Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.

BACKGROUND: TGF-ß is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-ß blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-ß type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. METHODS: This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0-2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m2 over 24 h daily 7 days per week during radiotherapy or oral capecitabine 825 mg/m2 twice per day 5 days per week during radiotherapy; radiotherapy consisted of 50·4-54·0 Gy in 28-30 fractions). 5-9 weeks later, patients underwent response assessment. Patients with a complete response could opt for non-operative management and proceed to modified FOLFOX6 (intravenous leucovorin 400 mg/m2 on day 1, intravenous fluorouracil 400 mg/m2 on day 1 then 2400 mg/m2 over 46 h, and intravenous oxaliplatin 85 mg/m2 on day 1 delivered every 2 weeks for eight cycles) or CAPEOX (intravenous oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks for four cycles). Patients with less than complete response underwent surgical resection. The primary endpoint was complete response rate, which was a composite of pathological complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with non-operative management. Safety was a coprimary endpoint. Both endpoints were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02688712, and is active but not recruiting. FINDINGS: Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI ≥19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred. INTERPRETATION: The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials. FUNDING: Eli Lilly via ExIST program, The Providence Foundation.

Life-Threatening Atypical Case of Acute Generalized Exanthematous Pustulosis.

Antibiotics are known to cause severe cutaneous adverse reactions, such as the rare acute generalized exanthematous pustulosis (AGEP). Unlike Stevens-Johnson syndrome or toxic epidermal necrolysis, AGEP is rarely life-threatening. Systemic involvement is not typical, and if present usually coincides with a mild elevation of the hepatic enzymes and a decrease in renal function. Hence, AGEP is known to have a good prognosis and to be life-threatening only in elderly patients or patients with chronic diseases. Herein, we report a case of AGEP in a young healthy male leading to systemic inflammatory response syndrome and to treatment in an intensive care unit after being treated with 5 different antibiotics. Initial symptoms were not indicative for AGEP and the patient's course of disease led promptly to critical cardiorespiratory symptoms and systemic inflammatory response syndrome. We assume that the administration of the 5 different antibiotics resulted in type IV allergy as well as secondary infection with Enterococcus faecium and Staphylococcus aureus, while the underlying periodontitis also contributed to the severity of this case.

Late syphilis mimicking a pseudolymphoma of the skin.

After a period of declining incidence of syphilis in most of Western Europe until the late 1990s, reports about an increasing trend have been published recently. In contrast to the rising incidence of early syphilis, cases of late (tertiary) syphilis are rarely seen in developed countries. In this report, we describe a 54-year-old patient with infiltrated erythematous plaques on his forehead and neck that histologically revealed a dense lymphocytic cell infiltrate with numerous plasma cells. The serologic examination was characteristic of syphilis and in conjunction with the clinical presentation and the patient's history led to the diagnosis of tertiary syphilis. The diagnosis of this late stage of syphilis can be difficult as clinical pictures can be misleading. Peculiar skin lesions should always remind clinicians of this infectious disease which has still to be considered in differential diagnoses in dermatology.

Mycosis fungoides palmaris et plantaris--an unusual variant of cutaneous T-cell lymphoma.

Mycosis fungoides (MF) represents a low-risk, cutaneous, non-Hodgkin, T-cell lymphoma with a wide spectrum of clinicopathological manifestations and therefore may mimic a number of other dermatoses. Sometimes the clinical diversity makes the diagnosis of MF, and especially its atypical forms, challenging. We report on an 18-year old male patient, who had been previously diagnosed with palmoplantar eczema. Clinical, histopathological, immunohistochemical and molecular findings revealed an atypical case of MF.

Progress in the therapy of small cell lung cancer.

Small cell lung cancer (SCLC) accounts for approximately 14% of all cases of lung cancer. Combination chemotherapy is the most effective treatment modality for SCLC and recently, several new active drugs have emerged. Combinations of platinum agents with CPT-11 or gemcitabine have been successfully compared in phase III trials against the cisplatin/etoposide standard. Modest improvements in the outcome of patients with SCLC have been noted over the last two decades. Thoracic irradiation given concurrently with chemotherapy improves survival compared with sequential chemotherapy and radiation, but this approach is associated with more toxicity. Moreover, the optimal doses and fractionation of thoracic irradiation remain to be determined. Three-dimensional treatment planning is under investigation. Prophylactic cranial irradiation (PCI) has established a role in the management of patients who have achieved a complete response to the initial therapy. Novel molecular targeted therapies are among the strategies currently being investigated in SCLC.

Concurrent presentation of hodgkin lymphoma and multiple myeloma.

The simultaneous presentation of the Hodgkin lymphoma and multiple myeloma in the absence of prior chemotherapy or radiation is very rare. Here, we discuss a 72-year-old patient who initially presented with generalized pruritis. Workup led to a diagnosis of multiple myeloma which progressed and required treatment. As part of his pretreatment workup, an MRI was performed to evaluate skeletal lesions. This revealed diffuse and bulky adenopathy which was confirmed by PET. A biopsy of an axillary node was consistent with the nodular sclerosing type Hodgkin lymphoma. He was treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy × 6 resulting in complete resolution of his adenopathy and pruritis as well as improvement in his myeloma.

Clinical complexity of Leishmania (Viannia) braziliensis infections amongst travelers.

The protozoan parasite Leishmania (Viannia) braziliensis is one of the main causes of cutaneous and mucocutaneous leishmaniasis in South America. Here, we describe three cases of L. (V.) braziliensis infection which were acquired during travelling in Bolivia, Peru or Paraguay and illustrate the phenotypic heterogeneity and therapeutic complexity of the disease. Two patients presented with unusual clinical manifestations, i.e. with prominent regional lymphadenopathy ("bubonic leishmaniasis") and with simultaneously emerged skin and mucosal lesions, respectively. Both patients insufficiently responded to oral treatment with miltefosine; resolution of the lesions was only achieved after a course of intravenous liposomal amphotericin B.

