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Pancreatic and colorectal cancers are often KRAS mutated and are incurable when tumor DNA or protein persists or recurs after curative intent therapy. Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909). We treated 25 patients (20 pancreatic and five colorectal) who were positive for minimal residual mKRAS disease (ctDNA and/or serum tumor antigen) after locoregional treatment in a phase 1 study of fixed-dose Amph-Peptides-2P and ascending-dose Amph-CpG-7909; study enrollment is complete with patient follow-up ongoing. Primary endpoints included safety and recommended phase 2 dose (RP2D). The secondary endpoint was tumor biomarker response (longitudinal ctDNA or tumor antigen), with exploratory endpoints including immunogenicity and relapse-free survival (RFS). No dose-limiting toxicities were observed, and the RP2D was 10.0 mg of Amph-CpG-7909. Direct ex vivo mKRAS-specific T cell responses were observed in 21 of 25 patients (84%; 59% both CD4+ and CD8+); tumor biomarker responses were observed in 21 of 25 patients (84%); biomarker clearance was observed in six of 25 patients (24%; three pancreatic and three colorectal); and the median RFS was 16.33 months. Efficacy correlated with T cell responses above or below the median fold increase over baseline (12.75-fold): median tumor biomarker reduction was -76.0% versus -10.2% (P

BackgroundWhether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.MethodsIn a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.ResultsAt a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group.ConclusionsAmong patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.

The peritoneum is the second most common site of metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). Up to half of all patients that undergo curative-intent resection eventually develop peritoneal metastasis (PM), which accounts for significant morbidity and drives mortality. Despite recent advances in management, PM is associated with very poor prognosis, which is often measured in weeks to months. Clinical manifestations including bowel obstruction, ascites, and urinary obstruction have profound impact on quality of life. Even with relatively advanced disease, PM often remains occult on imaging and thus tend to be underdiagnosed and understudied. Many patients with peritoneal-only PM are excluded from clinical trials because response cannot be measured by standard radiographic criteria. Furthermore, as patients with PM are not eligible for surgical resection and low-volume peritoneal disease is often not amenable to percutaneous biopsy, tissue samples for peritoneal-specific translational studies are limited. Intraperitoneal therapeutics have been proposed as an attractive option for PM, as better penetration of tumor tissue can be achieved with less systemic toxicity compared with intravenous chemotherapy. Heated intraperitoneal chemotherapy (HIPEC), typically combined with cytoreductive surgery (CRS), is an option for select patients with PM from gynecologic or gastrointestinal primary, and for patients with primary peritoneal mesothelioma. However, the incorporation of locoregional therapy for PM in patients with PDAC has been poorly studied given the aggressive nature of pancreatic cancer and overall poor prognosis. With recent advances in existing treatment options, there may be a subset of patients who may derive benefits from locoregional control with cytoreduction and/or intraperitoneal chemotherapy. Critically, additional work is needed to determine PM-favorable clinical and tumoral predictive biomarkers to identify patients who may benefit from a more aggressive approach. We describe the current state of management of patients with peritoneal metastasis from PDAC and review the available data exploring peritoneal-directed therapy with cytoreductive surgery and/or intraperitoneal chemotherapy. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

Background: Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchymal tumors of the GI tract. SEER is an extensive cancer database which proves useful in analyzing population trends. This analysis investigated GIST outcomes between geriatric & non‐geriatric patients. Methods: SEER*STAT 8.4.0.1 was used to extract relevant GIST data from 2000 to 2019. Geriatric age was defined as ≥70 years. Variables included age, sex, surgery, cancer‐specific death, and overall survival. Statistical tests included univariate analysis using KM survival estimate (95% confidence interval) to calculate 5‐year survival (5YS). Log‐Rank tests determined statistical significance. Multivariable Cox's PH regression estimated the geriatric hazard death ratio adjusted for sex, stage, and surgery. Results: The number of patients included was 13,579, yielding overall 5YS of 68.6% (95% CI 67.7–69.5). Cancer‐specific death was 39.11% in 2000 & 3.33% in 2019. Non‐geriatric & geriatric patient data yielded 5YS of 77.4% (76.4%–78.3%) and 53.3% (51.7%–54.8%) respectively (p < 0.0001). For no surgery/surgery, younger patient data yielded 5YS of 48.7% (45.8%–51.4%) and 83.7% (82.7%–84.7%) respectively (p < 0.0001); geriatric data yielded 5YS of 29.3% (26.5%–32.1%) and 62.8% (60.8%–64.6%) respectively (p < 0.0001). Multivariable analysis yielded a geriatric hazard death of 2.56 (2.42–2.70) (p < 0.0001). Conclusions: Cancer‐specific death decreased since 2000, indicating an improvement in survival & treatment methods. Observed lower survival rates overall in the geriatric group. Surgery appeared to enhance survival rates in both groups, suggesting that surgery is an important factor in GIST survival regardless of age. Large prospective studies will help define clinical management for geriatric patients. [ABSTRACT FROM AUTHOR]

