Adjuvant Chemoradiation in Resected Biliary Adenocarcinoma: Evaluation of SWOG S0809 with a Large National Database.

BACKGROUND: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer. METHODS: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching. RESULTS: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004). CONCLUSION: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.

Impact of safety-net hospital burden on achievement of textbook oncologic outcomes following resection in for stage I-IV colorectal cancer.

BACKGROUND AND OBJECTIVES: Textbook oncologic outcome (TOO) is a benchmark for high-quality surgical cancer care but has not been studied at safety-net hospitals (SNH). The study sought to understand how SNH burden affects TOO achievement in colorectal cancer. METHODS: The National Cancer Database was queried for colorectal cancer patients who underwent resection for stage I-III plus stage IV with liver-only metastases (2010-2019). TOO was defined as R0 resection, AJCC-compliant lymphadenectomy (>12 nodes), no prolonged LOS, no 30-day mortality/readmission, and receipt of stage-appropriate adjuvant chemotherapy. RESULTS: Of 487,195 patients, 66.7% achieved TOO. Lower achievement was explained by adequate lymphadenectomy (87.3%), non-prolonged LOS (76.3%), and receipt of adjuvant chemotherapy in stage III (60.3%) and IV (54.1%). Treatment at high burden hospitals (HBH, >10% Medicaid/uninsured) was a predictor of non-TOO (Stage I/II: OR 0.83, III: OR 0.86, IV: OR 0.83; all p < 0.001). Achieving TOO was associated with decreased mortality (Stage I/II: HR 0.49, III: HR 0.48, IV: HR 0.57; all p < 0.001), and HBH treatment was a predictor of mortality (Stage I/II: HR 1.09, III: HR 1.05, IV: HR 1.07; all p < 0.05). CONCLUSIONS: Treatment at higher SNH burden hospitals was associated with less frequent TOO achievement and increased mortality. Quality improvement targets include receipt of adjuvant chemotherapy and avoidance of prolonged LOS.

Shared decision-making needs, barriers, and facilitators of patients with newly diagnosed advanced cancer in the hospital: a multi-level, mixed-methods study.

PURPOSE: Little is known about the shared decision-making (SDM) needs, barriers, and facilitators of patients with newly diagnosed advanced cancer in the hospital. Understanding this may improve SDM and cancer care quality in this vulnerable population. METHODS: A single-site, mixed-methods study of hospitalized patients with newly diagnosed advanced cancer, caregivers, and oncologists was conducted. After discharge, patient ± caregiver semi-structured interviews exploring SDM needs, barriers, and facilitators regarding their most important upcoming cancer-related decision were conducted. Oncologists were surveyed about patient knowledge and SDM needs using closed- and open-ended questions, respectively. Thematic analysis was performed for qualitative data with a focus on themes unique to or amplified by hospitalization. Descriptive statistics and the Chi-squared test were performed for quantitative data. RESULTS: Patients and caregivers reported high SDM needs surrounding treatment and prognostic information, leading to decisional conflict. Eight themes emerged: anticipated cancer treatment decisions, variable control preferences in decision-making, high cancer-related information needs and uncertainty, barriers and facilitators to information gathering during and post hospitalization, and decision-making facilitators. Among 32 oncologists, most (56%) reported patients were poorly informed about treatment and prognosis. Oncologists reported variable expectations about patient knowledge after hospitalization, facilitators to patient decision-making, and patient uncertainty while awaiting an outpatient oncologist appointment. CONCLUSION: Patients newly diagnosed with advanced cancer in the hospital have high SDM needs and experience decisional conflict. This may be due to barriers unique to or exacerbated by hospitalization. Further research is needed to develop strategies to address these barriers and enhance the facilitators identified in this study.

Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors.

