The study, conducted across three academic medical centers — Nanfang Hospital of Southern Medical University, The Sixth Affiliated Hospital of Sun Yat-sen University, and Sun Yat-sen University Cancer Center — collected patients treated between September 2015 and October 2022. All had received chemotherapy or chemotherapy combined with immunotherapy before undergoing gastrectomy. The regimens reflected current standards of care: doublet or triplet combinations of fluoropyrimidine-based and platinum-based chemotherapy, including XELOX, SOX, FOLFOX, and the docetaxel-containing FLOT protocol, with some patients also receiving PD-1 immune checkpoint inhibitors every three weeks. Radiological response was assessed by enhanced computed tomography after two to three cycles using the RECIST 1.1 criteria, and the overall response rate across the cohort reached 48.4 percent.

Of the 488 patients, 80 — or 16.4 percent — achieved a pathological complete response. To ensure the finding was robust, the researchers harmonized tumor regression grading across institutions: because one center used the National Comprehensive Cancer Network classification while the other two applied the American Joint Committee on Cancer 8th edition system, three blinded gastrointestinal pathologists conducted a centralized review of all specimens, resolving discrepancies by panel consensus. The definition was strict — no residual tumor cells anywhere in the resection specimen or in any of the resected lymph nodes. Notably, seven patients who had no residual tumor in the primary lesion still harbored carcinoma in their regional lymph nodes, and all seven fell into the non-pCR group.

The survival signal was dramatic. Patients with pCR had significantly better overall survival and recurrence-free survival than those with residual disease, with neither median overall survival nor median recurrence-free survival reached in the pCR group during follow-up. For non-pCR patients, median overall survival was 62.8 months and median recurrence-free survival was 20.9 months. Recurrence rates diverged just as sharply: only 7.5 percent of pCR patients — six of eighty — relapsed, compared with 40.2 percent of non-pCR patients, or 164 of 408. Across the entire cohort, 170 patients, or 34.8 percent, experienced recurrence after neoadjuvant treatment and surgery.

But the study’s most provocative finding concerns the six pCR patients who did relapse. Every single one of them had received adjuvant therapy after surgery, while none of the seventeen pCR patients who were simply observed after surgery experienced recurrence. The authors are careful not to overinterpret this counterintuitive pattern. They suggest two possible explanations: selection bias, in which clinicians may have reserved adjuvant treatment for patients perceived to be at higher risk, or the development of chemotherapy resistance to the specific adjuvant regimen used. With only six events among eighty patients, the statistical power is limited, and the researchers explicitly caution that this observation should not be read as evidence against adjuvant therapy. Instead, they argue, it underscores the need for better risk stratification to identify the minority of pCR patients harboring residual micrometastatic disease who might genuinely benefit from additional systemic treatment.

The timing and location of relapse told another important story. There was no significant difference between the pCR and non-pCR groups in when or where recurrence occurred, echoing earlier work — including a 2011 cohort study by Fields and colleagues that found 27 percent of pCR gastric cancer patients relapsed within five years. Among all patients with recurrence in the current study, 73.5 percent developed distant metastases, 8.8 percent had local recurrence, and 6.5 percent had both. Of the six relapsed pCR patients, all were male; two developed locoregional recurrence while three developed distant disease involving the peritoneum, distant lymph nodes, or bone, and three of the six died of their recurrence during follow-up.

To predict who might achieve pCR in the first place, the team built a statistical model using logistic regression and a nomogram — a graphical scoring tool that translates patient characteristics into a personalized probability. Multivariate analysis identified radiological response under RECIST 1.1 as a powerful predictor: patients with a complete or partial radiological response had roughly eight times the odds of achieving pCR compared with those with stable or progressive disease. Even more striking, Epstein-Barr virus-encoded RNA positive status carried an odds ratio of 20.65, making EBER positivity the single strongest molecular predictor in the analysis. After excluding variables with too many missing values, the final nomogram incorporated the neoadjuvant treatment regimen and histological type as independent predictors. The model performed well, achieving a concordance index of 0.844 in the training set and 0.820 in the validation set, with calibration curves showing satisfactory agreement between predicted and observed outcomes and decision curve analysis confirming clinical utility.

The immunotherapy question yielded a nuanced answer. Adding immune checkpoint inhibitors to neoadjuvant chemotherapy significantly increased the pCR rate and cut the recurrence rate nearly threefold — 15.1 percent versus 40.3 percent for chemotherapy alone. Yet this did not translate into significantly longer recurrence-free or overall survival, with Kaplan-Meier comparisons showing no statistically significant difference between the two treatment groups. The finding mirrors results from major international trials: the phase III KEYNOTE-585 study demonstrated that pembrolizumab plus chemotherapy significantly raised pCR rates in locally advanced gastric and gastroesophageal junction cancer but failed to significantly improve event-free survival, while the DANTE trial reported promising pathological responses with atezolizumab-based perioperative therapy. The disconnect between pathological response and hard survival endpoints remains one of the field’s central puzzles, and the authors call for research integrating circulating tumor DNA, radiomics, and digital pathology to predict long-term outcomes more accurately.

