Tumor Immune Microenvironment and Its Clinicopathological and Prognostic Associations in Canine Splenic Hemangiosarcoma.

Tumor cells can induce important cellular and molecular modifications in the tissue or host where they grow. The idea that the host and tumor interact with each other has led to the concept of a tumor microenvironment, composed of immune cells, stromal cells, blood vessels, and extracellular matrix, representing a unique environment participating and, in some cases, promoting cancer progression. The study of the tumor immune microenvironment, particularly focusing on the role of tumor-infiltrating lymphocytes (TILs), is highly relevant in oncology due to the prognostic and therapeutic significance of TILs in various tumors and their identification as targets for therapeutic intervention. Canine splenic hemangiosarcoma (HSA) is a common tumor; however, its immune microenvironment remains poorly understood. This retrospective study aimed to characterize the histological and immunohistochemical features of 56 cases of canine splenic HSA, focusing particularly on tumor-infiltrating lymphocytes (TILs). We assessed the correlations between the lymphocytic response, the macroscopic and histological characteristics of the tumor, and the survival data. Our study demonstrated that FoxP3 distribution was associated with tumor-related death and survival, while the CD20 count was associated with metastasis. This study provides an in-depth characterization of the tumor immune microenvironment in canine splenic HSA and describes potential prognostic factors.

Tonsillar carcinoma in dogs: Treatment outcome and potential prognostic factors in 123 cases.

BACKGROUND: Tonsillar carcinomas are rarely reported in dogs. Information on outcome after treatment is sparse and prognosis is guarded to poor. HYPOTHESIS/OBJECTIVES: Assess treatment outcome and potential prognostic factors in a population of dogs with cytological or histopathological diagnosis of tonsillar carcinoma. ANIMALS: A total of 123 client-owned dogs with diagnosis of tonsillar carcinoma confirmed by cytology or histopathology. METHODS: Retrospective, multi-institutional study. Medical records of 12 institutions were reviewed from 2012 to 2021. RESULTS: Treatment included surgery, chemotherapy (conventional, tyrosine kinase inhibitors or metronomic chemotherapy), radiotherapy, nonsteroidal anti-inflammatory drugs (NSAIDs) or a combination of these. Surgery was performed in 68 cases, chemotherapy was administered in association with NSAIDs in 64 cases, NSAIDs were used alone in 14 cases and in association with surgery in 21 cases, whereas radiotherapy was used alone or in combination with surgery or chemotherapy in 20 cases. Overall survival time (OST) was 126 days (95% confidence interval [CI], 88-164). Significantly longer survival (P < .001) was seen in dogs without evidence of metastatic disease (median survival time, 381 days; 95% CI, 116-646). Other significant positive prognostic factors included absence of clinicals signs at presentation, surgery (tonsillectomy), use of adjuvant chemotherapy and use of NSAIDs. CONCLUSION AND CLINICAL IMPORTANCE: Asymptomatic dogs, those treated with surgery, those that received adjuvant chemotherapy, and those that received NSAIDs may have a better prognosis than previously expected, but overall survival remains short for dogs with tonsillar carcinoma.

Clinical presentation, treatment and outcome in 23 cats with laryngeal or tracheal lymphoma.

