Human Granzyme K Is a Feature of Innate T Cells in Blood, Tissues, and Tumors, Responding to Cytokines Rather than TCR Stimulation.

NK cells and CD8 T cells use cytotoxic molecules to kill virally infected and tumor cell targets. While perforin and granzyme B (GzmB) are the most commonly studied lytic molecules, less is known about granzyme K (GzmK). However, this granzyme has been recently associated with improved prognosis in solid tumors. In this study, we show that, in humans, GzmK is predominantly expressed by innate-like lymphocytes, as well as a newly identified population of GzmK+CD8+ non- mucosal-associated invariant T cells with innate-like characteristics. We found that GzmK+ T cells are KLRG1+EOMES+IL-7R+CD62L-Tcf7int, suggesting that they are central memory T and effector memory T cells. Furthermore, GzmK+ cells are absent/low in cord blood, suggesting that GzmK is upregulated with immune experience. Surprisingly, GzmK+ cells respond to cytokine stimuli alone, whereas TCR stimulation downregulates GzmK expression, coinciding with GzmB upregulation. GzmK+ cells have reduced IFN-γ production compared with GzmB+ cells in each T cell lineage. Collectively, this suggests that GzmK+ cells are not naive, and they may be an intermediate memory-like or preterminally differentiated population. GzmK+ cells are enriched in nonlymphoid tissues such as the liver and adipose. In colorectal cancer, GzmK+ cells are enriched in the tumor and can produce IFN-γ, but GzmK+ expression is mutually exclusive with IL-17a production. Thus, in humans, GzmK+ cells are innate memory-like cells that respond to cytokine stimulation alone and may be important effector cells in the tumor.

Nodal positivity in patients with clinically and radiologically node-negative breast cancer treated with neoadjuvant chemotherapy: multicentre collaborative study.

BACKGROUND: The necessity of performing a sentinel lymph node biopsy in patients with clinically and radiologically node-negative breast cancer after neoadjuvant chemotherapy has been questioned. The aim of this study was to determine the rate of nodal positivity in these patients and to identify clinicopathological features associated with lymph node metastasis after neoadjuvant chemotherapy (ypN+). METHODS: A retrospective multicentre study was performed. Patients with cT1-3 cN0 breast cancer who underwent sentinel lymph node biopsy after neoadjuvant chemotherapy between 2016 and 2021 were included. Negative nodal status was defined as the absence of palpable lymph nodes, and the absence of suspicious nodes on axillary ultrasonography, or the absence of tumour cells on axillary nodal fine needle aspiration or core biopsy. RESULTS: A total of 371 patients were analysed. Overall, 47 patients (12.7%) had a positive sentinel lymph node biopsy. Nodal positivity was identified in 22 patients (29.0%) with hormone receptor+/human epidermal growth factor receptor 2- tumours, 12 patients (13.8%) with hormone receptor+/human epidermal growth factor receptor 2+ tumours, 3 patients (5.6%) with hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 10 patients (6.5%) with triple-negative breast cancer. Multivariable logistic regression analysis showed that multicentric disease was associated with a higher likelihood of ypN+ (OR 2.66, 95% c.i. 1.18 to 6.01; P = 0.018), whilst a radiological complete response in the breast was associated with a reduced likelihood of ypN+ (OR 0.10, 95% c.i. 0.02 to 0.42; P = 0.002), regardless of molecular subtype. Only 3% of patients who had a radiological complete response in the breast were ypN+. The majority of patients (85%) with a positive sentinel node proceeded to axillary lymph node dissection and 93% had N1 disease. CONCLUSION: The rate of sentinel lymph node positivity in patients who achieve a radiological complete response in the breast is exceptionally low for all molecular subtypes.

Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa.

