Mean-field model of synchronization for open-loop, swirl controlled thermoacoustic system.

Open-loop control is known to be an effective strategy for controlling self-excited periodic oscillations, known as thermoacoustic instability, in turbulent combustors. Here, we present experimental observations and a synchronization model for the suppression of thermoacoustic instability achieved by rotating the otherwise static swirler in a lab-scale turbulent combustor. Starting with the state of thermoacoustic instability in the combustor, we find that a progressive increase in the swirler rotation rate leads to a transition from the state of limit cycle oscillations to the low-amplitude aperiodic oscillations through a state of intermittency. To model such a transition while also quantifying the underlying synchronization characteristics, we extend the model of Dutta et al. [Phys. Rev. E 99, 032215 (2019)] by introducing a feedback between the ensemble of phase oscillators and the acoustic. The coupling strength in the model is determined by considering the effect of the acoustic and swirl frequencies. The link between the model and experimental results is quantitatively established by implementing an optimization algorithm for model parameter estimation. We show that the model is capable of replicating the bifurcation characteristics, nonlinear features of time series, probability density function, and amplitude spectrum of acoustic pressure and heat release rate fluctuations at various dynamical states observed during the transition to the state of suppression. Most importantly, we discuss the flame dynamics and demonstrate that the model without any spatial inputs qualitatively captures the characteristics of the spatiotemporal synchronization between the local heat release rate fluctuations and the acoustic pressure that underpins a transition to the state of suppression. As a result, the model emerges as a powerful tool for explaining and controlling instabilities in thermoacoustic and other extended fluid dynamical systems, where spatiotemporal interactions lead to rich dynamical phenomena.

Immunotherapy use in oesophagogastric cancers-a review of the literature.

Cancers of the upper gastrointestinal tract are a leading cause of cancer-related death world-wide and historically have a poor prognosis. The incidence and histology of these cancers have varied temporally and geographically over the last three decades, with an emerging understanding of the differences in the molecular and genetic profiles across different subgroups. Management of oesophagogastric cancers is by a multidisciplinary team with utilisation of surgery, radiotherapy and systemic treatments in combinations where appropriate. Immune checkpoint inhibition (ICI) has drastically changed the treatment landscape of multiple solid malignancies in the last 5 years. In oesophagogastric cancer, clinical trials have only recently shown activity that is often associated with the molecular characteristics of these tumours, in particular PD-L1 scores or microsatellite instability (MSI-H). This review looks to present the pivotal trials in this space, discuss the complexities between trials that may explain the disparate results and assess the benefit ICI offers in the treatment landscape at present.

Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic oesophageal and gastrooesophageal carcinoma with dysphagia: a single arm phase II clinical trial (PALEO, sponsored by the Australasian Gastro-Intestinal Trials Group).

BACKGROUND: Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations. METHODS: PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy. DISCUSSION: This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189 , registered 8 October 2019.

Treatment and outcomes of metastatic colorectal cancer patients in public and private hospitals: results from the South Australian Metastatic Colorectal Cancer Registry.

BACKGROUND: Studies have reported significant differences in baseline characteristics and outcomes of metastatic colorectal cancer (mCRC) patients when managed in private versus public hospitals. AIMS: To compare disease, treatment and survival outcomes of patients with mCRC in public versus private hospitals in South Australia (SA). METHODS: Analysis of prospectively collected data from the SA mCRC Registry. Patterns of care and outcome data according to location of care and socioeconomic status based on Index of Relative Socio-Economic Advantage and Disadvantage were analysed. RESULTS: A total of 3470 patients' data was analysed during February 2006-January 2015. The majority (70%) of patients received treatment in public hospitals. Patients in the upper 50% for Index of Relative Socio-Economic Advantage and Disadvantage score were more likely to receive treatment at a private hospital (41.2% vs 21.56%) compared to <50%. Public patients had higher burden of disease (10.49% vs 7.41%, P = 0.005). Public patients received less treatment compared to the private patients (odds ratio = 0.48 (0.38-0.61), P = 0.01) and rates of surgical resections were lower in public patients. After adjusting for the covariates, public patients survive 1.33 months (P = 0.025) shorter than private patients with follow-up time of 5 years. Patients receiving metastasectomy and more than three lines of treatment were shown to have the greatest survival benefit. CONCLUSION: Public patients have a higher burden of disease and in comparison are less likely to receive systemic therapy and have lower survival than patients treated in private hospitals.