OBJECTIVES: Feline primary laryngeal or tracheal lymphoma (PLTL) is an uncommon extranodal presentation. Information on long-term survival is scarce, although some small case series describe this being achieved with multiagent protocols; an accurate outcome for cats with PLTL is yet to be determined. The aim of this study was to gather information on the clinical presentation, response to treatment and outcome in a large case series of feline PLTL. METHODS: This retrospective multicentre study included cats with a cytological or histopathological confirmation of PLTL. Histopathology samples, when available, were reassessed for grade and immunophenotype. Clinical (age, signalment, retroviral status, presence of anaemia, clinical signs, location and therapy type) and outcome (response, progression-free survival [PFS] and overall survival [OS]) variables were recorded. Survival analyses to assess the impact of variables on PFS and OS were performed. RESULTS: Twenty-three cases were included; cats had a median age of 11 years (range 2-16) and the male:female ratio was 3.6:1. Common clinical signs at presentation included increased respiratory effort (74%) and abnormal upper respiratory tract sounds (48%). Immunophenotyping was performed in 48% of cases and all were B cell. Debulking surgery was performed in 26% of cases. All cats received chemotherapy, COP (cyclophosphamide, vincristine and prednisolone; 39%), CHOP (cyclophosphamide, vincristine, doxorubicin and prednisolone; 44%) and other protocols (17%); 35% had a partial response and 65% a complete response. Median PFS and OS were 909 days (range 23-1484) and 909 days (range 23-2423), respectively. Complete response was associated with longer PFS (P <0.001) and OS (P = 0.012). Pretreatment with steroids was associated with longer OS (P = 0.003). No other variable was found to be significant. CONCLUSIONS AND RELEVANCE: PLTL in cats is mostly of a B-cell phenotype, could be of a low-to-medium grade, and may respond to surgical and medical treatment with a longer survival time than has previously been reported.

Risk factors associated with the onset of lomustine-induced neutropenia in tumour-bearing dogs.

Lomustine (1-[2-chloroethyl]3-cyclohexyl-1-nitrosurea, CCNU) is an oral alkylating agent in the nitrosourea subclass that can cause myelosuppression, with neutropenia being the main dose-limiting toxicity. The aim of this study was to define the frequency of neutropenic events and to identify predisposing risk factors in tumour-bearing dogs treated with CCNU. Dogs receiving CCNU for various malignancies were identified following a search of hospital databases. Variables analysed for correlation with neutropenia included signalment, body weight, tumour type, CCNU total dose, steroid use, protocol type, use of L-asparaginase, previous anthracycline administration and use of the drug as first-line or in the rescue setting. One-hundred and fifteen cases were included; median age was 7 years (range 1-14 years) and median body weight 27.6 kg (range 3-74 kg). The median CCNU dose was 63.5 mg/m2 (range 27.7-84.9 mg/m2 ). Neutropenia occurred in 75 cases (65%) and was comprised of grade 1 (28%), 2 (16%), 3 (29.3%) and 4 (26.7%) events. Tumour type (histiocytic sarcoma [HS]), use of CCNU first line, dose >70 mg/m2 , absence of co-morbidities and previous anthracycline administration, were significantly associated with an increased risk of developing neutropenia, including high-grade events. There was a 1.7% reported mortality rate. When CCNU is used in dogs with HS, first-line, at a starting dosage >70 mg/m2 , in patients with no co-morbidities or with a history of previous anthracycline administration, there may be an increased risk of developing neutropenia. These data may help guide treatment decisions and minimize treatment delays or potentially life-threatening complications.

Extravascular papillary endothelial hyperplasia mimicking soft tissue sarcoma in 2 cats: a potential diagnostic pitfall.

Papillary endothelial hyperplasia (PEH) is a rare soft tissue lesion arising from excessive reactive endothelial cell proliferation described in humans, dogs, and horses. PEH is considered a diagnostic challenge in humans, in which it is frequently misdiagnosed as angiosarcoma. We describe here PEH that developed at injection sites in 2 cats that were initially misdiagnosed as feline injection-site sarcoma by cytology and as subcutaneous angiosarcoma by histopathology. Morphologic features included sharp demarcation from surrounding tissues, and a layered microscopic architecture with an outer fibrous capsule from which emerged fibrovascular stalks covered by a monolayer of factor VIII-related antigen and CD31-positive flat-to-plump endothelial cells. Both lesions had a cystic core containing abundant erythrocytes and fibrin. PEH lesions did not recur in either case. Immunohistochemistry for α-smooth muscle actin and desmin demonstrated that the capsule was devoid of smooth muscle cells, excluding an intravascular origin. PEH in these cats was hypothesized to have developed extravascularly following trauma related to injection. We wish to provide awareness of PEH in domestic cats and of the risk of misdiagnoses leading to overtreatment.

Should we be discouraging use of 'anticancer' supplements in dogs and cats with cancer?