BACKGROUND: Metastatic melanoma to the small bowel is an aggressive disease often accompanied by obstruction, abdominal pain, and gastrointestinal bleeding. With advancements in melanoma treatment, the role for metastasectomy continues to evolve. Inclusion of novel immunotherapeutic agents, such as checkpoint inhibitors, into standard treatment regimens presents potential survival benefits for patients receiving metastasectomy. CASE PRESENTATION: We report an institutional experience of 15 patients (12 male, 3 female) between 2014-2022 that underwent small bowel metastasectomy for metastatic melanoma and received perioperative systemic treatment. Median age of patients was 64 years (range: 35-83 years). No patients died within 30 days of their surgery, and the median hospital length of stay was 5 days. Median overall survival in these patients was 30.1 months (range: 2-115 months). Five patients died from disease (67 days, 252 days, 426 days, 572 days, 692 days postoperatively), one patient died of non-disease related causes (1312 days postoperatively), six patients are alive with disease, and three remain disease free. CONCLUSIONS: This case series presents an updated perspective of the utility of metastasectomy for small bowel metastasis in the age of novel immunotherapeutic agents as standard systemic treatment. Small bowel metastasectomy for advanced melanoma performed in conjunction with perioperative systemic therapy is safe and appears to promote long-term survival and enhanced quality of life.

The Landmark Series: Intraductal Papillary Mucinous Neoplasms of the Pancreas-From Prevalence to Early Cancer Detection.

Modern series report a prevalence of pancreatic cysts in the general population of up to 50% in prospective studies. Of these, about half will be pancreatic cystic neoplasms (PCNs) that have varying degrees of malignant potential. Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are the most common PCNs and are known predecessors of pancreatic adenocarcinoma. Critically, they are one of the only radiographically identifiable precursors of pancreatic cancer and thus provide an opportunity for early cancer detection and surgical resection with curative intent. The combination of high prevalence and potential for malignant degeneration underscore the relevance of discussing the best management of IPMNs and improving the existing standard of care. Landmark data on IPMN prevalence, guidelines, surveillance, biomarkers, and immune landscape are highlighted.

Combined Liver and Colon Resection of Synchronous Colorectal Liver Metastases at a Quaternary Center.

INTRODUCTION: Existing literature on the safety of combined liver and colorectal resections for synchronous colorectal liver metastases is mixed. Using a retrospective review of our institutional data, we aimed to show that combined colorectal and liver resections for synchronous metastases is both feasible and safe in a quaternary center. METHODS: A retrospective review of combined resections for synchronous colorectal liver metastases at a quaternary referral center from 2015 to 2020 was completed. Clinicopathologic and perioperative data was collected. Univariate and multivariable analyses were performed to identify risk factors for major postoperative complications. RESULTS: One hundred one patients were identified, with 35 undergoing major liver resections ( ≥ 3 segments) and 66 undergoing minor liver resections. The vast majority of patients (94%) received neoadjuvant therapy. There was no difference in postoperative major complications (Clavien-Dindo grade 3+) between major and minor liver resections (23.9% versus 12.1%, P = 0.16). On univariate analysis, Albumin-Bilirubin (ALBI) score >1 (P < 0.05) was predictive of major complication. However, on multivariable regression analysis, no factor was associated with significantly increased odds of major complication. CONCLUSIONS: This work demonstrates that with thoughtful patient selection, combined resection for synchronous colorectal liver metastases can be safely performed at a quaternary referral center.

Low anterior resection syndrome.

Low anterior resection syndrome represents a clinical state wherein a constellation of gastrointestinal symptoms is a direct result of anatomic changes to the rectum. Patients who undergo operations to create a neorectum often develop persistent symptoms of increased frequency, urgency, diarrhea, and these symptoms are debilitating and impact patients' quality of life. A stepwise approach to treatment can improve many patients' symptoms with the most invasive options reserved for highly refractory symptoms.

The meaning of love and its bittersweet nature.

Love is the core of human experience and central to our meaning in life and wellbeing, yet it is also a complex concept full of ambiguity and contradiction. The main purpose of this paper is fourfold: Firstly, we want to clarify questions such as 'What is the meaning of love?' and 'Why is meaning of love so important to us?' Secondly, we want to explain why love is both suffering and essential for our happiness and mental health. Thirdly, we identify the major types of love and clarify which types are constructive and which are destructive. We also identify the key dimensions of true love. Finally, we emphasise that love does not always mean happiness; rather, it is meant to be a school to teach us important lessons and to make us complete. Therefore, we need to embrace suffering and at the same time cultivate the constructive types of love to improve our mental health and to make the world a more compassionate place.

Cross-Cultural Psychometric Analysis of the Mature Happiness Scale-Revised: Mature Happiness, Psychological Inflexibility, and the PERMA Model.

