Melissa Joyner

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.

Merkel cell carcinoma (MCC) is an uncommon but malignant cutaneous neuroendocrine carcinoma with a high incidence of local recurrence, regional lymph node metastases, and subsequent distant metastases. The etiology of MCC remains unknown. It usually occurs in sun-exposed areas in elderly people, many of whom have a history of other synchronous or metachronous sun-associated skin lesions. The outcome for most patients with MCC is generally poor. Surgery is the mainstay of treatment. The role of adjuvant therapy has been debated. However, data from recent development support a multimodality approach, including surgical excision of primary tumor with adequate margins and sentinel lymph node dissection followed by postoperative radiotherapy in most cases, as current choice of practice with better locoregional control and disease-free survival. Patients with regional nodal involvement or advanced disease should undergo nodal dissection followed by adjuvant radiotherapy and, perhaps, systemic platinum-based chemotherapy in most cases.

Presentation of outcomes of patients treated by stereotactic body radiation therapy (SBRT) for lung lesions located within or touching a 2 cm zone around major airways. Serial tomotherapeutic SBRT has been planned and delivered at our institution since August 2001. Of 108 patients treated for primary and secondary lung tumors, nine harbored tumors (8 metastases, 1 recurrent NSCLC) located in close proximity to carina, right and left main bronchi, right and left upper lobe bronchi, intermedius, right middle lobe, lingular, or right and left lower lobe bronchi. SBRT was delivered to total doses of 36 Gy in 3 fractions (n = 8) or 6 fractions (n = 1), using a serial tomotherapy system (Nomos Peacock). We assessed local tumor control, clinical toxicity, normal tissue imaging changes, and overall survival. Median tumor volume was 26 cm3 (range 1.7 to 135 cm3). Tumor locations were hilar (n = 3), and parenchymal in six cases. Hilar lesions accounted for the three largest tumor volumes in the series. During a median follow-up of 10.6 months (range 2.5 to 41.5 months), all lesions treated were locally controlled as confirmed by CT or CT/PET imaging. Parenchymal imaging changes included focal lung fibrosis and major airway wall thickening. One occurrence of major airway occlusion (right lower lobe bronchus) was observed. This event was diagnosed by chest x-ray at 36 months, following treatment of the second largest hilar lesion in the present series. Based on the outcomes observed in this small sample series, SBRT for centrally located lung lesions appears feasible, was associated with low incidence of toxicities, and provided sustained local tumor control. However, long-term survival may be associated with major airway injury. As long-term follow-up in larger numbers of patients is lacking at this time, exclusion of patients with centrally located lesions may be considered when patients are treated in curative intent.

Importance: Premastectomy radiotherapy (PreMRT) is a new treatment sequence to avoid the adverse effects of radiotherapy on the final breast reconstruction while achieving the benefits of immediate breast reconstruction (IMBR). Objective: To evaluate outcomes among patients who received PreMRT and regional nodal irradiation (RNI) followed by mastectomy and IMBR. Design, Setting, and Participants: This was a phase 2 single-center randomized clinical trial conducted between August 3, 2018, and August 2, 2022, evaluating the feasibility and safety of PreMRT and RNI (including internal mammary lymph nodes). Patients with cT0-T3, N0-N3b breast cancer and a recommendation for radiotherapy were eligible. Intervention: This trial evaluated outcomes after PreMRT followed by mastectomy and IMBR. Patients were randomized to receive either hypofractionated (40.05 Gy/15 fractions) or conventionally fractionated (50 Gy/25 fractions) RNI. Main Outcome and Measures: The primary outcome was reconstructive failure, defined as complete autologous flap loss. Demographic, treatment, and outcomes data were collected, and associations between multiple variables and outcomes were evaluated. Analysis was performed on an intent-to-treat basis. Results: Fifty patients were enrolled. Among 49 evaluable patients, the median age was 48 years (range, 31-72 years), and 46 patients (94%) received neoadjuvant systemic therapy. Twenty-five patients received 50 Gy in 25 fractions to the breast and 45 Gy in 25 fractions to regional nodes, and 24 patients received 40.05 Gy in 15 fractions to the breast and 37.5 Gy in 15 fractions to regional nodes, including internal mammary lymph nodes. Forty-eight patients underwent mastectomy with IMBR, at a median of 23 days (IQR, 20-28.5 days) after radiotherapy. Forty-one patients had microvascular autologous flap reconstruction, 5 underwent latissimus dorsi pedicled flap reconstruction, and 2 had tissue expander placement. There were no complete autologous flap losses, and 1 patient underwent tissue expander explantation. Eight of 48 patients (17%) had mastectomy skin flap necrosis of the treated breast, of whom 1 underwent reoperation. During follow-up (median, 29.7 months [range, 10.1-65.2 months]), there were no locoregional recurrences or distant metastasis. Conclusions and Relevance: This randomized clinical trial found PreMRT and RNI followed by mastectomy and microvascular autologous flap IMBR to be feasible and safe. Based on these results, a larger randomized clinical trial of hypofractionated vs conventionally fractionated PreMRT has been started (NCT05774678). Trial Registration: ClinicalTrials.gov Identifier: NCT02912312.

Squamous cell anal cancer remains an uncommon entity; however, the incidence appears to be increasing in at-risk populations, especially those infected with human papillomavirus (HPV) and human immunodeficiency virus (HIV). Given the ability to cure this cancer using synchronous chemoradiotherapy, management practices of this disease are critical. This article considers treatment strategies for HIV-positive patients with anal cancer, including the impact on chemoradiation-induced toxicities and the role of highly active antiretroviral therapy in the treatment of this patient population. The standard treatment has been fluorouracil (5-FU) and mitomycin (or cisplatin) as chemotherapy agents plus radiation. Consideration to modifying the standard treatment regime is based on the fact that patients with HIV tend to experience greater toxicity, especially when CD4 counts are below 200; these patients also require longer treatment breaks. Additional changes to the chemotherapy dosing, such as giving 5-FU continuously and decreasing mitomycin dose, are evaluated and considered in relation to radiation field sizes in an effort to reduce toxicity, maintain local tumor control, and limit need for colostomy. The opportunity for decreasing the radiation field size and using intensity-modulated radiation therapy (IMRT) is also considered, particularly in light of the fact that IMRT provides dose-sparing while maximizing target volume dose to involved areas. The impact of the immune system in patients with HIV and squamous cell carcinoma of the anus and the associated response to therapy remains unknown. Continued studies and phase III trials will be needed to test new treatment strategies in HIV-infected patients with squamous cell cancer of the anus to determine which treatment protocols provide the greatest benefits.