Celiac plexus radiosurgery for pain management in advanced cancer: a multicentre, single-arm, phase 2 trial.

BACKGROUND: Refractory upper abdominal pain or lower back pain (retroperitoneal pain syndrome) related to celiac plexus involvement characterises pancreatic and other upper gastrointestinal malignancies and is an unmet need. We hypothesised that ablative radiation delivered to the celiac plexus would decrease pain. METHODS: This multicentre, single-arm, phase 2 study was done at eight hospitals in five countries (Israel, Poland, Canada, the USA, and Portugal). Eligible patients aged 18 years or older with an average pain level of 5-10 on the Brief Pain Inventory short form (BPI-SF), an Eastern Cooperative Oncology Group performance status score of 0-2, and either pancreatic cancer or other tumours involving the celiac axis, received a single fraction of 25 Gy of external-beam photons to the celiac plexus. The primary endpoint was complete or partial pain response based on a reduction of the BPI-SF average pain score of 2 points or more from baseline to 3 weeks after treatment. All evaluable patients with stable pain scores were included in response assessment. The trial is registered with ClinicalTrials.gov, NCT03323489, and is complete. FINDINGS: Between Jan 3, 2018, and Dec 28, 2021, 125 patients were treated, 90 of whom were evaluable. Patients were followed up until death. Median age was 65·5 years (IQR 58·3-71·8), 50 (56%) were female and 40 (44%) were male, 83 (92%) had pancreatic cancer, and 77 (86%) had metastatic disease. Median baseline BPI-SF average pain score was 6 (IQR 5-7). Of the 90 evaluable patients at 3 weeks, 48 (53%; 95% CI 42-64) had at least a partial pain response. The most common grade 3-4 adverse events, irrespective of attribution, were abdominal pain (35 [28%] of 125) and fatigue (23 [18%]). 11 serious adverse events of grade 3 or worse were recorded. Two grade 3 serious adverse events were probably attributed to treatment by the local investigators (abdominal pain [n=1] and nausea [n=1]), and nine were possibly attributed to treatment (seven were grade 3: blood bilirubin increased [n=1], duodenal haemorrhage [n=2], abdominal pain [n=2], and progressive disease [n=2]; and two were grade 5: gastrointestinal bleed from suspected varices 24 days after treatment [n=1] and progressive disease [advanced pancreatic cancer] 89 days after treatment [n=1]). INTERPRETATION: Celiac plexus radiosurgery could potentially be a non-invasive palliative option for patients with retroperitoneal pain syndrome. Further investigation by means of a randomised comparison with conventional celiac block or neurolysis is warranted. FUNDING: Gateway for Cancer Research and the Israel Cancer Association.

Tumor Differentiation as a Prognostic Marker in Clinically Staged T1bN0 Esophageal Adenocarcinoma.

Current guidelines recommend that clinically staged T1N0 esophageal cancers are to be referred to surgery or endoscopic resection. Using the National Cancer Database, we identified 733 individuals with clinically staged T1N0 esophageal carcinoma, who underwent upfront surgery and did not receive any prior treatment. We assessed upstaging, which was defined as ≥ T2 disease or positive lymph nodes. Poorly differentiated adenocarcinomas were associated with upstaging, whereas squamous cell carcinomas were not. Specifically, the percentage of upstaging among individuals with clinically staged T1b and poorly differentiated tumor was 33.8%. Therefore, clinically staged T1bN0 poorly differentiated esophageal adenocarcinomas are at high risk for upstaging following surgery.

Natural History and Management of Small-Bowel Obstruction in Patients After Cytoreductive Surgery and Intraperitoneal Chemotherapy.