Antonio Giuliano and colleagues argue that 'anticancer' supplements could be harmful and hinder chemotherapy and radiotherapy treatment, and so their use should be discouraged in cancer patients.

Long-term survival in a cat with tonsillar squamous cell carcinoma treated with surgery and chemotherapy.

CASE SUMMARY: A 13-year-old neutered female domestic shorthair cat was presented for further investigation of a right-sided cervical mass. Oral cavity examination revealed a unilateral, right tonsillar mass. Following a contrast-enhanced CT scan of head, thorax and abdomen, which showed no clear evidence of distant metastasis, cytology of the cervical mass was consistent with a metastatic retropharyngeal lymph node, and the patient underwent tonsillectomy and lymphadenectomy. The tumour was histopathologically confirmed to be a well-differentiated squamous cell carcinoma with lymph node metastasis, and sequential chemotherapy treatments with carboplatin were administered. The cat underwent a second surgery to treat local recurrence and chemotherapy was continued. Subsequently, multiple lymphadenectomies to remove additional metastatic lymph nodes were performed, followed by adjuvant treatment with doxorubicin. Restaging procedures, performed every 3-6 months did not document any local recurrence nor any local or distant metastasis. The patient was euthanased after developing neoplastic pleural effusion 965 days following tonsillectomy. RELEVANCE AND NOVEL INFORMATION: Tonsillar tumours are rare in cats, but clinical presentation can be similar to that in dogs. Treatment with surgery and chemotherapy, and more importantly multiple lymphadenectomies, may delay the onset of distant metastasis and it should be considered in similar cases to possibly prolong survival.

Quality of life assessment in cancer patients receiving single-agent versus multidrug chemotherapy protocols.

BACKGROUND: Quality of life (QoL) is an essential factor in therapeutic decision-making for human patients and is commonly used as an endpoint in clinical trials of cancer treatments. AIM: To compare owners' perception of QoL in canine and feline patients affected by different tumor histotypes treated with single-agent or multidrug protocols. METHODS: Owners were asked to assess the impact on QoL of their pets undergoing chemotherapy treatment by answering a questionnaire and assigning a score to different health-related parameters reported to affect QoL. RESULTS: Questionnaires of 101 patients (85 dogs and 16 cats), collected at different time points, were analyzed. Fifty-seven patients were given single-agent chemotherapy (carboplatin, doxorubicin, lomustine, melphalan, mitoxantrone, vinblastine, and vinorelbine), whereas 44 were given multiple-agent treatment. When diverse factors including chemotherapy treatment type (single-agent vs. multidrug regimens) and the onset and kind of adverse effects were considered, no significant variations in owners' perceptions of their pets' QoL were discovered. CONCLUSION: Chemotherapy type (single-agent vs. multidrug protocol) and related adverse events are shown, which did not influence owners' perception of their pet's QoL.Future prospective studies should look into clinical characteristics that might affect QoL, such as the patient's age, tumor stage, and protocol purpose (curative vs. palliative).

Incidence of postoperative complications and outcome of 48 dogs undergoing surgical management of insulinoma.

BACKGROUND: Information regarding outcome of dogs undergoing surgical management for insulinoma is based on studies of a small number of dogs. OBJECTIVES: To report the outcomes of dogs undergoing surgery as treatment for insulinoma, the prevalence of postoperative diabetes mellitus (DM) in this group and to determine if development of DM can be predicted. ANIMALS: Forty-eight client-owned dogs, with a histopathological diagnosis of insulinoma, from three European referral hospitals. METHODS: Retrospective observational study. Dogs were identified from a search of electronic hospital records. Cox's regression was used to determine factors associated with postoperative survival and relapse, and logistic regression was used to determine factors associated with the development of DM. RESULTS: Median survival time (MST) was 372 days (range 1-1680 days), with dogs with stage I disease having the longest survival time. Stage I dogs had MST of 652 days (range 2-1680 days), whereas dogs with either stage II or III disease had MST of 320 days (range 1-1260 days; P = 0.045). Postoperative hyperglycemia was identified in 33% (16/48) of the dogs, of which 9 (19% of the total population) developed persistent DM. No factors that could be used as predictors for development of DM were identified. CONCLUSIONS AND CLINICAL IMPORTANCE: Stage of disease and postoperative hypoglycemia were associated with greater odds of relapse and decreased survival time; these could be used when discussing prognosis. In this study, postoperative DM developed more commonly than previously reported, but no factors were identified that might be useful predictors.