Circulating epigenetic biomarkers for detection of recurrent colorectal cancer.

BACKGROUND: The sensitive detection of recurrent colorectal cancer (CRC) by the measurement of circulating tumor DNA (ctDNA) might improve the chance of a cure. This study compared a quantitative methylated ctDNA test with carcinoembryonic antigen (CEA) in the setting of surveillance for recurrence. METHODS: Blood samples collected either during surveillance or within 12 months of the confirmation of recurrence were assayed for ctDNA (methylated branched-chain amino acid transaminase 1 [BCAT1]/Ikaros family zinc-finger 1 protein [IKZF1]) and CEA. The optimal ctDNA threshold was determined by receiver operating characteristic analysis, and the test performance for the detection of recurrence was compared with CEA (5 ng/mL threshold). RESULTS: The study cohort comprised 144 eligible patients and included 50 recurrence events. The sensitivity of the methylated ctDNA test for recurrence was 66.0% (95% confidence interval [CI], 57.1%-69.3%), which was significantly higher than the sensitivity of CEA (31.9%; 95% CI, 22.8%-36.6%; P < .001). The sensitivity for resectable recurrence (n = 20) was also higher (ctDNA, 60.0%; CEA, 20.0%; P = .01). The specificity did not differ between the tests (ctDNA, 97.9%; 95% CI, 93.2%-99.6%; CEA, 96.4%; 95% CI, 91.4%-99.0%). When adjustments were made for other predictors of the presence of recurrence, a positive ctDNA test was an independent predictor (odds ratio, 155.7; 95% CI, 17.9-1360.6; P < .001), whereas CEA was not (odds ratio, 2.5; 95% CI, 0.3-20.6; P = .407). CONCLUSIONS: The quantitative ctDNA test showed superior sensitivity in comparison with CEA without a difference in the specificity for detecting recurrent CRC. Longitudinal studies are warranted to further assess the utility (specifically the survival benefit) of methylated BCAT1/IKZF1 ctDNA in the surveillance of patients with CRC.

Internet use and preferences among women living with advanced breast cancer.

Despite high distress and unmet informational and psychosocial needs, and recommendations for development of advanced breast cancer (ABC)-specific resources, there remains a paucity of appropriate, accessible psychological interventions. This survey study examined internet use and preferences of women with ABC, to gauge feasibility of providing an ABC-specific internet intervention. Most participants (83%) used the internet daily. Results indicated most women with ABC would find an ABC-specific internet intervention helpful, and that it would address gaps in current internet resources, including provision of strategies to manage treatment side-effects and fear of cancer progression.

Online information and support needs of women with advanced breast cancer: a qualitative analysis.

PURPOSE: Women with advanced breast cancer (ABC) face significant adjustment challenges, yet few resources provide them with information and support, and attendance barriers can preclude access to face-to-face psychosocial support. This paper reports on two qualitative studies examining (i) whether information and support-seeking preferences of women with ABC could be addressed in an online intervention, and (ii) how an existing intervention for patients with early stage cancer could be adapted for women with ABC. METHODS: Women with ABC participated in telephone interviews about their information and support-seeking preferences (N = 21) and evaluated an online intervention focused on early-stage cancer (N = 15). Interviews were transcribed and underwent thematic analysis using the framework method to identify salient themes. RESULTS: Participants most commonly sought medical, lifestyle-related, and practical information/support; however, when presented with an online intervention, participants most commonly gave positive feedback on content on coping with emotional distress. Difficulty finding information and barriers to using common sources of information/support including health professionals, family and friends, and peers were reported; however, some women also reported not wanting information or support. All participants evaluating the existing intervention gave positive feedback on various components, with results suggesting an online intervention could be an effective means of providing information/support to women with ABC, given improved specificity/relevance to ABC and increased tailoring to individual circumstances and preferences. CONCLUSIONS: Adaptation of an existing online intervention for early stage cancer appears to be a promising avenue to address the information and support needs of women with ABC.