BACKGROUND: Small-bowel obstruction (SBO) after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is a common complication associated with re-admission that may alter patients' outcomes. Our aim was to characterize and investigate the impact of bowel obstruction on patients' prognosis. METHODS: This was a retrospective analysis of patients with SBO after CRS/HIPEC (n = 392). We analyzed patients' demographics, operative and perioperative details, SBO re-admission data, and long-term oncological outcomes. RESULTS: Out of 366 patients, 73 (19.9%) were re-admitted with SBO. The cause was adhesive in 42 (57.5%) and malignant (MBO) in 31 (42.5%). The median time to obstruction was 7.7 months (range, 0.5-60.9). Surgical intervention was required in 21/73 (28.7%) patients. Obstruction eventually resolved (spontaneous or by surgical intervention) in 56/73 (76.7%) patients. Univariant analysis identified intraperitoneal chemotherapy agents: mitomycin C (MMC) (HR 3.2, p = 0.003), cisplatin (HR 0.3, p = 0.03), and doxorubicin (HR 0.25, p = 0.018) to be associated with obstruction-free survival (OFS). Postoperative complications such as surgical site infection (SSI), (HR 2.2, p = 0.001) and collection (HR 2.07, p = 0.015) were associated with worse OFS. Multivariate analysis maintained MMC (HR 2.9, p = 0.006), SSI (HR 1.19, p = 0.001), and intra-abdominal collection (HR 2.19, p = 0.009) as independently associated with OFS. While disease-free survival was similar between the groups, overall survival (OS) was better in the non-obstruction group compared with the obstruction group (p = 0.03). CONCLUSIONS: SBO after CRS/HIPEC is common and complex in management. Although conservative management was successful in most patients, surgery was required more frequently in patients with MBO. Patients with SBO demonstrate decreased survival.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Elderly is Safe and Effective.

INTRODUCTION: An increasing proportion of elderly patients (EP) are undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC). They have increased comorbidities and perioperative risk. Current literature is deficient in describing the outcomes of EP undergoing CRS/HIPEC. MATERIALS AND METHODS: A retrospective review of our prospectively maintained CRS/HIPEC database analyzed perioperative and oncological outcomes of EP (>70 y) compared to younger patients (YP) (<60 y). RESULTS: Of 500 CRS/HIPEC patients, 62 EP and 210 YP were included. Median age was 73 y in EP and 46 y in YP. Demographic, clinical, operative, and perioperative outcomes were similar between groups. American Society of Anesthesiologists > 3 was more prevalent in the EP with 88.2% versus 54.8% in the YP (P < 0.001). Comorbidities were higher in the EP with 87.1% versus 39.0% in the YP (P < 0.001). Peritoneal Cancer Index score was similar with a median of 9. All postoperative and severe complications were similar with 55.2% and 17.1% in the YP and 64.5% and 21.0% in the EP (P = 0.242; P = 0.448). Postoperative mortality was similar with 1.5% in the YP and 5.0% in the EP (P = 0.134). In colorectal primary patients, median overall and disease-free survival was 61.8 and 12.9 mo in the YP and 64.6 and 11.3 mo in the EP (P = 0.363; P = 0.845). CONCLUSIONS: Despite a significant age difference, increased comorbidities, worse American Society of Anesthesiologists, and similar Peritoneal Cancer Index burden, we found no significant differences in perioperative complications or oncological benefit in elderly CRS/HIPEC patients. EP appear to have similar perioperative and oncological outcomes as YP.

Prognostic Implications of Tumor Differentiation in Clinical T1N0 Gastric Adenocarcinoma.

