.

Influence of facility type on survival outcomes after pancreatectomy for pancreatic adenocarcinoma.

INTRODUCTION: Although a volume-outcome relationship has been well established for pancreatectomy, little is known about differences in mortality by facility type. The objective of this study is to evaluate the impact of facility type on short-term and long-term survival outcomes for patients with pancreatic adenocarcinoma who underwent pancreatectomy and identify determinants of overall survival (OS). METHODS: A cohort of 33,382 patients with Stage I-III pancreatic adenocarcinoma diagnosed between 1998 and 2011 were evaluated from the National Cancer Data Base. Clinicopathological, sociodemographic and treatment variables were compared among three facility types where patients received resection: (i) community cancer program (CCP), (ii) comprehensive community cancer program (CCCP), and (iii) academic research program (ARP). 5-year OS was calculated using the Kaplan-Meier method. RESULTS: Despite ARP having significantly higher percentage of poorly differentiated tumors, higher T-stage tumors, more positive lymph nodes, and greater circle distance compared to the other facilities, it had the highest 5-yr OS. The 5-yr OS for CCP, CCCP, and ARP was 11.2%, 13.2%, and 16.6%, respectively (P < 0.0001) and the median survival time (months) was 12.4, 15.6 and 19.1, respectively. CONCLUSION: Patients receiving pancreatic resection at an ARP yielded a higher 5-year OS compared to CCP or CCCP.

Poor survival in stage IIB/C (T4N0) compared to stage IIIA (T1-2 N1, T1N2a) colon cancer persists even after adjusting for adequate lymph nodes retrieved and receipt of adjuvant chemotherapy.

BACKGROUND: A survival paradox between Stage IIB/C and Stage IIIA colon cancers exists. It is unclear how adequate lymph nodes dissection (LN) and post-surgery chemotherapy contribute to the survival paradox. We intended to assess the impact of these two factors on the survival paradox. RESULTS: We evaluated 34,999 patients diagnosed with stage IIIA or stage IIB/C colon cancer in 2003-2012 from the National Cancer Data Base. The 5-year overall survival (OS) was 73.5 % for stage IIIA and 51.1 % for stage IIB/C (P < 0.0001). The 5-year OS was 84.1 % for stage IIIA with post-surgery chemotherapy, 70.8 % for stage IIB/C with ≥ 12 LNs retrieved with chemotherapy, 53.9 % for stage IIB/C < 12 LNs with chemotherapy, 49.5 % for stage IIIA without chemotherapy, 43.7 % for stage IIB/C ≥ 12 LNs retrieved without chemotherapy, to 27.7 % for stage IIB/C < 12 LNs without chemotherapy. Even among stage IIB/C who had optimal treatment (≥12 LNs retrieved, received chemotherapy), OS remains lower than stage IIIA with chemotherapy. After adjusting LN dissection and chemotherapy in addition to the adjustment of other clinical factors, the survival paradox was reduced from HR = 1.76 (95 % CI: 1.68-1.85) to HR 1.51 (95 % CI: 1.44-1.59). CONCLUSIONS: LN dissection and post-surgery chemotherapy partially explained the survival paradox. More research is warranted to identify other factors that contribute to this paradox. Future iteration of TNM staging system should take this into consideration.

Histiocytic sarcoma as a secondary malignancy: pathobiology, diagnosis, and treatment.

Histiocytic sarcoma (HS) is an extremely rare non-Langerhans cell disorder with an aggressive course and limited treatment options. Recent advances in molecular/genetic sequencing have suggested a common clonal origin between various hematolymphoid disorders and cases of secondary HS. Deriving conclusions from previously reported cases of HS arising secondarily to certain hematolymphoid disorders, here we have tried to provide insight into the mechanisms influencing this evolution. We also discuss a clinical case of a 72-year-old man with a diagnosis of chronic myeloid leukemia (CML), presenting subsequently with a heterogeneous liver mass positive with a diagnosis of HS. The liver mass showed a retained BCR-ABL1 translocation suggesting clonality between the CML and HS. As seen in our case and other reported cases of HS derived secondarily, the concurrent expression of immunoglobulin heavy (IGH)-/light-chain rearrangements or cytogenetic markers common to the primary malignancy suggests an evolutionary mechanism involving lineage switching that could potentially be influenced by genetic or epigenetic cues which may occur at the level of a progenitor or the malignant cell itself.

Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library.

For patients with solid tumors, the tolerance of surrounding tissues often limits the dose of radiation that can be delivered. Thus, agents that preferentially increase the cytotoxic effects of radiation toward tumor cells would significantly alter the therapeutic ratio and improve patient survival. Using a high-throughput, unbiased screening approach, we have identified 4'-bromo-3'-nitropropiophenone (NS-123) as a radiosensitizer of human glioma cells in vitro and in vivo. NS-123 radiosensitized U251 glioma cells in a dose-dependent and time-dependent manner, with dose enhancement ratios ranging from 1.3 to 2.0. HT-29 colorectal carcinoma and A549 lung adenocarcinoma cells were also radiosensitized by NS-123 in vitro, whereas NS-123 did not increase the radiation sensitivity of normal human astrocytes or developmental abnormalities or lethality of irradiated Zebrafish embryos. In a novel xenograft model of U251 cells implanted into Zebrafish embryos, NS-123 enhanced the tumor growth-inhibitory effects of ionizing radiation (IR) with no apparent effect on embryo development. Similar results were obtained using a mouse tumor xenograft model in which NS-123 sensitized U251 tumors to IR while exhibiting no overt toxicity. In vitro pretreatment with NS-123 resulted in accumulation of unrepaired IR-induced DNA strand breaks and prolonged phosphorylation of the surrogate markers of DNA damage H2AX, ataxia telangiectasia mutated protein, DNA-dependent protein kinase, and CHK2 after IR, suggesting that NS-123 inhibits a critical step in the DNA repair pathway. These results show the potential of this cell-based, high-throughput screening method to identify novel radiosensitizers and suggest that NS-123 and similar nitrophenol compounds may be effective in antiglioma modalities.

Iatrogenic constipation from barium blockade: A case report.

Barolith, a mixture of inspissated barium and feces, is a rare complication of barium-contrast studies that lead to intestinal obstruction. With the high morbidity associated with barolith impaction, we recommend that physicians be more aware of complications, increase prompt diagnosis, and initiation of laxatives once discovered.

Induction and processing of complex DNA damage in human breast cancer cells MCF-7 and nonmalignant MCF-10A cells.

Oxidatively induced stress and DNA damage have been associated with various human pathophysiological conditions, including cancer and aging. Complex DNA damage such as double-strand breaks (DSBs) and non-DSB bistranded oxidatively induced clustered DNA lesions (OCDL) (two or more DNA lesions within a short DNA fragment of 1-10 bp on opposing DNA strands) are hypothesized to be repair-resistant lesions challenging the repair mechanisms of the cell. To evaluate the induction and processing of complex DNA damage in breast cancer cells exposed to radiotherapy-relevant gamma-ray doses, we measured single-strand breaks (SSBs), DSBs, and OCDL in MCF-7 and HCC1937 malignant cells as well as MCF-10A nonmalignant human breast cells. For the detection and measurement of SSBs, DSBs, and OCDL, we used the alkaline single-cell gel electrophoresis, gamma-H2AX assay, and an adaptation of pulsed-field gel electrophoresis with E. coli repair enzymes as DNA damage probes. Increased levels for most types of DNA damage were detected in MCF-7 cells while the processing of DSBs and OCDL was deficient in these cells compared to MCF-10A cells. Furthermore, the total antioxidant capacity of MCF-7 cells was lower compared to their nonmalignant counterparts. These findings point to the important role of complex DNA damage in breast cancer and its potential association with breast cancer development especially in the case of deficient BRCA1 expression.

Radiation Therapy for Positive Surgical Margins in Women ≥70 Years with Stage I, Estrogen Receptor-positive Breast Cancer.