The present study aimed to evaluate the psychometric properties of the Mature Happiness Scale, a measure focused on inner harmony. Mature happiness is achieved when a person can live in balance between both positive and negative aspects of their life. A total sample of 2,130 participants from five countries (Canada: n = 390, United States: n = 223, United Kingdom: n = 512, Spain: n = 724, and Hungary: n = 281) responded to an online survey including the original Mature Happiness Scale, the PERMA-Profiler, and the Acceptance and Action Questionnaire-II. Exploratory and confirmatory factor analyses yielded a one-factor solution with seven positive items (non-reversed). We called this new version of the questionnaire the Mature Happiness Scale-Revised (MHS-R). Measurement invariance was found across countries, age groups, gender, and mental disorder diagnosis. Internal consistency and test-retest reliability were high. Older people, males, and people without a mental disorder diagnosis scored higher in mature happiness than younger ones, females, and those with a mental health disorder diagnosis, respectively. Mature happiness showed strong positive associations with various subscales of the PERMA-Profiler, specifically with positive emotions and meaning in life. In addition, mature happiness was strongly correlated with less negative affect and inner conflict and lower psychological inflexibility, whereas it was moderately correlated with lower loneliness. This validity evidence supports the cross-cultural use of the MHS-R in the aforementioned countries to reliably measure happiness among adults. With its holistic approach, the MHS-R may be a unique complement to other well-being measures, particularly to better predict mental health problems.

Probiotics in Health and Disease: Distinct Roles of Different Strains in Natural Killer Cell Activation and Regulation.

Elucidating the role of probiotic bacteria in health and disease perhaps constitutes one of the most exciting and fastest growing fields in medicine as we uncover the beneficial roles of these bacteria in many disease processes including cancer. We and others have reported previously that probiotic bacteria play a significant role in the activation of many cells including the cancer fighting natural killer (NK) cells. NK cells are the key immune effectors which control tumor growth and metastasis due to their ability to mediate direct cytotoxicity and/or differentiation of cancer stem cells/undifferentiated tumors through secreted and membrane bound interferon-gamma and tumor necrosis factor-alpha. In this review, we present an overview of recent studies from our laboratory and those of the others on their beneficial effects on immune cell function in particular on NK cells. In addition, we also highlight the current understanding of the role of probiotics in enhancement of the effectiveness of cancer therapeutics. Moreover, we discuss the functional impairment of cancer patients' NK cells and the role of probiotics in reversal of such functional impairment. NK cell-based immuno-therapies in combination with well-selected strains of probiotic bacteria may probably represent one of the best adjunct therapeutic approaches to prevent and treat cancer in the future.

Meaningful living, resilience, affective balance, and psychological health problems among Turkish young adults during coronavirus pandemic.

The present study sought to investigate the mediating effect of the affective balance and resilience on the association between meaningful living and psychological health problems among Turkish young adults in the context of COVID-19. The participants were 359 Turkish young adults, comprising of primarily female (68.2%), and their age ranged between 18 to 43 (age M = 20.67, SD = 3.62). Findings from this study indicated that meaningful living had a positive predictive effect on resilience and positive affect, as well as a negative predicative on psychological health challenges and negative affect. Resilience and affective balance also mediated the effect of meaningful living on psychological health of young adults. These results suggest that resilience and affective balance are important aspects of meaning-focused preventions and interventions designed to build up resilience, positive affectivity, and psychological health.

Spanish Version of the Death Attitude Profile-Revised. Translation and Validation Into Spanish.

The Death Attitude Profile-Revised (DAP-R) was developed in English-speaking cultures with the aim of measuring attitudes towards death. This measure consists of 32 items, grouped into five factors (Fear of Death, Avoidance of Death, Neutral Acceptance, Approach Acceptance, and Escape Acceptance). The DAP-R was translated and adapted to Spanish (DAP-RSp), and the psychometric properties were analyzed accross a general sample. The face validity was evaluated by 20 experts in palliative care. N = 417 (X = 39.06 years) took part in the validation. DAP-RSp showed adequate internal consistency (Cronbach's alpha ranging from 0.67 for Neutral Acceptance to 0.95 for Escape a Acceptance, and 0.88 for the total), a multitrait scaling analysis and a confirmatory factor analysis reproduced the five dimensions of the original scale. The Spanish version of the DAP-R can be used as a valid scale to assess attitudes towards death in Spanish speaking population.