BACKGROUND: Current guidelines recommend neoadjuvant chemotherapy in patients with locoregional gastric adenocarcinoma. Patients diagnosed with early stage gastric adenocarcinoma are usually managed with upfront surgical intervention. However, pathologic staging in a subset of these clinically staged patients identifies more advanced locoregional disease requiring adjuvant treatment. Therefore, identifying these patients prior to surgical intervention is critical to ensure employment of the appropriate treatment paradigm. The aim of the current study was to define patient characteristics associated with clinical understaging in early gastric cancer. METHODS: Using the National Cancer Database (2004-2014) we identified 3,892 individuals with clinical T1N0 gastric adenocarcinoma who underwent upfront definitive surgery, had negative surgical margins, and did not receive preoperative chemotherapy or radiotherapy. Patient characteristics were compared between those with pathologic stage T1N0 disease and those who were upstaged upon surgery. RESULTS: Twenty-seven percent of clinical T1N0 gastric adenocarcinomas had a change in stage because of pathologically defined ≥T2 disease or positive lymph nodes. Individuals who were upstaged had a higher tumor grade compared with those with pathologic stage T1N0 disease. Specifically, 41.9% (530/1,264) of individuals with a poorly differentiated tumor were upstaged, compared with only 10.7% (70/656) with a well-differentiated tumor. Approximately 75% of cases involved upstaging because of T misclassification. The highest percentage of upstaging was shown for tumors located at the fundus and body of the stomach. CONCLUSION: Upstaging of clinical T1N0 gastric adenocarcinoma is characterized by higher tumor grade and is mostly a result of a change in T stage. These findings mandate thorough workup in order to identify patients with clinically staged T1N0 disease requiring preoperative chemotherapy. IMPLICATIONS FOR PRACTICE: Upstaging of clinical T1N0 gastric adenocarcinoma is characterized by higher tumor grade and is mostly a result of a change in T stage. These findings mandate thorough workup in order to identify patients with clinically staged T1N0 disease requiring preoperative chemotherapy.

Perioperative and Oncological Outcomes of Combined Hepatectomy with Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer.

BACKGROUND: Synchronous peritoneal and liver metastasis in colorectal cancer is a relative contraindication for curative surgery. We aimed to evaluate the safety and oncological outcomes of combined treatment of peritoneal and liver metastasis. METHODS: We conducted a retrospective analysis of metastatic colorectal cancer patients from two prospective databases: peritoneal surface malignancy (n = 536) and hepatobiliary (n = 286). We compared 60 patients treated with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) and hepatectomy; 80 patients treated with cytoreduction and HIPEC only; and 63 patients treated with hepatectomy alone. RESULTS: No differences in demographics were observed between the groups. Median hospital and intensive care unit (ICU) stay was shorter in group C (7 and 1 days, respectively) versus groups A and B (13 and 1 days, and 12 and 1 days, respectively; p < 0.001). Postoperative complications were not significantly different. Median follow-up was 18.6, 23.1, and 30.6 months for groups A, B, and C, respectively. Estimated 5-year overall survival (OS) was 48.8% (group A), 55.4% (group B), and 60.2% (group C) [p = 0.043 for group A vs. group C], and estimated 5-year disease-free survival (DFS) was 14.2% (group A), 23.0% (group B), and 18.6% (group C). Five-year OS was superior in group C compared with group A (p = 0.043), and DFS was superior in group C compared with groups A and B (p = 0.043 and 0.03, respectively). The peritoneum was the site of first recurrence in groups A and B (23.3% and 32.5%, respectively), and the liver was the site of first recurrence in group C (44.4%). CONCLUSIONS: We report favorable perioperative and oncological outcomes in combined cytoreduction/HIPEC and hepatectomy for patients with peritoneal and liver metastasis. Surgical intervention after multidisciplinary discussion should be considered in patients with both peritoneal and hepatic lesions when complete cytoreduction is feasible.

Ratio of Pathological Response to Preoperative Chemotherapy in Patients Undergoing Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer Correlates with Survival.