BACKGROUND/AIM: A re-excision for positive margin(s) following a lumpectomy for invasive breast cancer is a standard recommendation. However, for elderly women with stage I estrogen receptor-positive (ER+) tumors, who may be at higher surgical risk, whether radiation therapy without re-excision will be adequate is not known. PATIENTS AND METHODS: We evaluated a cohort of 53,950 women aged ≥70 years with Stage I, ER+ breast cancer who had lumpectomy and anti-hormone therapy diagnosed between 2004 and 2011 in the National Cancer Data Base. Patients were divided into four groups: 1) negative margins without radiation (XRT), 2) negative margins with XRT, 3) positive margins without XRT, and 4) positive margins with XRT. Clinicopathological and sociodemographic variables were compared among these groups. Univariable and multivariable analysis were employed. RESULTS: The 5-year overall survival (OS) rates for the groups were as follows: 1) negative margins without radiation (XRT); 77.1%, 2) negative margins with XRT; 90.0%, 3) positive margins without XRT; 62.9%, and 4) positive margins with XRT; 86.8% (p<0.0001). Significant predictors (p<0.01) of OS include treatment groups, age, income status, facility type, facility location, tumor size, tumor grade, and comorbidities. CONCLUSION: Radiation therapy for positive surgical margins without re-excision may be a viable option for elderly women with stage I, ER+ tumor treated with lumpectomy and hormonal therapy.

Outcomes in real-world practice are different than cooperative trial for elderly patients with early breast cancer treated with adjuvant radiation therapy.

BACKGROUND: The Cancer and Leukemia Group B 9,343 demonstrated that postoperative radiation can be safely omitted in women ≥70 years who underwent breast-conserving therapy for clinical stage I (T1N0M0) estrogen receptor positive breast cancer treated with antihormonal therapy. Whether such results are observed in real-world population is unknown. In this hospital-based data, we report the survival outcomes of patients who received adjuvant radiation therapy versus those who did not. METHODS: Using the National Cancer Data Base, we evaluated a cohort of 47,358 women with newly diagnosed breast cancer between 2004 and 2011 who underwent a lumpectomy and antihormonal therapy with the following criteria: age ≥70 years, clinical stage I, estrogen receptor positive, and negative margins. Patients were stratified into 2 groups: (1) radiation therapy and (2) no radiation therapy. Propensity score matching was used to compensate for differences in demographic and clinical characteristics of the patients. Univariate and multivariable survival analysis were employed to determine factors associated with overall survival. RESULTS: The 5-year overall survival after propensity score matching was 87.2% for radiation therapy and 79.4% for no radiation therapy (P < .0001). The median survival time was 113.7 months for radiation therapy and 105.2 months for no radiation therapy. After adjusting for sociodemographic and clinical factors, the risk of overall deaths was significantly higher for those not receiving radiation therapy (hazard ratio = 1.66; 95% confidence interval, 1.54-1.79). Other significant adjusted predictors (P < .05) of poor overall survival were, advanced age, comprehensive community cancer program, facility location, poorly differentiated tumor, and high comorbidity index. CONCLUSION: Patients who received radiation therapy had better survival outcomes than those who did not, revealing discordance between results of randomized trials and real-world setting.

Recurrent Malignant Melanoma Presenting as Isolated Pleural Metastases in a Patient with Chronic Lymphocytic Leukemia.

Isolated pleural metastasis with pleural effusion is a rare occurrence in malignant melanoma. We report an unusual case of a patient with chronic lymphocytic leukemia (CLL) and recurrent pleural effusions. The pleural fluid cytology and immunohistochemistry profile were consistent with the diagnosis of CLL. However, chemotherapy with pentostatin, cyclophosphamide, and rituximab did not result in any meaningful clinical response. A video-assisted thoracoscopic surgery and biopsy of the affected nodular parietal layer of the pleura were consistent with malignant melanoma. Our case underlines the importance of having a suspicion for secondary causes of effusion in patients with CLL. We briefly discuss the mechanisms of an increased incidence of secondary cancers in CLL and the diagnosis of isolated pleural metastases in malignant melanoma.