Introduction: Retrospective studies have suggested that patients with poor performance status treated with immune checkpoint inhibitors have shorter overall survival and poorer response rates. This study was undertaken to investigate the possible relationships between inpatient immune checkpoint inhibitor use and clinical outcomes. Methods: This was a retrospective chart review of cancer patients who received an immune checkpoint inhibitor while hospitalized from 1 January 2016 to 30 December 2020. The primary outcome was 90-day mortality or admission to hospice rate. Secondary outcomes included overall survival, time to death or discharge to hospice, and descriptive summarization of patient characteristics. Results: A total of 52 patients were analyzed. At 90 days, 68.2% of subjects were expired or admitted to hospice (95% CI: 54.7–81%). 90-day overall survival was 47.1%; median survival time was 81 days (95% CI: 28–242 days). The median time to death or hospice was 35 days (95% CI: 24–72 days). The time to death or hospice was shorter for immune checkpoint inhibitor-naive patients compared to those who received immune checkpoint inhibitors prior to admission (29 days, 95% CI: 12–43 days vs. 242 days, 95% CI: 36–1288 days, respectively; HR: 2.74, 95% CI: 1.2–6.25; p = 0.0121). No differences were found when comparing other baseline characteristics. Conclusion: A majority of patients who received an immune checkpoint inhibitor while hospitalized were either discharged to hospice or expired by 90 days. An increased rate of death or discharge to hospice was observed for patients who were immune checkpoint inhibitor-naive prior to their admission. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) treats Acute Promyelocytic Leukemia (APL). ATO is converted from inorganic arsenic (iAs) to methylated (MAs) and dimethylated (DMAs) metabolites, which are excreted in the urine. Methylation of iAs is important in detoxification, as iAs exposure is deleterious to health. We examined ATO metabolism in 25 APL patients, measuring iAs, MAs, and DMAs. Plasma total iAs increased after ATO administration, followed by a rapid decline, reaching trough levels by 4–6 h. We identified two patterns of iAs metabolism between 6 and 24 h after infusion: in Group 1, iAs increased and were slowly converted to MAs and DMAs, whereas in Group 2, iAs was rapidly metabolized. These patterns were associated with smoking and different treatments: ATO with all-trans retinoic acid (ATRA) alone vs. ATO preceded by ATRA and chemotherapy. Our data suggest that smoking and prior chemotherapy exposure may be associated with ATO metabolism stimulation, thus lowering the effective blood ATO dose. [ABSTRACT FROM AUTHOR]

Background: Electronic health records (EHRs) may help enable reliable, rapid data management for many uses, such as facilitating communication of advance care planning (ACP). However, issues with validity and accuracy of EHRs hinder the use of ACP information for practical applications. Design: We present a cross-sectional pilot study of 433 older adults with cancer from three large health care systems, participating in an ongoing multisite pragmatic trial (4UH3AG060626-02). We compared data extracted from dedicated structured EHR fields for ACP to a chart review of corresponding ACP documentation contained in the medical chart. Results: Structured ACP data existed for 43.2% of patients and varied by site (25.7% −48.9%). Of the identified structured ACP data elements, 59.2% of recorded elements were correct, 23.7% were incorrect, and 17.1% were duplicates with heterogeneity across sites. Conclusion: Structured ACP data in EHRs were frequently incorrect. This represents a problem for patients and their families, as well as quality improvement and research efforts. Clinical Trials Registration: NCT03609177. [ABSTRACT FROM AUTHOR]

Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1+ tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC. Clinical responses were assessed by irRC. T cell and Ab responses were assessed by ex vivo IFN-gamma ELIspot and ELISA. Tumor biopsies pre- and post-treatment were evaluated for immune infiltrates. Eight patients were enrolled: 5, 2, and 1 in Arms A-C, respectively. There were no DLTs. Best clinical responses were SD (4) and PD (4). T-cell and antibody (Ab) responses to NY-ESO-1 were detected in 6 (75%) and 7 (88%) patients, respectively, and were associated with SD. The breadth of Ab responses was greater for patients with SD than PD (p = .036). For five patients evaluable in the TME, treatment was associated with increases in proliferating (Ki67+) CD8+ T cells and decreases in RORyt+ CD4+ T cells. T cell densities increased for those with SD. Detection of T cell responses to NY-ESO-1 ex vivo in most patients suggests that IPI may have enhanced those responses. Proliferating intratumoral CD8+ T cells increased after vaccination plus IPI suggesting favorable impact of IPI plus NY-ESO-1 vaccines on the TME. [ABSTRACT FROM AUTHOR]

Unresectable gastroesophageal junction (GEJ) cancers have a poor prognosis and limited treatment options. We report the case of a patient with a Siewert class III gastroesophageal junction squamous carcinoma with metastatic spread into the liver who had an exceptional response to a combination therapy of nivolumab and ipilimumab despite being programmed death-ligand 1 (PD-L1) negative, microsatellite stable (MSS), and having a low tumor mutational burden. He initially experienced disease progression on the chemotherapy regimens modified DCF and FOLFIRI resulting in limited functional status, esophageal stent placement, and feeding tube placement. After about 6 months on nivolumab and ipilimumab, he had near-complete disease resolution. He was able to return to his baseline functional status, as well as have the esophageal stent and feeding tube removed. Our case contributes to the value of exploring immunotherapy as an option for a variety of hard to treat cancers. [ABSTRACT FROM AUTHOR]

Background: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient's own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers.Summary: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important. [ABSTRACT FROM AUTHOR]

The article presents a case study of 79-year old male who received external beam radiation therapy (EBRT) and brachytherapy for prostate cancer in 2007. Topics include three sequential development of two separate therapy-related myeloid neoplasms following radiotherapy for prostate cancer and complete blood count (CBC) stated to have revealed pancytopenia.

Background: Outcomes among older patients with acute lymphoblastic leukemia remain poor. This study sought to determine the efficacy of an intensified, multi-agent approach derived from a Dana-Farber consortium trial in younger adults for patients older than 50 years (trial identifier NCT00973752).Methods: The primary endpoint was overall survival (OS) at 1 year. Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase. Imatinib was incorporated for Philadelphia chromosome-positive disease. After induction, the first consolidation incorporated clofarabine. Patients in remission could proceed to allogeneic hematopoietic cell transplantation (HCT) after induction and consolidation I. Those not receiving HCT went on to receive central nervous system, consolidation II, and continuation phases of treatment.Results: Thirty patients were enrolled: 19 achieved a complete remission (CR) after induction and 1 achieved CR after consolidation I for a CR rate of 67%. Sixteen patients underwent HCT. The proportion surviving at 1 year was 63%, and this met the primary endpoint. The 2-year OS rate was 52% (n = 30), and the 2-year disease-free survival rate was 52% for patients achieving CR (n = 20). There was no survival advantage among those undergoing HCT. Therapy-related hyperbilirubinemia prompted adjustments and limitations to asparaginase dosing.Conclusions: Intensified chemotherapy can result in improved outcomes in comparison with historical data. Additional studies of similarly intensive regimens are warranted in this population. Cancer 2016;122:2379-2388. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Pomalidomide is an analog of thalidomide with immunomodulatory, anti-angiogenic, and anti-neoplastic activity indicated for the treatment of multiple myeloma refractory to at least two prior therapies. The incidence for renal failure was <5% in a single phase II study of pomalidomide and dexamethasone in patients with multiple myeloma that failed both lenalidomide and bortezomib therapy. We report a case suggesting crystal nephropathy as the mechanism for acute kidney injury in pomalidomide and fluoroquinolone use. [ABSTRACT FROM AUTHOR]