BACKGROUND: Pathological response of colorectal peritoneal metastasis (CRPM) may affect prognosis. We investigated the relationship between oncological outcomes and pathological response to chemotherapy of CRPM following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: We conducted a retrospective analysis of a prospectively maintained Peritoneal Surface Malignancies database between 2015 and 2020. Analysis included patients with CRPM who underwent a CRS/HIPEC procedure (n = 178). The cohort was divided into three groups according to the response ratio (ratio of tumor-positive specimens to the total number of specimens resected): Group A, complete response; Group B, high response ratio, and Group C, low response ratio. RESULTS: The group demographics were similar, but the overall complication rate was higher in Group C (65.2%) compared with Groups A (55%) and B (42.8%) [p = 0.03]. Survival correlated to response ratio; the estimated median disease-free survival of Group C was 9.1 months (5.97-12.23), 14.9 months (4.72-25.08) for Group B, and was not reached in Group A (p = 0.001). The estimated median overall survival in Group C was 35 months (26.69-43.31), and was not reached in Groups A and B (p = 0.001). CONCLUSIONS: The pathological response ratio to systemic therapy correlates with survival in patients undergoing CRS/HIPEC. This study supports the utilization of preoperative therapy for better patient selection, with a potential impact on survival.

Assessing the effects of beta-blockers on pancreatic cancer risk: A nested case-control study.

PURPOSE: Both ß1- and ß2-adrenoceptor proteins were detected on the cell surface of pancreatic ductal adenocarcinoma. The current study evaluated the association between beta-blocker use and pancreatic cancer risk. METHODS: We conducted a nested case-control study in a large population representative database. Each pancreatic cancer case was matched with four controls based on age, sex, practice site, and duration of follow-up using incidence density sampling. Beta-blocker use was defined as any prescription prior to index date and was stratified into non-selective and selective ß1 -blockers. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for pancreatic cancer risk associated with beta-blocker use was estimated using conditional logistic regression. RESULTS: The study included 4113 patients with pancreatic cancer and 16 072 matched controls. When compared to never users, there was no association between any beta-blocker use and pancreatic cancer risk (adjusted OR 1.06, 95% CI 0.97-1.16, P = .16). Analysis by receptor selectivity showed use of non-selective beta-blockers for more than 2 years was associated with a reduced pancreatic cancer risk (OR 0.75, 95% CI 0.57-1.00, P = .05). When compared to former users both users of selective ß1-blockers and non-selective beta-blockers had a reduced pancreatic cancer risk (OR 0.78, 95% CI 0.67-0.90, P = .001) and (OR 0.67, 95% CI 0.49-0.92, P = .01), respectively. CONCLUSION: Beta-blocker use was not associated with increased pancreatic cancer risk. However, long-term use of beta-blockers may be associated with decreased pancreatic cancer risk.

Refining the Use of Adjuvant Oxaliplatin in Clinical Stage II or III Rectal Adenocarcinoma.

BACKGROUND: Current guidelines include the use of adjuvant oxaliplatin in clinical stage II or III rectal adenocarcinoma. However, its efficacy is supported by a single phase II trial. We aimed to examine whether oxaliplatin confers survival benefit in this patient population. METHODS: Using the National Cancer Database (2006-2013) we identified 6,868 individuals with clinical stage II or III rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy. We used multivariate Cox regression to evaluate survival differences according to treatment intensity and change from clinical to pathological stage. RESULTS: We demonstrated an association with improved overall survival with the use of doublet adjuvant chemotherapy in pathological stage III rectal adenocarcinoma (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.92). This association was confirmed in patients with clinical stage III and subsequent pathological stage III disease (HR, 0.69; 95% CI, 0.57-0.83) and was not observed in patients who progressed from clinical stage II to pathological stage III disease. Doublet adjuvant chemotherapy was not associated with improved overall survival in patients with pathological stage 0 or I disease, regardless of their clinical stage. CONCLUSION: Adjuvant oxaliplatin following neoadjuvant chemoradiotherapy in rectal adenocarcinoma was confirmed in patients with clinical stage III and subsequent pathological stage III disease. Omission of oxaliplatin can be considered in pathological complete response or pathological stage I disease. IMPLICATIONS FOR PRACTICE: Current guidelines include the use of oxaliplatin as part of adjuvant chemotherapy (AC) in patients with clinical stage II or III rectal adenocarcinoma (RAC). However, its efficacy is supported only by a single phase II trial. This study found an association with improved overall survival with the use of doublet AC in patients diagnosed with clinical stage III and subsequent pathological stage III, and not in patients with pathological stage 0 or I, regardless of their clinical stage. Therefore, omission of oxaliplatin can be considered in patients with either pathological complete response or pathological stage I RAC, thereby avoiding oxaliplatin-induced neuropathy.