Is Survival for Patients with Resectable Lung Metastatic Colorectal Cancer Comparable to Those with Resectable Liver Disease? Results from the South Australian Metastatic Colorectal Registry.

BACKGROUND: Hepatic resection for colorectal (CRC) metastasis is considered a standard of care. Resection of metastasis isolated to lung also is considered potentially curable, although there is still some variation in recommendations. We explore outcomes for patients undergoing lung resection for mCRC, with the liver resection group as the comparator. METHODS: South Australian (SA) metastatic CRC registry data were analysed to assess patient characteristics and survival outcomes for patients suitable for lung or liver resection. RESULTS: A total of 3241 patients are registered on the database to December 2014. One hundred two (3.1 %) patients were able to undergo a lung resection compared with 420 (12.9 %) who had a liver resection. Of the lung resection patients, 62 (61 %) presented with lung disease only, 21 % initially presented with liver disease only, 11 % had both lung and liver, and 7 % had brain or pelvic disease resection. Of these patients, 79 % went straight to surgery without any neoadjuvant treatment and 34 % had lung resection as the only intervention. Chemotherapy for metastatic disease was given more often to liver resection patients: 76.9 versus 53.9 %, p = 0.17. Median overall survival is 5.6 years for liver resection and has not been reached for lung resection (hazard ratio 0.82, 95 % confidence interval 0.54-1.24, p = 0.33). CONCLUSIONS: Lung resection was undertaken in 3.1 % of patients with mCRC in our registry. These data provide further support for long-term survival after lung resection in mCRC, survival that is at least comparable to those who undergo resection for liver metastasis in mCRC.

A Pilot Study of Self-Management-based Nutrition and Physical Activity Intervention in Cancer Survivors.

Exercise and a healthy diet are beneficial after cancer, but are not uniformly adopted by cancer survivors. This study reports on the feasibility, acceptability, and effectiveness of a self-management-based nutrition and exercise intervention for Australian cancer survivors. Adult survivors (n  =  25) during curative chemotherapy (stratum 1[S1]; n  =  11) or post-treatment (stratum 2 [S2]; n  =  14) were recruited prospectively from a single center. The Flinders Living Well Self-Management Program™ (FLW Program) was utilized to establish patient-led nutrition and exercise goals and develop a tailored 12-wk intervention plan. Fortnightly reviews occurred with assessments at baseline, 6 and 12 wk. A recruitment and retention rate of 38% and 84% were observed. Both strata maintained total skeletal muscle mass. Small reductions in body mass index, hip circumference, and percentage body fat, and small increases in hand grip strength and exercise capacity among subjects in both strata were observed. No significant differences were observed between strata; however, significant increases in exercise capacity and global health status for S2 were observed from baseline to 12 wk. FLW Program is a feasible mode of delivering nutrition and exercise intervention to cancer survivors and it appears that there are no barriers to implementing this program early during chemotherapy. Hence, the additive effect of gains achieved over a longer duration is promising and this should be explored in randomized controlled trials adequately powered to observe clinically and statistically significant improvements in relevant outcomes.

Survival improvements associated with access to biological agents: Results from the South Australian (SA) metastatic colorectal cancer (mCRC) registry.