Retrospective comparison of first-line adjuvant anthracycline vs metronomic-based chemotherapy protocols in the treatment of stage I and II canine splenic haemangiosarcoma.

Splenectomy followed by adjuvant chemotherapy is commonly used to treat canine splenic haemangiosarcoma (HSA), although it is unclear if different treatment protocols may have a similar efficacy. The objective of this retrospective study was to assess outcome in dogs with stage I and II splenic HSA treated with either first-line adjuvant anthracycline (AC) or metronomic (MC)-based chemotherapy protocols, by comparing median time to progression (TTP) and median survival time (MST). Medical records of nine institutions were searched for dogs diagnosed with stage I and II splenic HSA that underwent adjuvant treatment with AC- or MC-based protocols following splenectomy. Patients treated with MC following AC were included in an additional group (AMC). Ninety-three dogs were included: 50 in the AC group, 23 in the AMC group and 20 in the MC group. The overall MST was 200 days (range 47-3352) and the overall median TTP was 185 days (range 37-1236). The median TTP of stage I dogs was significantly longer compared to stage II dogs (338 vs 151 days, respectively, P = .028). When adjusting for treatment type, the MST was 154 days for the AC group (range 47-3352 days), 338 days for the AMC group (range 79-1623 days) and 225 days for the MC group (range 57-911 days). The difference in MST and median TTP was not found to be statistically significant between treatment groups. This study suggests that adjuvant MC in canine splenic HSA may result in a similar outcome when compared to other treatment protocols. Further studies are warranted to confirm these findings.

Neoadjuvant and adjuvant doxorubicin chemotherapy in a case of feline soft tissue sarcoma.

CASE SUMMARY: A 7-year old male neutered domestic shorthair cat was presented with a 2 month history of a slow-growing mass on the right zygomatic area. A CT scan revealed a soft tissue mass in the right zygomatic region with no alterations of the underlying bone and features of local invasiveness. Cytology was suggestive of a mesenchymal tumour and histopathology from an incisional biopsy was consistent with a soft tissue sarcoma (STS). The cat was treated with neoadjuvant intravenous doxorubicin chemotherapy at a dose of 25 mg/m2, every two weeks. The patient experienced a partial response and underwent surgical excision of the tumour. Doxorubicin was continued as an adjuvant treatment for three further chemotherapy sessions, at a dose of 25 mg/m2 every 21 days. Local tumour recurrence was detected on clinical examination and cytologically confirmed 259 days following surgery. RELEVANCE AND NOVEL INFORMATION: Treatment with neoadjuvant doxorubicin can be considered in cases of inoperable STSs in order to cytoreduce the tumour and improve the chances of achieving complete surgical margins. The role of adjuvant chemotherapy in this setting remains unclear.

Clinical response to a lomustine/cytarabine-based chemotherapy protocol in a case of canine large granular lymphocyte T-cell lymphoma with spinal involvement.

A 7-year-old, female neutered cross-breed dog was referred to our institution with a history of progressive hind limb weakness, which then progressed to paraplegia. An MRI of the spine revealed severe meningeal infiltrate consistent with lymphoma involvement, located at the level of L2-L7 with concurrent lymph node enlargement and abnormal bone marrow. Abdominal ultrasonography also identified changes in the spleen and confirmed enlargement of the lumbar aortic lymph node. Cytology of lymph nodes and spleen confirmed a high-grade lymphoma with features of a large granular lymphocyte (LGL) variant; PCR for antigen receptor re-arrangements (PARR) was positive for a clonal T-cell receptor rearrangement. The dog was started on a chemotherapy protocol with lomustine and cytarabine incorporation and had a rapid improvement in neurological status. Chemotherapy was continued until relapse and rescue treatment used at that time. The dog was euthanased at the time of recurrence of neurological signs, 195 days since medical treatment was started. This case report suggests that combination chemotherapy may be of use when treating LGL lymphoma with spinal involvement and survival time may potentially exceed 6 months.