Posttraumatic Stress Disorder and Cancer Risk: A Nested Case-Control Study.

Data regarding cancer risk for individuals who were exposed to traumatic and stressful life events are conflicting. We sought to evaluate the association between posttraumatic stress disorder (PTSD) and the risk of the four most common solid tumors: lung, breast, prostate, and colorectal cancers. We conducted four nested case-control studies using a large UK population-based database. Cases were defined as individuals with any medical code for the specific malignancy. For every case, we used incidence-density sampling to match four controls by age, sex, practice site, and both duration and calendar time of follow-up. Exposure of interest was any diagnosis of PTSD prior to cancer diagnosis. The odds ratios (ORs) and 95% confidence intervals (CIs) for cancer risk associated with PTSD were estimated using multivariable conditional logistic regression and were adjusted for smoking status, obesity, and antidepressant use. The study population included four case groups according to cancer type. There were 19,143 cases with lung cancer (74,473 matched controls), 22,163 cases with colorectal cancer (86,538 matched controls), 31,352 cases with breast cancer (123,285 matched controls), and 27,212 cases with prostate cancer (105,940 matched controls). There was no statistically significant association between PTSD and cancer risk among any of the cancer types: lung, OR = 0.73, 95% CI [0.43, 1.23]; breast, OR = 0.73, 95% CI [0.52, 1.01]; prostate, OR = 1.24, 95% CI [0.87, 1.77]; and colorectal, OR = 1.05, 95% CI [0.68, 1.62]. Our findings indicated that participants in our study with PTSD were not at increased risk of lung, breast, prostate, and colorectal cancers.

Short- and Long-Term Survival in Metastatic Pancreatic Adenocarcinoma, 1993-2013.

Background: During the past 2 decades, numerous clinical trials have focused on improving outcomes in patients with metastatic pancreatic cancer (mPDAC). The efficacy of new treatments has been demonstrated among highly selected patients in randomized phase III trials; hence, it is not clear to what extent these advances are reflected within the broader mPDAC population. Materials and Methods: Survival statistics were extracted from the SEER database for patients diagnosed with mPDAC between 1993 and 2013. Survival was analyzed using the Kaplan-Meier method and proportional hazard models. Results: The study population consisted of 57,263 patients diagnosed with mPDAC between 1993 and 2013; 52% were male, with a median age of 69 years (range, 15-104). Superior prognosis correlated with younger age, being married, tumor located within the head of the pancreas, lower grade disease, and more recent year of diagnosis. Median overall survival (OS) remained stable at 2 months between 1993 and 2013. Improvements in OS were seen for younger patients (age <50 years) and those with a more recent year of diagnosis (2009-2013). The percentage of patients who died within 2 months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%; P<.0001). The percentage of patients surviving ≥12 months improved from 4.9% in 1993 to 12.7% in 2013 (P<.0001). Conclusions: In recent years a modest improvement in OS has been seen among younger patients with mPDAC. The percentage of patients living beyond 1 year has significantly increased over time; however, the percentage of those dying within 2 months remains substantial.

CG100649, a novel COX-2 inhibitor, inhibits colorectal adenoma and carcinoma growth in mouse models.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors (COXIBs) can reduce the risk of developing colorectal cancer (CRC) and are being considered for use as adjuvant therapy for treatment of CRC patients. However, long-term use of most NSAIDs, except aspirin, increases cardiovascular risk, hampering use of these drugs in CRC prevention and possibly for treatment. CG100649 is a new member of the COXIB family, which is proposed to inhibit both COX-2 and carbonic anhydrase-I/-II (CA-I/-II) activity. Using mouse models, we show here that CG100649 inhibits premalignant and malignant colorectal lesions in mouse models, partly through inhibiting tumor cell proliferation. These pre-clinical findings suggest a need for further exploration of CG100649 for CRC prevention and treatment. The long-term safety profile of CG100649, particularly regarding its effect on cardiovascular risk, is yet to be determined.