Background Randomized controlled trials evaluating biological therapy have shown improvements in survival from metastatic colorectal cancer (mCRC). Subjects in the trials represent a selected proportion of mCRC patients. We have the potential to assess the impact of biological therapy on mCRC outcomes, particularly the effect of bevacizumab, from a population-based clinical registry by comparing two time cohorts with differences in therapy accessibility. Material and methods A retrospective cohort study was performed by analyzing the South Australian (SA) mCRC registry data based on diagnosis in two time periods: 1 February 2006-31 May 2009 (Cohort A) versus 1 June 2009-30 June 2014 (Cohort B). The demarcation for these cohorts was chosen to reflect the change in accessibility of bevacizumab from July 2009. Results Between February 2006 and June 2014, 3308 patients were identified through the SA mCRC registry: 1464 (44%) in Cohort A and 1844 (56%) in Cohort B. 61 and 59% patients in Cohort A and B, respectively received systemic therapy (p = 0.26). Major differences in clinical characteristics were: biological therapy use 18 versus 33% (p < 0.001) and clinical trial enrolment 12 versus 7% (p < 0.001). Uptake of bevacizumab was: first-line 9 versus 42% and second-line 6 versus 16%. Median overall survival (mOS) for the entire group was: 13.1 versus 17.1 months (HR 0.80; 95% CI 0.74-0.87). Evaluation restricted to patients receiving systemic therapy was 20.5 versus 25.2 months (HR 0.80; 95% CI 0.72-0.89). Multivariate analysis indicated that biological therapy and Cohort B were associated with improved mOS. Conclusion The expected rise in bevacizumab administration was observed in Cohort B. Its use in first-line therapy remained relatively low even after the reimbursement, potentially reflecting real world practice where comorbidities, primary in-situ and age may contraindicate its use. mOS improvement over time was attributed to increased access to biological therapy, especially bevacizumab and possibly advance in peri-operative and supportive care.

Comparable survival outcome of metastatic colorectal cancer in Indigenous and non-Indigenous patients: Retrospective analysis of the South Australian metastatic colorectal cancer registry.

OBJECTIVE: This study aims to investigate disparities in demographics, disease characteristics, treatment and overall survival between South Australian (SA) Indigenous and non-Indigenous patients with metastatic colorectal cancer (mCRC). DESIGN: This employs a retrospective population study using the SA mCRC registry. SETTING: The SA mCRC registry identifies mCRC patients from hospital encounters, histopathology reports, medical oncology letters, clinician notification, attendances at multidisciplinary meetings and death audits by the SA Cancer Registry. PARTICIPANTS: A total of 2865 adult mCRC patients including 14 Indigenous patients were identified through the SA mCRC registry between February 2006 and August 2013. Patients were linked to the SA Cancer Registry to obtain Indigenous status. MAIN OUTCOME MEASURES: Demographic, disease and treatment characteristics were compared using Chi-squared test and t-test; while overall survival defined as time to any cause of death was analysed using Cox regression. RESULTS: No difference was observed for clinical characteristics, except for a higher proportion of Indigenous patients receiving chemotherapy (85.7% versus 58.5%; P = 0.04). The rate of liver surgery was similar across the two groups (21.0% versus 15.1%; P = 0.40). The median overall survivals were equivalent (11.9 months versus 15.1 months; hazard ratio = 1.00; 95% confidence interval for hazard ratio, 0.54-1.86). CONCLUSIONS: Clinical characteristics and survival outcomes were similar between Indigenous and non-Indigenous patients captured on the SA mCRC registry, and outcome of those who have an access to comprehensive cancer care appeared independent of Indigenous status and in line with large clinical trials. Underestimation of Indigenous cases due to their lower utilisation of cancer service could not be excluded and ultimately the accurate reporting of these patients is crucial.

Does the primary site of colorectal cancer impact outcomes for patients with metastatic disease?

BACKGROUND: Previous reports have described differences in biology and outcome for colorectal cancer based on whether the primary is right or left sided. Further division by right, left, and rectum or even exact primary site has also been explored. Possible differences in response to biological agents have also been reported based on side of primary lesion. METHODS: We explored the South Australian registry for metastatic colorectal cancer to assess if there were any differences in patient characteristics, prognostic markers, and treatment received and outcomes based on whether the primary was right or left sided. We also explored if differences exist based on left colon and rectum and by exact primary site. RESULTS: Two thousand nine hundred seventy-two patients were analyzed. Thirty-five percent had a right-sided primary. The median overall survival for the entire group right versus left was 9.6 versus 20.3 months (P < .001). Multivariate analysis confirmed side of primary as an independent prognostic factor. For the group that had active therapy, defined as chemotherapy (± metastasis resection), median overall survival was right, 18.2 months; and left, 29.4 months (P < .001). Importantly, we found no suggestion of major differences if left side was divided by left colon and rectum, and trends by individual site still supported a left and right division. CONCLUSIONS: Patients with a right-sided primary have more negative prognostic factors and indeed have inferior outcomes compared with those with a left-sided primary. Our data with further breakdown by exact site still favor a simple left-versus-right division moving forward for metastatic colorectal cancer.