t is estimated that 80 percent of patients who undergo high-dose chemotherapy prior to transplantation develop mucositis. Mucositis is a painful complication, which can lead to poor nutrition, increased use of narcotics, dehydration, greater risk for infection and bacteremia and altered quality of life. Patients can have oral ulceration, epigastric discomfort, diarrhea, rectal irritation and bleeding. It is likely that the complications of mucositis can contribute to increased length of stay during stem cell transplantation. The purpose of this study is to compare patients who received Kepivance ® (palifermin) with patients that did not receive this medication regimen during autologous stem cell transplantation. We performed a retrospective analysis of 40 patients; 20 prior to the institution of Kepivance ® (palifermin), and 20 patients after. The objective of this study was to determine whether the use of Kepivance decreases the incidence and duration of mucositis. A retrospective comparison study is appropriate for this research. Data for this study was taken from forty discharged inpatient medical records. No patient identifiers were used, instead a number for each group from 1 to 20 was given. The data collection tool was approved by the Institutional Review Board. A descriptive statistical analysis was performed by an independent statistician. The data points extracted were the following: diagnosis, length of stay, oral mucositis, GI mucositis, narcotics, TPN, antifungals, antidiarrheals and antibiotic use. The findings of this study support the clinical decision to include Kepivance® (palifermin)in the preventive treatment for mucositis in Autologous BMT/Stem Cell Transplant Patients. The average length of stay for non-Kepivance patients was 32.3 days compared to 28.3 days in patients who received the drug. The severity of both oral and GI mucositis appeared to be less. 17 out of 20 non-Kepivance patients experienced diarrhea or rectal irritation versus 9 out of 20 with Kepivance. There was a trend toward earlier engraftment in the Kepivance group. This pilot study suggests an improvement in mucositis symptoms with the use of Kepivance® (palifermin). It appears that mucositis and its treatment contribute to the length of stay and costs of stem cell transplantation. Quality of life for these patients can be greatly improved if mucositis is eliminated or reduced during the course of stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background: Noninvasive biomarkers predicting immune checkpoint inhibitor (ICI) response are urgently needed. We evaluated the predictive value of pretreatment neutrophil-to-lymphocyte ratio (NLR), smoking history, smoking intensity, BMI and programmed death ligand 1 (PD-L1) expression in non-small-cell lung cancer (NSCLC) patients treated with ICIs., Materials & Methods: Single-center retrospective study included 137 patients from July 2015 to February 2018. Outcomes included 3-month disease control rate, progression-free survival, and overall survival. Predictive value of biomarkers was assessed independently and in a multivariable model., Results: NLR was associated with all outcomes. Smoking history was predictive of progression-free survival and smoking intensity was predictive of disease control rate. BMI and PD-L1 were not associated with any outcome. High BMI was associated with low NLR., Conclusion: Simple clinical biomarkers can predict response to ICIs. A score incorporating both clinical factors and established tissue/serum biomarkers may be useful in identifying NSCLC patients who would benefit from ICIs., Competing Interests: Financial & competing interests disclosure I Preeshagul served on advisory boards for Pfizer, AstraZeneca, Blueprint Medicines, and Eli Lilly this past year. C Devoe has been a consultant for Pfizer this past year. N Seetharamu served on advisory boards for Pfizer, Takeda, Amgen, AstraZeneca, and Genentech this past year. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2020 James Newman and Nagashree Seetharamu.)

Background: Checkpoint inhibitors are integral to non-small-cell lung cancer treatment. Existing data suggests that nutritional status may play a role in antitumor immunity., Materials & Methods: This retrospective study of 106 non-small-cell lung cancer patients who started checkpoint inhibitors between 2014 and 2017 at our institution assessed relationship of nutritional parameters to overall survival (OS) and progression-free survival., Results: Mean age was 68.7 ± 9.2 years and 59.4% patients were male. On multivariate analysis for OS, hypoalbuminemia and significant weight loss were prognostic at p-values of 0.0005 and 0.0052, respectively. We noted a parabolic association between age and OS (p = 0.026, 0.0025)., Conclusion: In our study, some malnutrition parameters were associated with decreased OS. U-shape relationship between age and OS noted here warrants further evaluation., Competing Interests: Financial & competing interests disclosure N Seetharamu has served on the advisory boards for Genentech and AstraZeneca in the last year. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2020 Chung-Shien Lee.)