BACKGROUND: Targeting immunometabolism has shown promise in treating autoimmune and inflammatory conditions. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease involving painful lesions in apocrine gland-bearing skin. Therapeutic options for HS are limited and often ineffective; thus, there is a pressing need for improved treatments. To date, metabolic dysregulation has not been investigated in HS. As HS is highly inflammatory, we hypothesized that energy metabolism is dysregulated in these patients. Metformin, an antidiabetic drug, which is known to impact on cellular metabolic and signalling pathways, has been shown to have anti-inflammatory effects in cancer and arthritis. While metformin is not licensed for use in HS, patients with HS taking metformin show improved clinical symptoms. OBJECTIVE: To assess the effect and mechanism of action of metformin in HS. METHODS: To assess the effect of metformin in vivo, we compared the immune and metabolic profiles of peripheral blood mononuclear cells (PBMCs) of patients with HS taking metformin vs. those not taking metformin. To examine the effect of metformin treatment ex vivo, we employed a skin explant model on skin biopsies from patients with HS not taking metformin, which we cultured with metformin overnight. We used enzyme-linked immunosorbent assays, multiplex cytokine assays and quantitative real-time polymerase chain reaction (RT-PCR) to measure inflammatory markers, and Seahorse flux technology and quantitative RT-PCR to assess glucose metabolism. RESULTS: We showed that metabolic pathways are dysregulated in the PBMCs of patients with HS vs. healthy individuals. In metformin-treated patients, these metabolic pathways were restored and their PBMCs had reduced inflammatory markers following long-term metformin treatment. In the skin explant model, we found that overnight culture with metformin reduced inflammatory cytokines and chemokines and glycolytic genes in lesions and tracts of patients with HS. Using in vitro assays, we found that metformin may induce these changes via the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, which is linked to glycolysis and protein synthesis. CONCLUSIONS: Our study provides insight into the mechanisms of action of metformin in HS. The anti-inflammatory effects of metformin support its use as a therapeutic agent in HS, while its effects on immunometabolism suggest that targeting metabolism is a promising therapeutic option in inflammatory diseases, including HS.

Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin.

BACKGROUND: Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life. OBJECTIVES: To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies. METHODS: We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays. RESULTS: Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (IL)-17, IL-1ß and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators, including IL-1ß and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these, as well as other, key mediators of inflammation. CONCLUSIONS: These data provide a rationale for targeting the NLRP3 inflammasome in HS using small-molecule inhibitors that are currently being tested for other indications.

A systematic review of oncological outcomes after nipple-sparing mastectomy for breast cancer.

Nipple-sparing mastectomy is an alternative to skin-sparing mastectomy in select patients. Increasing evidence supports its use in the setting of breast cancer, however concerns still exist regarding oncological safety. The aim of this systematic review was to evaluate long-term oncological outcomes of patients who underwent nipple-sparing mastectomy for breast cancer. A systematic review of the literature was performed to evaluate oncological outcomes in patients with breast cancer who underwent nipple-sparing mastectomy. Five major databases (PubMed, Embase, Scopus, Web of Science and Cochrane) were searched. The review included all original articles published in English reporting long-term oncological outcomes. 2334 studies were identified. After applying inclusion and exclusion criteria, 17 retrospective studies involving 7107 patients were included. The indication for nipple-sparing mastectomy was invasive carcinoma in 6069 patients (85.4%) and in situ disease in 1038 (14.6%). Median follow up was 48 months (range 25-94). The weighted mean rates of local recurrence and recurrence involving the nipple-areola complex were 5.4% (0.9-11.9) and 1.3% (0-4.9), respectively. The weighted mean distant failure rate was 4.8% (1.5-23.0). Therapeutic nipple-sparing mastectomy is oncologically safe in select patients with breast cancer.

The therapeutic and prognostic implications of immunobiology in colorectal cancer: a review.

Colorectal cancer represents the second leading cause of cancer-related death worldwide. The therapeutic field of immuno-oncology has rapidly gained momentum, with strikingly promising results observed in clinical practice. Increasing emphasis has been placed on the role of the immune response in tumorigenesis, therapy and predicting prognosis. Enhanced understanding of the dynamic and complex tumour-immune microenvironment has enabled the development of molecularly directed, individualised treatment. Analysis of intra-tumoural lymphocyte infiltration and the dichotomisation of colorectal cancer into microsatellite stable and unstable disease has important therapeutic and prognostic implications, with potential to capitalise further on this data. This review discusses the latest evidence surrounding the tumour biology and immune landscape of colorectal cancer, novel immunotherapies and the interaction of the immune system with each apex of the tripartite of cancer management (oncotherapeutics, radiotherapy and surgery). By utilising the synergy of chemotherapeutic agents and immunotherapies, and identifying prognostic and predictive immunological biomarkers, we may enter an era of unprecedented disease control, survivorship and cure rates.

Anastomotic leak risk in complete responders to neoadjuvant therapy for rectal cancer: a systematic review.