Beyond pCR, the study identified clear risk factors for recurrence in the broader population: patients with five or more positive regional lymph nodes had nearly four times the recurrence risk, those with poorly differentiated tumors and neurovascular invasion were also at elevated risk, and a high lymph node ratio — above 30 percent — predicted significantly shorter overall and recurrence-free survival. Tumor regression grade itself mattered, with a three-year recurrence-free survival of 66.5 percent for patients with the best regression grades compared with 50.9 percent for those with lesser responses. Intriguingly, among patients with the best regression grades, those who skipped postoperative systemic therapy had a numerically higher three-year recurrence-free survival of 81.4 percent versus 64.4 percent, though the difference was not statistically significant.

The study has limitations the authors acknowledge candidly: its retrospective design invites selection and treatment bias, the small number of recurrence events among pCR patients limits statistical power, center heterogeneity introduced variability in practices and data collection, and the nomogram lacks external validation. Missing data on Lauren classification and PD-L1 combined positive scores further constrained the analysis. Still, as the largest sample of gastric and gastroesophageal junction cancer patients with pCR after neoadjuvant treatment and radical surgery to date, the study delivers a clear message for clinicians and patients alike: a pathological complete response is one of the most favorable outcomes in this disease, associated with dramatically lower recurrence and superior survival, but it is not a guarantee of cure. The role of adjuvant therapy for these patients remains unresolved, and the authors argue that only prospective randomized trials can settle whether additional postoperative treatment helps or harms the patients whose tumors have already vanished.

Subject of Research: Pathological complete response and survival after neoadjuvant treatment of locally advanced gastric cancer

Article Title: Characteristics and survival associated with pathological complete response following neoadjuvant treatment of locally advanced gastric cancer: a multicenter analysis in a real-world setting

Article References: Lai, M.-Y., Luo, D.-D., Chen, S., Yan, X., Tan, W.-Y., Guan, W.-L., Zhou, Z.-W., Zhao, L.-Y., & Qiu, M.-Z. (2026). Characteristics and survival associated with pathological complete response following neoadjuvant treatment of locally advanced gastric cancer: a multicenter analysis in a real-world setting. Holistic Integrative Oncology, 5(1), Article 53. https://doi.org/10.1007/s44178-026-00273-w

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00273-w

Keywords: gastric cancer, pathological complete response, neoadjuvant treatment, immunotherapy, chemotherapy, recurrence, overall survival, recurrence-free survival, nomogram, tumor regression grade, gastroesophageal junction cancer, adjuvant therapy

Oral squamous cell carcinoma, or OSCC, is a formidable enemy in canine medicine. Oral tumors affect an estimated half a percent of dogs over their lifetimes and account for about six percent of the canine cancer burden, with OSCC making up roughly nineteen percent of all oral tumors. The disease is locally invasive, growing through multiple anatomical planes of the jaw and surrounding tissue, causing severe pain, difficulty eating, and in some cases pathological fractures of the bone. Up to twenty percent of affected dogs show signs of metastasis by the time they are diagnosed. Left untreated, it is deadly.

The current standard of care is blunt: wide-margin surgical excision. While surgery is highly effective when non-metastatic tumors are completely removed, with very low recurrence rates, it is also highly invasive and invariably disfiguring. Roughly thirty percent of dogs have difficulty eating after surgery, and larger operations bring longer healing times, greater postoperative pain, and higher risks of complications. Radiation is occasionally used for tumors that cannot be surgically removed or as an adjunct to surgery, but the fundamental treatment paradigm has not changed in decades, even as researchers have made major strides in understanding the molecular machinery driving the disease.

That machinery centers on the RAS signaling pathway. Recent studies have shown that canine OSCC displays highly activated RAS signaling compared with healthy gingival tissue, a finding confirmed by gene set enrichment analysis comparing tumor samples with normal tissue. RAS is a small GTPase that, when activated by extracellular signals binding to receptors on the cell surface, launches a cascade of molecular events that ultimately drive cell growth and survival. The most important arm of this cascade for tumor growth is the RAS-RAF-MEK-ERK pathway, which ends with ERK initiating the gene transcription programs that keep a tumor expanding. The question facing the Cornell team was whether this pathway could be pharmacologically attacked in a way that would benefit dogs whose tumors are driven by a variety of different upstream mutations.

The answer they settled on was trametinib, a small molecule that inhibits MEK1 and MEK2, the kinases sitting in the middle of the pathway. Trametinib binds to the non-phosphorylated form of MEK in an allosteric pocket near the ATP binding site, blocking its catalytic activity and its ability to activate ERK. Crystal structures show the drug does more than simply plug the pocket: it also prevents BRAF from binding to MEK and appears to stabilize MEK’s association with KSR, the kinase suppressor of RAS, further reducing MEK’s affinity for BRAF. Crucially, the team chose trametinib precisely because it works on wildtype, unmutated proteins. Since RAS itself is rarely mutated in canine OSCC and BRAF mutations appear in only about a third of tumors, drugs like sotorasib, which bind only mutant RAS, would have left most patients out in the cold. Trametinib, by contrast, targets the pathway regardless of what triggered its activation.