Reversal of isolated 20q deletion with vitamin B12 replacement in a patient with pernicious anaemia.

Severe vitamin B12 deficiency is well known to cause morphological alterations in bone marrow. In rare instances, these myelodysplastic and megaloblastic changes can coexist with cytogenetic abnormalities. Here, we report a case of a 38-year-old African-American woman with pernicious anaemia, who was found to have an isolated 20q deletion and which resolved after vitamin B12 replacement. We also discuss various mechanisms in which vitamin B12 deficiency can lead to chromosomal abnormalities. A literature review is also performed to evaluate various other chromosomal aberrations associated with B12 deficiency.

Spontaneous tumor lysis syndrome in colon cancer: a case report and literature review.

Although tumor lysis syndrome is well described, it is rarely seen or suspected in solid malignancies. Early recognition of this entity is paramount in reducing morbidity and mortality. Treating physicians should be aware of this possibility in solid tumor patients with either bulky disease or extensive liver involvement.

Follicular dendritic sarcoma masquerading as fibrosing mediastinitis.

Fibrosing mediastinitis (FM) is a rare disorder resulting from abnormal immunological-mediated fibro-proliferative reaction in the mediastinum. Here, we describe a case of a 46-year-old female with an incidentally found 11×9 cm posterior mediastinal mass. Multiple biopsies of this unresectable, 18-fluorodeoxyglucose avid mass revealed marked fibrosis without any evidence of malignancy, suggesting idiopathic fibrosing mediastinitis as our initial diagnosis. Multiple interventions including a trial of steroids, fluconazole, and azathioprine to target fibrosing mediastinitis were not successful. Repeat biopsy was consistent with primary mediastinal follicular dendritic cell sarcoma. The manuscript highlights the heightened need for suspecting occult malignancies in cases of FM presenting with an indeterminate cause.

Impact of CALGB 9343 Trial and Sociodemographic Variation on Patterns of Adjuvant Radiation Therapy Practice for Elderly Women (≥70 Years) with Stage I, Estrogen Receptor-positive Breast Cancer: Analysis of the National Cancer Data Base.

BACKGROUND: The Cancer and Leukemia Group B (CALGB) 9343 trial demonstrated that adjuvant radiation therapy (RT) can be omitted in women 70 years or older, with small (≤2 cm), negative lymph nodes, estrogen receptor (ER)-positive breast cancer. We examined whether RT usage following the CALGB publication had decreased over time and evaluated sociodemographic and clinical factors associated with RT omission. MATERIALS AND METHODS: From the National Cancer Data Base, we analyzed a cohort of 120,308 women aged 70 years or older with stage I, ER-positive breast cancer who underwent lumpectomy. Patients were classified into two groups based on the time of CALGB 9343 publication: (i) pre-CALGB (up to 2004), and (ii) post-CALGB (2005-2012). Clinicopathological and sociodemographic variables were compared between pre- and post-CALGB groups. Chi-square and multivariable logistic regression were employed, with the omission of adjuvant RT as the primary outcome in the regression analysis. RESULTS: Radiation therapy usage decreased by 4.1% after CALGB publication (on average 71.6% pre-CALGB vs. 67.5% post-CALGB; p<0.0001). Almost one-third of women aged ≥85 years received RT in the post-CALGB group. In a multivariable model, the variables significantly associated with increased odds for omission of RT in the post-CALGB group were: advanced age, African-American, increased great circle distance, therapy under academic research program, residents of East South-Central region, living in a rural population <2,500 not adjacent to a metropolitan area, low income level, Medicaid recipients, high comorbidity index, small tumor, well-differentiated histology, residual tumor, and lack of receipt of chemotherapy and anti-hormonal therapy. CONCLUSION: During the study period, the CALGB trial publication had a minimal impact on the rate of adjuvant RT use among elderly women with small, ER-positive breast cancers. Significant variation in RT usage existed across sociodemographic strata.

Excellent response to chemotherapy post immunotherapy.