Survival rates for pancreatic cancer (PC) remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops leading to poor outcomes. PC is a relatively chemoresistant tumor and one of the explanations for this is attributed to desmoplasia that impedes drug delivery. Based on this, stromal modifying agent such as Pegvorhyaluronidase alfa (PEGPH20) was developed and investigated in phase I-III studies. Although phase I-II studies showed promising results in patients with high hyaluronic acid (HA) expressing tumors, the phase III HALO 301 study failed to miss it's primary endpoint and further development of PEHPH20 is halted. This failure implies that targeting desmoplasia alone is not sufficient and other intrinsic factors such as lack of significant neoantigens, low tumor mutational burden, and epithelial to mesenchymal transition may be at play. It is also important to consider that although the tumor stroma may be a physical barrier hampering drug delivery, it may also have protective effects in restraining tumor growth and progression. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted., Competing Interests: CONFLICT OF INTEREST The authors declare that they have no conflicts of interest.

Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative. Experimental Design: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with gastrointestinal carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples. Results: Evidence of ctDNA was detected in 344 of 417 samples (82%), and of these, ≥1 reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented. Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with gastrointestinal carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced gastrointestinal cancers as a complementary approach to tissue testing, and further investigation is warranted. Clin Cancer Res; 24(8); 1881-90. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated., Experimental Design: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated., Results: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 μg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for "high"-HA patients (n = 6), and 3.5 and 5.7 months for "low"-HA patients (n = 11), respectively., Conclusions: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors. Clin Cancer Res; 22(12); 2848-54. ©2016 AACR., (©2016 American Association for Cancer Research.)

Asparaginase (ASP) is an effective chemotherapy agent extensively used in children with acute lymphocytic leukemia (ALL). There has been a recent interest in using ASP in adults with ALL, particularly the less toxic pegylated (PEG) formulation. Hypertriglyceridemia (HTG) is a rare complication of PEG-ASP therapy. We report two cases of obese patients who developed severe HTG after receiving PEG for ALL. Both patients were incidentally found to have severe HTG (TG of 4,330 and 4,420 mg/dL). In both patients, there was no personal or family history of dyslipidemia or hypothyroidism. There was no evidence of pancreatitis or skin manifestations of HTG. Both patients were treated with PEG cessation, low-fat diet and pharmacotherapy. Both patients were re-challenged with PEG, with subsequent increase in TG but no associated complications. TG returned to baseline after discontinuing PEG and while on therapy for HTG. A literature review of PEG-induced HTG in adults demonstrated similar results: asymptomatic presentation despite very severe HTG. HTG is a rare but clinically important adverse effect of PEG. Underlying obesity and/or diabetes may represent risk factors. Clinicians should monitor TG levels during PEG therapy to avoid TG-induced pancreatitis.

We present two rare cases of in situ mantle cell lymphoma ("in situ MCL") and three cases of MCL with mantle zone growth pattern (MCL-MZGP). The patients include four males and one female, with a median age of 66 years (range, 52 to 86 years). Two present with isolated lymphadenopathy and three with multiple lymphadenopathy. At presentation, the complete blood count (CBC) and serum lactate dehydrogenase (LDH) are normal in all cases. Histologic examination reveals an in situ pattern in two cases and a mantle zone growth pattern in three cases. The staging bone marrow biopsies show minimal involvement by lymphoma in one case and no morphologic evidence of lymphoma in four cases. All cases are positive for cyclin D1, including two with typical MCL phenotype and three with CD5-negativity. Four out of five cases express kappa light chain. FISH study for t(11;14) is performed in three cases, of which one is positive and two are inconclusive. For four patients with a median follow-up of 38 months, three are in clinical remission and one has persistent disease. In conclusion, the "in situ MCL" is associated with incidental finding, indolent clinical course and lower tumor burden. The predominant usage of kappa light chain and frequent CD5-negativity observed in our cases are unusual. We review the clinical and laboratory features of "in situ MCL" cases in the literature.