Immunotherapy in mismatch repair-deficient metastatic colorectal cancer - Outcome and novel predictive markers.

BACKGROUND: This study aims to assess predictive markers for response to immunotherapy in dMMR/MSI-H metastatic colorectal cancer (mCRC) patients. MATERIALS AND METHODS: A study using two prospective cohorts from MD Anderson Cancer Center and Sheba Medical Center of consecutive patients with dMMR/MSI-H mCRC that were treated with immunotherapy between 2014-2022. Primary outcome was progression-free survival (PFS) and secondary outcome was overall response rate (ORR). Evaluated predictors included ECOG-PS score, RAS/BRAF status, single-agent versus doublet immunotherapy, metastatic sites, disease burden, and CEA levels prior to treatment initiation. Kaplan-Meier analysis and Cox proportional hazard regression model were used to analyze the effect of exposure variables on PFS. RESULTS: The study included 153 patients. Median follow-up time was 26 months (IQR 11-48). Median PFS was 51.6 months (95%CI 38.1-NR) and ORR was 58.1%. In a univariate analysis, male sex was associated with worse PFS with a HR of 1.67 (95% CI 1.00-2.79); Right-sided tumors were associated with improved PFS with a HR of 0.56 (95% CI 0.32-0.97); Liver or lung metastasis were associated with worse PFS with HRs of 2.35 (95%CI 1.43-3.88) and 2.30 (95%CI 1.31-4.04), respectively; ECOG-PS score ≥ 2, CEA levels ˃5 µg/L prior to treatment initiation and ≥ 3 metastatic sites were associated with worse PFS with HRs of 2.09 (95%CI 0.98-4.47), 2.23 (95%CI 1.30-3.81) and 3.11 (95%CI 1.61-6.03), respectively. Liver or lung metastasis remained significant in a multivariable model. CONCLUSIONS: Extent of disease (worse PFS with high CEA, poor ECOG-PS and ≥3 metastatic sites) and disease location (worse PFS with liver or lung metastasis and left sided tumor) were associated with immunotherapy outcome in dMMR/MSI-H mCRC.

Inflammatory Bowel Disease in Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy.

BACKGROUND: Inflammatory bowel diseases (IBDs) pose an increased risk of gastrointestinal cancer with especially worse prognosis. Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) improves outcomes in selected patients with colorectal peritoneal metastases. Little published data describes the outcomes of CRS/HIPEC in IBD patients. METHODS: We performed a retrospective review of a prospectively maintained CRS/HIPEC database. Outcomes in patients with and without IBD were compared for short-term outcomes such as hospital/intensive care unit stay, blood loss/transfusions, complications, and reoperations. We also examined oncological outcomes including recurrence, overall (OS), and disease-free survival (DFS). RESULTS: We identified 232 patients that underwent CRS/HIPEC for colorectal or small bowel adenocarcinoma, of which 10 were with IBD. Patients with IBD had lower ASA (p=0.005), less hypertension (p=0.033), and 30% small bowel primary compared to none in the non-IBD cohort (p<0.001). Otherwise, demographic and perioperative characteristics were similar between the groups. The median peritoneal cancer index (PCI) was 7 and similar between the cohorts (p=0.422). Extent of organ resections and peritonectomies performed were similar. Complications occurred in 60.3% of patients (21.2% major), similar between the groups (p=0.744 and p=0.444, respectively). Reoperation rate of 27% was similar between groups (p=0.097). The median OS in the IBD cohort was 19.6 vs 53.2 months in the non-IBD cohort (p = 0.056). The median DFS in the IBD cohort was 4.9 vs 9.4 months in the non-IBD cohort (p=0.174). DISCUSSION: Cytoreductive surgery and heated intraperitoneal chemotherapy in patients with IBD has similar complication profile and trended towards poorer oncological outcomes as CRS/HIPEC in non-IBD patients.