Multiple Defects of Natural Killer Cells in Cancer Patients: Anarchy, Dysregulated Systemic Immunity, and Immunosuppression in Metastatic Cancer.

We have previously demonstrated that natural killer (NK) cells are the main immune effectors that can mediate selection and differentiation of different cancer stem cells and undifferentiated tumors via lysis and secreted or membrane-bound interferon-γ and tumor necrosis factor-α, respectively. This leads to growth inhibition and tumor metastasis curtailment. In this review, we present an overview of our findings on NK cell biology and its significance in selection and differentiation of stem-like tumors using in vitro and in vivo studies conducted in nonobese diabetic/severe combined immunodeficiency (scid)/interleukin-Rγ--, humanized-bone-marrow/liver/thymus (hu-BLT) mice, and those of human cancer patients. Moreover, we present recent advances in NK cell expansion and therapeutic delivery and discuss the superiority of allogeneic supercharged NK cells over their autologous counterparts for cancer treatment. We review potential loss of NK cell numbers and function at neoplastic and preneoplastic stages of tumorigenesis as a potential mechanism for pancreatic cancer induction and progression. We believe that NK cells should be placed highly in the armamentarium of tumor immunotherapy due to their indispensable role in targeting cancer stem-like/poorly differentiated tumors and a variety of other key NK cell functions that are discussed in this report, including their role in CD8+ T-cell expansion and targeting gene knockout or dedifferentiated tumors. The combination of allogeneic supercharged NK cells and other immunotherapeutic strategies such as oncolytic viruses, antibody-dependent cellular cytotoxicity-inducing antibodies, checkpoint inhibitors, chimeric antigen receptor (CAR)-T cells and CAR-NK cells, chemotherapeutics, and radiotherapeutic strategies can be used for optimal eradication of tumors.

Existential Suffering in Palliative Care: An Existential Positive Psychology Perspective.

The COVID-19 pandemic has exposed the inadequacies of the current healthcare system and needs a paradigm change to one that is holistic and community based, illustrated by the healing wheel. The present paper proposes that existential positive psychology (PP 2.0) represents a promising approach to meet the rising needs in palliative care. This framework has a twofold emphasis on (a) how to transcend and transform suffering as the foundation for wellbeing and (b) how to cultivate our spiritual and existential capabilities to achieve personal growth and flourishing. We propose that these objectives can be achieved simultaneously through dialectical palliative counselling, as illustrated by Wong's integrative meaning therapy and the Conceptual Model of CALM Therapy in palliative care. We then outline the treatment objectives and the intervention strategies of IMT in providing palliative counselling for palliative care and hospice patients. Based on our review of recent literature, as well as our own research and practice, we discover that existential suffering in general and at the last stage of life in particular is indeed the foundation for healing and wellbeing as hypothesized by PP 2.0. We can also conclude that best palliative care is holistic-in addition to cultivating the inner spiritual resources of patients, it needs to be supported by the family, staff, and community, as symbolized by the healing wheel.

Robotic minor hepatectomy: optimizing outcomes and cost of care.

BACKGROUND: The advantages of robotic liver surgery are strongest for minor resections, where incision size drives recovery time, but cost remains a concern. We hypothesized that patients who underwent robotic minor liver resections would have superior peri-operative outcomes resulting in decreased cost. METHODS: We queried the medical record and cost data for patients who underwent open or robotic minor (1-2 segment) liver resection from 1/2016-8/2019. Financial data were normalized to Medicare reimbursements. RESULTS: There were 87 patients who underwent minor liver resections (robotic n = 46, open n = 41). Specimen size (173 ± 203 vs 257 ± 481 cm3), surgical duration (233 ± 87 vs 227 ± 83 min), estimated blood loss (187 ± 236 vs 194 ± 165 mL), and margin status (89% vs 93% R0) were similar for robotic and open resections respectively, yet complications (3/46, 7% vs 10/41, 24%, p = 0.02) and length of stay (2.2 ± 2.2 vs 6.2 ± 2.9, p < 0.001) were significantly lower for patients who underwent robotic resection. These factors contributed to minor robotic liver resections costing $534 less than open resections ($3597 ± 1823 vs $4131 ± 1532, p = 0.03). CONCLUSION: Patients undergoing robotic minor hepatectomy had superior peri-operative outcomes resulting in lower total cost of care when compared to open minor hepatectomy. Financial considerations should not adversely influence selection of a robotic approach for minor hepatectomy.