INTRODUCTION: Immunotherapy in the form of immune checkpoint inhibitors has changed the landscape of cancer treatment. Newer monoclonal antibodies are coming up and are being tested in various cancers during different stages of treatment. With the increasing use of immune checkpoint inhibitors in the management of various types of cancers, the question is raised as to what next can be offered to a patient who has progressed on this newer treatment. Does Sequence matter? There have been reports of improved responses to chemotherapy after immunotherapy in the form of vaccines. Here we present a case series of 6 patients who progressed on immunotherapy with immune checkpoint inhibitors after initial modality of treatment (chemotherapy/radiation), subsequently received chemotherapy with excellent response. METHODS: We have a cohort of six patients who had disease progression on second line Immunotherapy for solid or hematological malignancies and had ECOG < 2. All these patients received third line salvage chemotherapy. Three patients had metastatic head and neck cancer, 2 had non-small cell lung cancer (NSCLC), and one had T -cell rich B- cell lymphoma. Prior review and approval were obtained from our institutional review board. RESULTS: All patients had an excellent response to chemotherapy in third line setting, after immune checkpoint inhibitors and most of them achieved a complete response. CONCLUSION: Targeting cancer with chemotherapy after failure of immunotherapy is a valid option and can lead to better response rates and PFS which may lead to OS. This effect may be secondary to immunotherapy removing the inhibition exerted by tumor cells or other immune cells initially followed by cytotoxic chemotherapy mediated killing of tumor cells.

Should Sentinel Lymph Node Biopsy for Patients with Early Breast Cancer Be Abandoned? Not So Fast.

As major advances are made in the management of early breast cancer, the role of sentinel lymph node biopsy (SLNBx) has been called into question. However, before abandoning SLNBx, a critical appraisal of its role should be done because we believe that it remains a critical component of care, especially when tailoring patient's adjuvant therapy. This commentary provides cogent arguments in favor of SLNBx in the management of patients with early breast cancer.

Charcot's osteoarthropathy mimicking an osteosarcoma of humerus.

Charcot's arthropathy or neuropathic osteoarthropathy is a form of destructive arthropathy associated with decreased sensory innervation. We present an unusual case of a patient referred to oncology clinic for further evaluation of a spindle cell neoplasm of the humerus concerning for malignancy. The mass presented as a lytic lesion associated with a right humerus fracture. This was later diagnosed as Charcot's shoulder secondary to cervical syringomyelia. A detailed case report and discussion are presented here.

Positive surgical margins contribute to the survival paradox between patients with stage IIB/C (T4N0) and stage IIIA (T1-2N1, T1N2a) colon cancer.

BACKGROUND: The underlying reasons for the survival paradox between stage IIB/C and stage IIIA colon cancer are elusive. We hypothesized that positive margins contribute to this paradox. METHODS: We evaluated a cohort of 16,471 patients with stage IIIA and stage IIB/C colon cancer from 709,583 cases diagnosed between 2003-2012 in the National Cancer Data Base. All patients had chemotherapy, and all stage IIB/C patients had ≥12 lymph nodes retrieved. Patients with stage IIIA were subdivided further into those with <12 lymph nodes retrieved and those with ≥12 lymph nodes retrieved. Univariable and multivariable survival analyses were used. RESULTS: The 5-year overall survival rate was 70.8% for stage IIB/C, 81.6% for stage IIIA with <12 lymph nodes, and 85.6% for stage IIIA with ≥12 lymph nodes (P < .0001). The 5-year overall survival rate was 84.3% for stage IIIA with no residual tumor, 74.8% for stage IIIA with residual tumor, 73.3% for stage IIB/C with no residual tumor, and 60.5% for stage IIB/C with residual tumor (P < .0001). Independent predictors (P < .01) of poor overall survival include stage IIB/C, advanced age, African American ethnicity, community cancer program, uninsured and Medicaid, low education level, high comorbidity index, and positive surgical margins. CONCLUSION: Positive surgical margins may contribute to the survival paradox between stage IIB/C and stage IIIA colon cancer patients.

Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment.

Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field.