Early Systemic Anti-neoplastic Treatment Post SARS-CoV-2 Infection in Patients with Breast Cancer.

INTRODUCTION: It is unclear how soon after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection it is safe to resume systemic anti-neoplastic treatment in patients with cancer. We assessed the risk of admissions or postponed treatment cycle in vaccinated patients with breast cancer receiving early systemic anti-neoplastic treatment following SARS-CoV-2 infection. METHODS: This was a retrospective cohort study conducted during Omicron SARS-CoV-2 outbreak in Israel, January-July 2022. SARS-CoV-2 cohort included 30 vaccinated patients with breast cancer with SARS-CoV-2 infection 7-14 days prior to systemic treatment. All patients had resolved symptoms and a negative antigen detection test on the day of treatment. The pre-coronavirus disease 2019 (COVID-19) pandemic cohort consisted of 49 matched patients with breast cancer treated with systemic anti-neoplastic agents during 2019. RESULTS: In 30 vaccinated patients with breast cancer who received systemic anti-neoplastic treatment 7-14 days following SARS-CoV-2 infection, compared with 49 matched patients treated in 2019, the rates of emergency department (ED) visits (13% versus 6%, respectively), hospitalizations (3% versus 4%), next cycle of treatment given per protocol (90% versus 88%), and death (0% versus 0%) were similar. CONCLUSION: In a cohort of vaccinated patients with breast cancer who received systemic anti-neoplastic treatment 7-14 days after SARS-CoV-2 infection, we did not observe substantially higher rates of ED visits, hospitalizations, or deaths compared with a similar cohort of pre-COVID-19 patients with breast cancer. Most patients received the next planned cycle on time. Early resumption of systemic anti-neoplastic treatment following SARS-CoV-2 infection in vaccinated patients with breast cancer with a negative antigen test at the day of treatment appeared to be safe. Additional data on larger cohorts and other malignancies are needed to support clinical guidelines.

Pelvic Peritonectomy Poorly Affects Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Metastases.

BACKGROUND: Constraints of pelvic anatomy render complete cytoreduction (CRS) challenging. The aim of this study is to investigate the impact of pelvic peritonectomy during CRS/HIPEC on colorectal peritoneal metastasis (CRPM) patients' outcomes. METHODS: This is a retrospective analysis of a prospectively maintained CRS/hyperthermic intraperitoneal chemotherapy (HIPEC) database. The analysis included 217 patients with CRPM who had a CRS/HIPEC between 2014 and 2021. We compared perioperative and oncological outcomes of patients with pelvic peritonectomy (PP) (n = 63) to no pelvic peritonectomy (non-PP) (n = 154). RESULTS: No differences in demographics were identified. The peritoneal cancer index (PCI) was higher in the PP group with a median PCI of 12 vs. 6 in the non-PP group (p < 0.001). Operative time was 4.9 vs. 4.3 h in the PP and non-PP groups, respectively (p = 0.63). Median hospitalization was longer in the PP group at 12 vs. 10 days (p = 0.007), and the rate of complications were higher in the PP group at 57.1% vs. 39.6% (p = 0.018). Pelvic peritonectomy was associated with worse disease-free (DFS) and overall survival (OS) with 3-year DFS and OS of 7.3 and 46.3% in the PP group vs. 28.2 and 87.8% in the non-PP group (p = 0.028, p .> 0.001). The univariate OS analysis identified higher PCI (p = 0.05), longer surgery duration (p = 0.02), and pelvic peritonectomy (p < 0.001) with worse OS. Pelvic peritonectomy remained an independent prognostic variable, irrespective of PCI, on the multivariate analysis (p < 0.001). CONCLUSIONS: Pelvic peritonectomy at the time of CRS/HIPEC is associated with higher morbidity and worse oncological outcomes. These findings should be taken into consideration in the management of patients with pelvic involvement.