Late effects of oxaliplatin-induced peripheral neuropathy (LEON)--cross-sectional cohort study of patients with colorectal cancer surviving at least 2 years.

OBJECTIVES: Oxaliplatin accumulates in dorsal root ganglia, causing an axonal neuronopathy. Symptoms include numbness, pain and gait disturbance which may persist and impact on quality of life (QOL). Despite widespread use of this drug, its late effects and patient satisfaction outcomes have not been widely reported. Furthermore, there has been limited qualitative research published in this area. The objectives of this study were to establish the incidence and clinical impact of chronic peripheral neuropathy. METHODS: We conducted a cross-sectional observational study of patients who started oxaliplatin treatment at least 2 years prior to study commencement. Patients were assessed in three ways: clinical assessment encompassing neurological examination and nerve conduction studies to calculate a total neuropathy score (TNS); self-reported assessment via validated questionnaires; and assessment by recorded interview. The clinical and questionnaire-based assessments were analysed quantitatively and the interview data used for qualitative assessment. RESULTS: Twenty-five patients consented to participate. The mean starting dose of oxaliplatin given was 92 mg/m(2). The cumulative dose received ranged from 375 to 2,400 mg, with a mean cumulative dose of 1,515 mg. Oxaliplatin was ceased due to neuropathy in six patients (24 %), after a mean of 9 cycles of treatment. Modified TNS ranged from 1 to 15 with a mean of 9.5. There was a statistically significant correlation between cumulative oxaliplatin dose and TNS. Quality of life and functional impact questionnaires showed mildly lower physical quality of life, higher pain scores and functional impairment secondary to sensory deficit. Qualitative analysis demonstrated variable bio-psycho-social effects of chronic neuropathy but, importantly, highlighted that many patients felt they had been insufficiently warned of the risk of neuropathy. Despite this, the majority was satisfied with their decision to receive the drug. CONCLUSION: Many patients objectively demonstrated mild to moderate oxaliplatin neuropathy >2 years post-treatment. The majority of patients did not recall being warned of the risks of chronic peripheral neuropathy. Many of those who recall being warned did not feel sufficient emphasis was placed on the issue. Despite a varying burden of neuropathic symptoms, the majority of patients were highly satisfied with their decision to receive oxaliplatin.

Emergence of order from chaos through a continuous phase transition in a turbulent reactive flow system.

As the Reynolds number is increased, a laminar fluid flow becomes turbulent, and the range of time and length scales associated with the flow increases. Yet, in a turbulent reactive flow system, as we increase the Reynolds number, we observe the emergence of a single dominant timescale in the acoustic pressure fluctuations, as indicated by its loss of multifractality. Such emergence of order from chaos is intriguing. We perform experiments in a turbulent reactive flow system consisting of flame, acoustic, and hydrodynamic subsystems interacting nonlinearly. We study the evolution of short-time correlated dynamics between the acoustic field and the flame in the spatiotemporal domain of the system. The order parameter, defined as the fraction of the correlated dynamics, increases gradually from zero to one. We find that the susceptibility of the order parameter, correlation length, and correlation time diverge at a critical point between chaos and order. Our results show that the observed emergence of order from chaos is a continuous phase transition. Moreover, we provide experimental evidence that the critical exponents characterizing this transition fall in the universality class of directed percolation. Our paper demonstrates how a real-world complex, nonequilibrium turbulent reactive flow system exhibits universal behavior near a critical point.