Survival trends in mantle cell lymphoma in the United States over 16 years 1992-2007.

A retrospective analysis was done using the Surveillance, Epidemiology, and End-Results (SEER) database to determine the trends in overall survival and identify prognostic factors in patients with mantle cell lymphoma (MCL). In total 5367 cases of MCL identified from 1992 to 2007 were split into three cohorts, group 1(1992-1999), group 2 (2000-2003) and group 3 (2004-2007). Survival was analyzed using the Cox proportional hazards model to correct for age, gender and stage of disease. The proportion of patients with advanced disease at diagnosis, male gender and advanced age increased over time and these were all associated with increased mortality. The overall survival remained unchanged. However, when adjusted for the increased proportion of patients with poor prognostic features noted above, we found a significant improvement in survival. The adjusted model also showed an improvement in predicted survival over time in patients with advanced stage. No change in survival was seen in patients with localized disease. Although this analysis is not designed to evaluate specific treatment modalities, these data suggest that the development of new treatment strategies over the past decade may be impacting the survival of patients with advanced MCL despite the finding that the overall survival remains unchanged in the general US population.

[Progressive nodular histiocytosis--rare variant of cutaneous non-Langerhans cell histiocytosis]. / Progressive noduläre Histiozytose--seltene Variante einer kutanen Non-Langerhanszell-Histiozytose.

Progressive nodular histiocytosis is an extremely rare skin disease is clinically characterized by the coincidence of two distinct lesions, namely, superficial xanthomatous papules up to 5 mm and deep nodules and tumors 1-3 cm. Histologically the nodules represent spindle cell xanthogranulomas. We report a 24-year-old women with these findings. The distinction from other non-Langerhans cell histiocytoses, in particular multiple juvenile xanthogranulomas, which may be more likely to show spontaneous remission, is somewhat unclear; patients with progressive nodular histiocytosis usually follow a serious and disfiguring clinical course.

Bilateral temporal arteritis.

Temporal arteritis is a giant cell arteritis that affects large- or medium-sized elastic arteries. Often, only 1 temporal artery is affected. We describe a patient with both temporal arteries being involved simultaneously. To our knowledge, this particular constellation has rarely been described so far.

[Cholesterol emboli during coumarin therapy]. / Cholesterin-Embolie unter Cumarin-Therapie.

A 71-year-old patient suddenly developed a painful, bizarre livid erythema on the right foot. Based upon the clinical and histological presentation, cholesterol emboli were diagnosed. These cholesterol emboli were induced by therapy with phenprocoumon (a coumarin derivative), which had been initiated 5 months previously. Arterial emboli may rarely occur during anticoagulation and have to be included in the differential diagnosis.

Plasmin promotes keratinocyte migration and phagocytic-killing accompanied by suppression of cell proliferation which may facilitate re-epithelialization of wound beds.

Keratinocytes were shown to induce the activation of plasminogen activator resulting in the formation of plasmin and the initiation of proteolysis in vitro. Activation of surface bound plasminogen may localize protease activity in the pericellular microenvironment and play a role in inducing both a conformational change and cell locomotion. Plasmin, however, can induce non-proteolytic effects on certain cell functions in a variety of cell lineages. In the present study we examined the effects of plasmin on keratinocytes with a focus on its role in the process of re-epithelialization, which included studies of cell migration, phagocytic-killing and cell proliferation. Migration of freshly isolated human epidermal keratinocytes was analyzed utilizing the agarose gel assay in the presence of 10% human serum. Plasmin at the concentration of 25 U/I induced a 160% increase in the chemotactic migration of keratinocytes that was completely blocked by the plasmin inhibitor alpha2-antiplasmin (Serpin). In the absence of serum, plasmin also induced a reversible chemotactic migration of HaCaT keratinocytes as determined utilizing the microchemotaxis assay. Dose-response analysis showed a bi-phasic effect of plasmin with a maximum increase of 52% in keratinocyte chemotaxis at a concentration of 25 U/I. HaCaT cells on the other hand, showed no detectable in vitro chemokinesis by plasmin. Phagocytic-killing of Candida albicans by freshly isolated epidermal keratinocytes was enhanced in the presence of 25 U/I plasmin which was also reversible by the addition of Serpin. Spontaneous proliferation of HaCaT keratinocytes as determined by 3H-Thymidine uptake on the other hand, was reduced by 47 and 13% in cultures with 25 U/I plasmin for 24 and 48 h respectively, in a Serpin reversible manner. These data suggest that plasmin-induced chemotactic migration of epidermal keratinocytes is accompanied by enhanced phagocytic-killing coupled with suppression of proliferation of these cells which may facilitate re-epithelialization following skin injury.

Blastic CD56+ natural killer-cell lymphoma with primary cutaneous manifestation.

T/natural killer-cell lymphomas belong to a heterogeneous group of non-Hodgkin lymphomas with predominant extranodal, often cutaneous, manifestations. In contrast to B- and T-cell lymphomas, T/NK-cell lymphomas were only recently regarded as a distinct entity. These rather aggressive malignancies arise from cytotoxic T cells, NK-cells or NK-like T cells, which share several phenotypic and functional properties. We report a man with a blastic NK-cell lymphoma with nodular skin infiltrations as the leading clinical manifestation of the disease. Complicated of tuberculosis, the patient died within 9 months of diagnosis, despite aggressive polychemotherapy.