The drug also came with a reassuring safety pedigree. It is FDA-approved in humans for BRAF-mutant melanoma and non-small cell lung cancer, typically alongside the BRAF inhibitor dabrafenib. A phase I trial in eighteen dogs had already demonstrated an acceptable safety profile over nine weeks of treatment, and the European Medicines Agency reported the drug was well tolerated in beagles over thirteen weeks and fully eliminated within about seven days. Its high oral bioavailability in both species meant it could be given at home, avoiding the stress and expense of repeated hospital visits.

The trial itself was designed with a do-no-harm philosophy. Twenty dogs with histologically confirmed OSCC were enrolled between October 2023 and February 2025, after approval by Cornell’s Institutional Animal Care and Use Committee and with informed consent from owners. Dogs received daily oral trametinib at doses escalating from 0.015 to 0.035 milligrams per kilogram, with examinations every two weeks including caliper tumor measurements, complete blood counts, and serum chemistry panels. Full tumor staging with contrast-enhanced computed tomography was performed at the start, around day 28, and around day 56, and tumor volumes were measured from CT slices by a board-certified veterinary radiologist. Response was categorized using veterinary RECIST criteria, and any dog showing progressive disease was removed immediately and returned to standard care. Because the typical two-week wait before surgery would not be compromised, owners could try the drug without sacrificing the earliest opportunity for curative excision.

The results were remarkable in some patients. One dog achieved a complete response, with no tumor detectable by CT, and five achieved partial responses, giving an overall response rate of thirty percent. Five more dogs had stable disease, meaning fifty-five percent of the cohort derived clinical benefit. Some tumors responded with startling speed: two dogs’ tumors had shrunk to less than one cubic centimeter after just two weeks of treatment, and in five dogs the mean volume reduction at the first post-treatment evaluation was forty-five percent. In two responsive patients, bone window CT scans showed actual bone regrowth at the tumor site, visible at 28 and 56 days after treatment began, a sign of genuine tissue healing rather than mere tumor shrinkage. In some cases the visible portions of tumors became difficult or impossible to identify by external inspection.

Safety data were equally encouraging. No high-grade adverse events were detected in any dog, though about thirty percent of owners reported transient flatulence that resolved on its own. Bloodwork showed mostly grade 1 and grade 2 abnormalities that were typically no worse than pre-treatment values. The only two grade 3 events, elevated alkaline phosphatase in two dogs, were preceded by grade 2 liver enzyme elevations present before treatment began, suggesting preexisting liver pathology unrelated to the drug. No dog was removed from the study or had its dose modified because of side effects, and no neutropenia was observed. Notably, a prior phase I study had flagged hypertension and proteinuria in some dogs at similar doses, but the Cornell team did not observe owner-reported behaviors consistent with those conditions, though blood pressure and urinalysis were not directly monitored.

The most scientifically compelling finding emerged when tumors were stratified by BRAF mutational status. Seven dogs carried tumors harboring the BRAF p.V595E mutation, the canine equivalent of the human V600E mutation, and these responded dramatically better than BRAF wildtype tumors. Among BRAF-mutant cases, one dog had a complete response and four had partial responses, for a seventy-one percent objective response rate and a mean volume reduction of seventy-one percent in responding tumors. Wildtype tumors, by contrast, showed a mean reduction of only seven percent among responders, and total clinical benefit in that group was just eight percent. The difference was statistically significant at p equals 0.01. Because BRAF genotyping requires only simple PCR amplification and Sanger sequencing, the authors suggest it could readily be implemented by diagnostic laboratories to identify dogs most likely to benefit. The team recommends a starting dose of 0.030 milligrams per kilogram daily while cautioning that dose-response analyses were underpowered. Limitations remain, including the absence of an untreated control group, the lack of long-term recurrence and survival data, and the small cohort size, but the study establishes trametinib as a safe, orally available neoadjuvant option that can shrink tumors in about a third of dogs before surgery, and in the majority of those whose tumors are BRAF-mutant, with results visible in as little as two weeks.

Subject of Research: Clinical trial of the MEK inhibitor trametinib for treating oral squamous cell carcinoma in dogs

Article Title: Clinical application of the MEK inhibitor trametinib in dogs with oral squamous cell carcinoma

Article References: Katt, W. P., Balkman, C. E., Byron, M., Carney, P. C., Chrostek, E., Drozd, M. E., Duhamel, G. E., Fiani, N., Hume, K. R., King, A. L., Sylvester, S. R., Todd-Donato, A. B., Winokur, C. E., Wright, A. L., & Peralta, S. (2025). Clinical application of the MEK inhibitor trametinib in dogs with oral squamous cell carcinoma. Veterinary Oncology, 2(1), Article 31. https://doi.org/10.1186/s44356-025-00042-3

Image Credits: AI Generated

DOI: 10.1186/s44356-025-00042-3

Keywords: trametinib, MEK inhibitor, oral squamous cell carcinoma, canine cancer, BRAF mutation, RAS signaling, veterinary oncology, targeted therapy, clinical trial, neoadjuvant treatment, Cornell University, dog health