Management of disappearing colorectal liver metastases: an international survey.

BACKGROUND: Improved chemotherapy response rates have lead to "disappearing" colorectal liver metastases (dCRLM). We aim to assess management patterns of dCRLM from an international body of hepatobiliary surgeons. METHODS: A survey was designed, tested for item relevance, readability and content validity, and distributed to the AHPBA, IHPBA and ANZHPBA. RESULTS: The majority of 226 respondents were <15 years from training (69%), practiced in academia (82%) and devoted >50% of their practice to hepatobiliary (75%). Surgeons utilize CT(45%) or MRI(47%) for preoperative planning with a preferred imaging interval of <6 weeks. Nearly all have experienced dCRLM (99%) and 63% of surgeons have waited a few months to assess for durability of response prior to definitive surgical/ablative therapy. Only 24% place fiducial markers for lesions <1-cm prior to neoadjuvant chemotherapy. Intra-operatively, 97% of surgeons perform ultrasound, and 71% ablation. When a tumor has "disappeared," 49% elect for observation and 31% resect if the dCRLM is superficial. Of those electing observation, 87% believe there is effective treatment with progression on surveillance imaging. CONCLUSIONS: Nearly all surgeons have experienced dCRLM with half choosing observation over intervention due to the belief that these lesions may be re-addressed in the future.

Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling.

BACKGROUND: Melanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort. METHODS: A retrospective review of MUP was performed at a tertiary referral cancer center. RESULTS: Of 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP. CONCLUSION: Multigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.

Minimally invasive distal pancreatectomy and the cost of conversion.

BACKGROUND: Minimally invasive surgery (MIS) is preferred for distal pancreatectomy but is not always attempted due to the risk of conversion to open. We hypothesized that the total cost for MIS converted to open procedures would be comparable to those that started open. METHODS: A prospectively collected institutional registry (2011-2017) was reviewed for demographic, clinical, and perioperative cost data for patients undergoing distal pancreatectomy. RESULTS: There were 80 patients who underwent distal pancreatectomy: 41 open, 39 MIS (11 laparoscopic and 28 robotic). Conversion to open occurred in 14 of 39 (36%, 3 laparoscopic and 11 robotic). Length of stay was shorter for the MIS completed (6 days; range, 3-8), and MIS converted to open (7 days; range, 4-10) groups, compared with open (10 days; range, 5-36; P = .003). Laparoscopic cases were the least expensive (P = .02). Robotic converted to open procedures had the highest operating room cost. However, the total cost for robotic converted to open cohort was similar to the open cohort due to cost savings associated with a shorter length of stay. CONCLUSIONS: Despite the higher intraoperative costs of robotic surgery, there is no significant overall financial penalty for conversion to open. Financial considerations should not play a role in selecting a robotic or open approach.

Existential positive psychology and integrative meaning therapy.

The unprecedented changes in our society because of COVID-19 and the fourth industrial revolution (4IR) shows that our healthcare system and the medical approach to psychotherapy can no longer meet the mental health needs of society. This paper first described the negative impact of COVID-19 and 4IR on our mental health. Then, following a brief critique of the medical model, this paper proposes that the future of psychotherapy needs to be based on the more inclusive and integrative framework of existential positive psychology (PP 2.0), which emphasizes flourishing through suffering. Finally, the paper emphasizes Viktor Frankl's cure and Wong's integrative meaning therapy. It concludes that integrative meaning therapy represents the future of psychotherapy, because it is situated in the area of interactions of at least three traditions: Clinical psychology, existential psychology, and positive psychology. This integrative model is holistic, recognising humans as bio-psycho-social-spiritual beings and considers several theoretical perspectives in both diagnosis and treatment.

Cornelia de Lange syndrome in diverse populations.

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.