Malignant pilomatricoma in a dog with local and distant metastases treated with chemotherapy and bisphosphonates.

A ten-year-old male neutered cross breed dog presented for evaluation of a mass associated with the left scapular bone, identified as a carcinoma. The dog had a malignant pilomatricoma removed from the left lateral thigh 6 months earlier. Histopathology review of the cutaneous and scapular mass identified the same tumour type, confirming metastatic disease; additional metastases to the inguinal lymph node, liver and lungs were identified. Chemotherapy resulted in partial responses/stable disease of very short duration. Bisphosphonates were administered due to lack of a measurable response and worsening of the associated lameness. The patient ultimately developed a symptomatic vertebral metastasis and was euthanased. The dog survived 255 days since medical treatment was started and 455 days since surgical removal of the primary tumour. This case report suggests that medical treatment with the addition of analgesia may be able to palliate clinical signs and possibly extend survival in dogs with metastatic epithelial cancer.

RETROSPECTIVE COMPARISON OF THREE-DIMENSIONAL CONFORMAL RADIATION THERAPY VS. PREDNISOLONE ALONE IN 30 CASES OF CANINE INFRATENTORIAL BRAIN TUMORS.

Infratentorial tumors are relatively infrequent in dogs and a lack of data makes it difficult to offer prognostic information. Untreated, dogs with these neoplasms have shorter survival times than those with supratentorial tumors. The role of radiation therapy (RT) in the management of infratentorial tumors is poorly defined and tumoral/peritumoral swelling in this site is a potential cause of serious acute side effects. The aim of this retrospective, cohort study was to describe cases of infratentorial tumors treated with fractionated three-dimensional conformal RT (3D CRT) and glucocorticoids (GC), and compare outcomes and survival with dogs affected by tumors in the same location that received GC alone. Thirty patients with a MRI diagnosis of infratentorial tumors were recruited (15 received RT and GC and 15 GC alone). None had mentation changes at presentation. For both groups, MRI and medical records were reviewed; and factors associated with survival were evaluated with Kaplan-Meier product limit survival and Cox regression analysis. Overall median survival time (MST) was 294 days (95% CI 42-545). The MST in the RT group was 756 days (95% CI 209-1302) vs. 89 days (95% CI 34.7-143.3 days) for those dogs treated palliatively with GC alone. This difference was statistically significant (P = 0.001). No other factors (including neurological signs, MRI features, tumor volume and total RT dose) were statistically associated with survival in the RT group. This study suggests that 3D CRT offers a survival advantage for dogs with infratentorial tumors compared to GC alone, and significant complications are uncommon.

A retrospective review of outcome and survival following surgery and adjuvant xenogeneic DNA vaccination in 32 dogs with oral malignant melanoma.

A xenogeneic DNA vaccination has been licensed for use in dogs with locally controlled stage II and III oral malignant melanoma (OMM). At present, there are limited outcome data for dogs with OMM treated with surgery and immunotherapy. The aim of this study is to retrospectively review the outcome and survival of 32 dogs affected by OMM that were treated with a combination of surgery and the xenogeneic DNA vaccination (with the addition of radiotherapy in some cases) and to determine the influence of surgical margins and delay in receiving vaccination. The overall median survival time (MST) was 335 days (95% CI: 301-540 days), and the overall median progression-free survival (PFS) was 160 days (mean 182 days, 95% CI: 132-232 days). Stage, completeness of surgical margins and delay in administration of the vaccine did not appear to statistically influence survival or PFS, although these results may reflect the low statistical power of the study due to small numbers. Further studies are required to assess whether the addition of any adjuvant treatment to surgery, including immunotherapy, is able to significantly prolong survival in cases of canine oral melanoma.