Metastatic colorectal cancer- third line therapy and beyond.

INTRODUCTION: The outcome of patients with metastatic colorectal cancer (mCRC) has improved significantly in the last few decades. Metastatic colorectal cancer is a highly heterogenous cancer. Beyond second line chemotherapy, treatment decisions are often based on molecular testing. METHOD: In this narrative review, we provide a comprehensive summary of data from key clinical trials and discuss how to integrate these agents into the current treatment landscape of metastatic colorectal cancer. EXPERT OPINION: In the era of precision medicine, molecular testing plays an increasingly important role in the management of mCRC. Efforts need to be made to target treatment based on molecular test results.

Evaluating the Role of Methylated Circulating Tumor DNA in Combination With Pathological Prognostic Factors for Predicting Recurrence of Colorectal Cancer.

Background: Colorectal cancer (CRC) has a high rate of recurrence, in particular for advanced disease, but prognosis based on staging and pathology at surgery can have limited efficacy. The presence of circulating tumor DNA (ctDNA) at diagnosis could be used to improve the prediction for disease recurrence. Objectives: To assess the impact of detecting methylated BCAT1/IKZF1 ctDNA at diagnosis in combination with demographic, lifestyle, clinical factors and tumor pathology, to assess predictive value for recurrence. Design: A retrospective cohort study. Methods: The cohort included 180 patients (36 with recurrent CRC), who had undergone complete treatment and surveillance for a minimum of 3 years. Participant clinical details and ctDNA methylated BCAT1/IKZF1 results were compared between those with and without recurrence, and cox regression analysis assessed each factor on disease-free survival. Results: Clinical factors independently associated with reduced disease-free survival included nodal involvement (HR = 3.83, 95% CI 1.56-9.43, P = .003), M1 stage (HR = 4.41, 95% CI 1.18-16.45, P = .027), a resection margin less than 2 mm (HR = 4.60, 95% CI 1.19-17.76, P = .027), perineural involvement (HR = 2.50, 95% CI 1.01-6.17, P = .047) and distal tumors (HR = 3.13, 95% CI 1.07-9.18, P = .037). Methylated BCAT1/IKZF1 was detected in 51.7% (93/180) of pre-treatment plasma samples. When a positive ctDNA finding was considered in combination with these clinical prognostic factors, there was improved predictive power of recurrence for patients with perineural involvement (HR = 4.44, 95% CI 1.92-10.26, P < .001), and it marginally improved the predictive factor for M1 stage (HR = 7.59, 95% CI 2.30-25.07, P = .001) and distal tumors (HR = 5.04, 95% CI 1.88-13.49, P = .001). Conclusions: Nodal invasion, metastatic disease, distal tumor site, low resection margins and perineural invasion were associated with disease recurrence. Pre-treatment methylated ctDNA measurement can improve the predictive value for recurrence in a subset of patients, particularly those with perineural involvement. Registration: Australian and New Zealand Clinical Trials Registry #12611000318987.

Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial.

PURPOSE: SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors. METHODS: This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose. RESULTS: From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors. CONCLUSION: SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

Primary site and treatment impact in unresectable metastatic colorectal cancer.

INTRODUCTION: Colorectal cancer is a heterogenous disease, with various clinical and molecular subtypes related to the primary site (left versus right colon) of the original tumor. Primary colon tumor side is both a prognostic and predictive marker in metastatic colorectal cancer. AREAS COVERED: There is an increasing body of evidence for how primary site may impact treatment decisions in metastatic colorectal cancer. We reviewed the evidence for its prognostic and predictive value. EXPERT OPINION: Primary site is a prognostic marker in metastatic colorectal cancer, with right colon tumors being associated with more aggressive disease behavior and poorer outcomes. Primary site also appears to predict for outcomes to various treatments, in particular anti-EGFR antibodies. As our understanding and testing of the molecular and biological differences within colorectal cancer increases beyond primary site, this should be integrated into the current treatment algorithm to ensure an individualized patient-centered approach to care.