Combination Treatment of Intratumoral Vidutolimod, Radiosurgery, Nivolumab, and Ipilimumab for Microsatellite Stable Colorectal Carcinoma With Liver Metastases.

INTRODUCTION: Microsatellite stable metastatic colorectal cancer (MSS mCRC) is largely refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response. PATIENTS AND METHODS: In this phase I single-institution study, patients with MSS mCRC were treated with a priming dose of s.c vidutolimod, 3 intratumoral injections of vidutolimod and radiosurgery, combined with nivolumab and ipilimumab. Cytokine levels were measured at baseline and at 7 (± 2) weeks. Patients were accrued to 4 consecutive cohorts: (1) Safety run-in without radiosurgery, (2) Radiosurgery prior to intratumoral therapy, (3) Radiosurgery prior to intratumoral therapy with a condensed timeline, and (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy. RESULTS: A total of 19 patients were accrued. Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2-5). None of the patients responded, aside from 1 patient, attributed to high tumor mutational burden. Grade 3 liver toxicity was reported in 0%, 0%, 75%, and 17% in cohorts 1 to 4, respectively. Systemic levels of CXCL10 and IL-10 increased, with a median of 407 versus 78 pg/mL (P = .01), and 66 versus 40 pg/mL (P = .03), respectively. CONCLUSIONS: The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS mCRC with liver metastases. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with high hepatic toxicity.

Evaluating sex as a predictive marker for response to bevacizumab in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database.

BACKGROUND: Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma (mCRC), showing a benefit in males, while the effect in females is less significant. METHODS: Data from 3369 patients with mCRC enrolled on four first-line randomised trials testing chemotherapy with or without bevacizumab (2000-2007) were pooled. Association between sex and progression-free survival and overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut point of 60 years to evaluate the possible role of menopausal-related effects. RESULTS: Bevacizumab was associated with an improved median OS in males and females, with a 2.3- and 0.6-months benefit, respectively. Stratified by age, bevacizumab resulted in improved OS in males at both age categories. In females at or above the age of 60 (n = 731), bevacizumab resulted in improved OS. However, in females below the age of 60 (n = 634), OS benefit did not reach statistical significance (adjusted hazard ratio = 0.94, 95% confidence interval 0.74-1.20). CONCLUSIONS: Our results confirmed the OS benefit from the addition of bevacizumab to first-line chemotherapy in mCRC in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no survival benefit. These findings could be used to relieve financial toxicity or be redistributed within healthcare systems for other health-related purposes.

Zinc supplementation augments in vivo antitumor effect of chemotherapy by restoring p53 function.

Activated p53 is necessary for tumor suppression. Homeodomain-interacting protein kinase-2 (HIPK2) is a positive regulator of functional p53. HIPK2 modulates wild-type p53 activity toward proapoptotic transcription and tumor suppression by the phosphorylation of serine 46. Knock-down of HIPK2 interferes with tumor suppression and sensitivity to chemotherapy. Combined administration of adriamycin and zinc restores activity of misfolded p53 and enables the induction of its proapoptotic and tumor suppressor functions in vitro and in vivo. We therefore looked for a cancer model where HIPK2 expression is low. MMTV-neu transgenic mice overexpressing HER2/neu, develop mammary tumors at puberty with a long latency, showing very low expression of HIPK2. Here we show that whereas these tumors are resistant to adriamycin treatment, a combination of adriamycin and zinc suppresses tumor growth in vivo in these mice, an effect evidenced by the histological features of the mammary tumors. The combined treatment of adriamycin and zinc also restores wild-type p53 conformation and induces proapoptotic transcription activity. These findings may open up new possibilities for the treatment of human cancers via the combination of zinc with chemotherapeutic agents, for a selected group of patients expressing low levels of HIPK2, with an intact p53. In addition, HIPK2 may serve as a new biomarker for tumor aggressiveness.