PURPOSE: The oncological benefits of achieving a complete pathological response following neoadjuvant chemoradiotherapy for rectal cancer are well defined. How a pathological response affects anastomotic healing or leak rates is not clear. The aim of this systematic review was to compare anastomotic leak rates among patients who did and did not achieve a complete pathological response. METHODS: Three major databases (PubMed, Embase, and Scopus) were searched. Predetermined inclusion criteria included prospective and retrospective articles published in English reporting complete pathological response and anastomotic leak rates following total mesorectal excision in ≥ 30 patients with rectal cancer who underwent neoadjuvant chemoradiotherapy and total mesorectal excision. The primary outcomes measured included complete pathological response and 30-day postoperative morbidity. RESULTS: From a total of 8919 patients with rectal cancer in 7 studies, 4165 fulfilled the criteria for inclusion. The majority (> 80%) of patients had clinical stage II or III disease. A defunctioning loop ileostomy was formed in 76.5%. A total of 589 (14.1%) patients achieved a pCR of whom 63 (10.7%) developed an anastomotic leak compared to 272/3576 (7.6%) patients without a pCR (p = 0.02). CONCLUSION: Patients with complete pathological response following neoadjuvant chemoradiotherapy and total mesorectal excision may be at higher risk of anastomotic leak than incomplete responders. This may need to be taken into account when counseling patients about the relative risks of organ preservation versus anterior resection.

Evidence-based treatment strategies for acute diverticulitis.

PURPOSE: Diverticular disease is a common acquired condition of the lower gastrointestinal tract that may be associated with significant morbidity. The term encompasses a spectrum of pathological processes with varying clinical manifestations. The purpose of this review was to update the reader on modern evidence-based treatment strategies for acute diverticulitis. METHODS: A literature search of the PUBMED database was performed using the keywords 'diverticulosis', 'diverticular disease' and 'diverticulitis'. Only articles published in the English language were included. RESULTS: Evidence-based treatment strategies for acute diverticulitis have evolved over time. Data have questioned the need for antibiotic therapy for Hinchey I disease and the role of percutaneous abscess drainage for Hinchey II. Clinical trials have demonstrated laparoscopic lavage is an appropriate option for select patients with Hinchey III disease and primary resection with anastomosis and defunctioning stoma may be considered in some cases of Hinchey IV disease. CONCLUSION: Risk-adapted treatment strategies and operative decision-making for acute diverticulitis are increasingly based on a combination of patient and disease factors.

Evidence-based Reviews in Surgery Long-term Outcome of Surgery Versus Conservative Management for Recurrent and Ongoing Complaints After an Episode of Diverticulitis: Five-year Follow-up Results of a Multicenter Randomized Controlled Trial (DIRECT-Trial).

QUESTION: Does surgery or conservative management of recurring diverticulitis/ongoing symptoms results in a higher quality of life (QoL) at 5-year follow-up. DESIGN: Randomized controlled trial. SETTING: Multicenter trial in the Netherlands. PATIENTS: Patients aged 18 to 75 years, who presented with either ongoing abdominal complaints (for >3 months) and/or frequently recurring left-sided diverticulitis (>2 episodes in 2 years) after an objectified (via Computed Tomography, Ultrasound or Endoscopy) episode of diverticulitis were included in this study. INTERVENTION: Elective Sigmoid Resection within 6 weeks vs. Conservative Management MAIN OUTCOME:: QoL at 5-year follow-up, as measured by the Gastrointestinal Quality of Life Index (GIQLI). Secondary outcomes included additional QoL assessments (including the EuroQoL-5D-3L, Visual Analogue Score for pain, and the short form 36 health survey) RESULTS:: The intention to treat analysis showed the surgical group had a higher quality of life (GIQLI) score than the conservative group (mean difference 9.7, 95% confidence interval 1.7-17.7, P = 0.018), which approached but did not meet the minimum important difference of 10. This difference was achieved in 67% of those in the operative group versus 57% in the conservative group (many of who eventually underwent surgery). CONCLUSIONS: The study results demonstrate that HRQOL at 5-year follow-up may be improved in patients undergoing surgical resection, although this difference did not meet the MID for the GIQLI.

The sentinel stent? A systematic review of the role of prophylactic ureteric stenting prior to colorectal resections.

PURPOSE: 'Prophylactic' ureteric stents potentially reduce rates, and facilitate intraoperative recognition, of iatrogenic ureteric injury (IUI) during colorectal resections. A lack of consensus surrounds the risk-benefit equation of this practice, and we aimed to assess the evidence base. METHODS: A systematic review was performed according to PRISMA guidelines. MEDLINE, Scopus, EMBASE and Cochrane databases were searched using terms 'ureteric/ureteral/JJ/Double J stent' or 'ureteric/ureteral catheter' and 'colorectal/prophylactic/resection/diverticular disease/diverticulitis/iatrogenic injury'. Primary outcomes were rates of ureteric injuries and their intraoperative identification. Secondary outcomes included stent complication rates. RESULTS: We identified 987 publications; 22 papers met the inclusion criteria. No randomised controlled trials were found. The total number of patients pooled for evaluation was 869,603 (102,370 with ureteric stents/catheters, 767,233 controls). The most frequent indications for prophylactic stents were diverticular disease (45.38%), neoplasia (33.45%) and inflammatory bowel disease (9.37%). Pooled results saw IUI in 1521/102,370 (1.49%) with, and in 1333/767,233 (0.17%) without, prophylactic ureteric stents. Intraoperative recognition of IUIs occurred in 10/16 injuries (62.5%) with prophylactic stents, versus 9/17 (52.94%) without stents (p = 0.579). The most serious complications of prophylactic stent use were ureteric injury (2/1716, 0.12%) and transient ureteric obstruction following stent removal (13/666, 1.95%). CONCLUSIONS: Placement of prophylactic ureteric stents has a low complication rate. There is insufficient evidence to conclude that stents decrease ureteric injury or increase intraoperative detection of IUIs. Apparently higher rates of IUI in stented patients likely reflect use in higher risk resections. A prospective registry with harmonised data collection points and stratification of intraoperative risk is needed.

Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.

OBJECTIVE: To study malabsorption and malnutrition after curative resection of esophageal and gastric cancer. DESIGN: Prospective cohort study. BACKGROUND: Improved cure rates for esophageal and gastric cancer have increased focus on health-related quality of life (HR-QL) in survivorship. Although malnutrition is well described in long-term follow-up, and gastrointestinal symptoms are common, data on gut and pancreatic-related malabsorption are scant. METHODS: Disease-free patients at least 18 months after esophageal or gastric oncologic resections represented the study cohort. A modified Gastrointestinal Symptom Rating Scale questionnaire was completed, and weight, fecal elastase (FE), albumin, vitamins, and micronutrients measured preoperatively and at 1, 6, and 18 to 24 months postoperatively. Small intestinal bacterial overgrowth (SIBO) and changes in body composition were also evaluated postoperatively. RESULTS: At a median follow-up of 23 months, 45 of 66 patients in a consecutive series were disease-free. Mean weight (78 ±â€Š19 vs 67 ±â€Š16 kg), body mass index (27 ±â€Š5 vs 24 ±â€Š5 kg/m), Vitamin A (1.7 ±â€Š0.6 vs 1.2 ±â€Š0.4 umol/L), and Vitamin E (28 ±â€Š7 vs 20 ±â€Š7 umol/L) were significantly decreased (P < 0.01) at last follow-up compared with preoperatively. Malabsorption was evident in 73% of patients, of whom 44% had FE < 200 µg/g and 38% had evidence of SIBO. Total body fat-free mass (175 ±â€Š96 vs 84 ±â€Š71, P < 0.001) and skeletal muscle index (44 ±â€Š8 vs 39 ±â€Š8, P = 0.007) were significantly decreased at 18 to 24 months. CONCLUSIONS: Malabsorption and malnutrition are prevalent in survivorship of esophageal and stomach cancer. This may be underappreciated, and both gut and pancreatic insufficiency represent modifiable targets in the interdisciplinary approach to recovery of HR-QL.

Colorectal Cancer in the Young: Research in Early Age Colorectal Cancer Trends (REACCT) Collaborative.

Background: The incidence of colorectal cancer (CRC) is increasing in the young (under 50). Defining the clinicopathological features and cancer-specific outcomes of patients with early-onset CRC is important to optimize screening and treatment strategies. This study evaluated disease-specific features and oncological outcomes of patients with early-onset CRC. Methods: Anonymized data from an international collaboration were analyzed. The inclusion criteria for this study were patients aged <50 years with stage I-III disease surgically resected with curative intent. Overall and disease-free survival were calculated using the Kaplan-Meier method. Results: A total of 3378 patients were included, with a median age of 43 (18-49) and a slight male preponderance (54.3%). One-third had a family history of colorectal cancer. Almost all (>95%) of patients were symptomatic at diagnosis. The majority (70.1%) of tumors were distal to the descending colon. Approximately 40% were node positive. Microsatellite instability was demonstrated in one in five patients, representing 10% of rectal and 27% of colon cancers. A defined inherited syndrome was diagnosed in one-third of those with microsatellite instability. Rectal cancer displayed a worse prognosis stage for stage. Five-year disease-free survival for stage I, II, and III colon cancer was 96%, 91%, and 68%, respectively. The equivalent rates for rectal cancer were 91%, 81%, and 62%. Conclusions and relevance: The majority of EOCRC would be captured with flexible sigmoidoscopy. Extending screening to young adults and public health education initiatives are potential interventions to improve survivorship.

Innate lymphoid cell (ILC) subsets are enriched in the skin of patients with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease manifested as painful inflamed lesions including deep-seated nodules, abscesses and sinus tracts. The exact aetiology of HS is unclear. Recent evidence suggests that immune dysregulation plays a crucial role in pathogenesis and disease progression. Innate lymphoid cells (ILC) are a recently identified immune cell subset involved in mediating immunity, however their role in HS has not yet been investigated. Three distinct subsets of ILC- ILC1, ILC2 and ILC3 have been described, and these are involved in skin tissue homeostasis and pathologic inflammation associated with autoimmunity and allergic diseases. In this study, we analysed by multiparameter flow cytometry the frequencies of ILC subsets in skin and peripheral blood mononuclear cells (PBMC) of HS patients and compared these to healthy control subjects and psoriasis patients. The absolute numbers of total ILC and subsets thereof were significantly reduced in the blood of HS patients relative to healthy controls. However, when patients were stratified according to treatment, this reduction was no longer observed in patients undergoing anti-TNF treatment. In HS lesional skin the absolute numbers of ILC were significantly increased relative to control skin. Furthermore, the frequencies of total ILC as well as ILC2 and ILC3 were significantly higher in non-lesional than lesional HS skin. This study analysed for the first time the presence of ILC subsets in the blood and skin of HS patients. Our findings suggest that ILC may participate in HS pathogenesis.

γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors.

γδ T cells are important tissue-resident, innate T cells that are critical for tissue homeostasis. γδ cells are associated with positive prognosis in most tumors; however, little is known about their heterogeneity in human cancers. Here, we phenotyped innate and adaptive cells in human colorectal (CRC) and endometrial cancer. We found striking differences in γδ subsets and function in tumors compared to normal tissue, and in the γδ subsets present in tumor types. In CRC, an amphiregulin (AREG)-producing subset emerges, while endometrial cancer is infiltrated by cytotoxic cells. In humanized CRC models, tumors induced this AREG phenotype in Vδ1 cells after adoptive transfer. To exploit the beneficial roles of γδ cells for cell therapy, we developed an expansion method that enhanced cytotoxic function and boosted metabolic flexibility, while eliminating AREG production, achieving greater tumor infiltration and tumor clearance. This method has broad applications in cellular therapy as an 'off-the-shelf' treatment option.

Characteristics of Early-Onset vs Late-Onset Colorectal Cancer: A Review.

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Neoadjuvant Chemoradiotherapy and Liver Transplantation for Unresectable Hilar Cholangiocarcinoma: The Irish Experience of the Mayo Protocol.

BACKGROUND: Pioneered by the Mayo Clinic, multimodal therapy with neoadjuvant chemoradiotherapy and orthotopic liver transplant has emerged as a promising option for unresectable hilar cholangiocarcinoma (hCCA). This study reports the experience of the Irish National Liver Transplant Programme with the Mayo Protocol. METHODS: All patients diagnosed with unresectable hCCA between 2004 and 2016, who were eligible for the treatment protocol, were prospectively studied. RESULTS: Thirty-seven patients commenced chemoradiotherapy. Of those, 11 were excluded due to disease progression and 26 proceeded to liver transplantation. There were 24 males, the median age was 49, and 88% had underlying primary sclerosing cholangitis. R0 and pathologic complete response rates were 96% and 62%, respectively. Overall median survival was 53 months and 1-, 3-, and 5-year survival was 81%, 69%, and 55%, respectively. The median survival of patients achieving a pathologic complete response was 83.8 months compared with 20.9 months in the group with residual disease (P = 0.036). Six patients (23%) developed disease recurrence. Among the patients who developed metastatic disease during neoadjuvant treatment, median survival was 10.5 months compared with 53 months in patients who proceeded to transplant (P < 0.001). CONCLUSIONS: Neoadjuvant chemoradiotherapy followed by liver transplantation substantially increases the survival of patients with unresectable hCCA. Achieving a pathologic complete response confers a significant survival benefit.